How is the growth of benign tumors suppressed?

How is the growth of benign tumors suppressed?

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A benign tumor has an outer layer of cancerous cells beyond which are regular cells (I Think). The Tumor must have some kind of boundary layer like a wall where somehow the cancerous cells can't affect any more normal cells outside the wall. A Benign Tumor I think can be inactive for many months; it might never grow anymore. Might it be that the cancer cells at this Benign Tumor Wall are inhibited from affecting any more cells? Could there be an Apoptosis shut-off inhibitor or a cell-death pathway shutting-off inhibitor in this case?

The primary difference between a benign tumor and a malignant tumor is that the former cannot metastasize; therefore they remain within the tissue boundaries.They grow slowly and are are not very de-differentiated thereby retaining some of the tissue organization.

Another point to be considered is that benign tumors do not cause vascularization (formation of blood vessels in the tumor tissue; triggered by secretion of VEGF), which also limits its growth.

Tumor suppressor gene

A tumor suppressor gene, or anti-oncogene, is a gene that regulates a cell during cell division and replication. [1] If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or reduction in its function. In combination with other genetic mutations, this could allow the cell to grow abnormally. The loss of function for these genes may be even more significant in the development of human cancers, compared to the activation of oncogenes. [2]

Tumor suppressor genes (TSGs) can be grouped into the following categories: caretaker genes, gatekeeper genes, and more recently landscaper genes. Caretaker genes ensure stability of the genome via DNA repair and subsequently when mutated allow mutations to accumulate. [3] Meanwhile, gatekeeper genes directly regulate cell growth by either inhibiting cell cycle progression or inducing apoptosis. [3] Lastly landscaper genes regulate growth by contributing to the surrounding environment, when mutated can cause an environment that promotes unregulated proliferation. [4] The classification schemes are evolving as medical advances are being made from fields including molecular biology, genetics, and epigenetics.


  1. Viruses are responsible for about 15% of the world&rsquos cancers.
  2. Up to 80% of these human viral-associated cancers are cervical cancer (associated with human papilloma virus or HPV) and liver cancer (associated with the hepatitis B virus or HBV and the hepatitis C virus or HCV).
  3. The Epstein-Barr virus (EBV) and human T-lymphotropic virus type I (HTLV-I) also increase the risk of certain cancers.
  4. The development of tumors is a multistep process depending on the accumulation of mutations altering a number of genes.
  5. Most virus-associated cancers have long latency periods of several decades and only a small percentage of the people infected with the virus actually develop the cancer. This indicates other factors promoting changes in cellular genes are also involved.

Identification of Tumor Suppressor Genes

The first insight into the activity of tumor suppressor genes came from somatic cell hybridization experiments, initiated by Henry Harris and his colleagues in 1969. The fusion of normal cells with tumor cells yielded hybrid cells containing chromosomes from both parents (Figure 15.32). In most cases, such hybrid cells were not capable of forming tumors in animals. Therefore, it appeared that genes derived from the normal cell parent acted to inhibit (or suppress) tumor development. Definition of these genes at the molecular level came, however, from a different approach—the analysis of rare inherited forms of human cancer.

Figure 15.32

Suppression of tumorigenicity by cell fusion. Fusion of tumor cells with normal cells yields hybrids that contain chromosomes from both parents. Such hybrids are usually nontumorigenic.

The first tumor suppressor gene was identified by studies of retinoblastoma, a rare childhood eye tumor. Provided that the disease is detected early, retinoblastoma can be successfully treated, and many patients survive to have families. Consequently, it was recognized that some cases of retinoblastoma are inherited. In these cases, approximately 50% of the children of an affected parent develop retinoblastoma, consistent with Mendelian transmission of a single dominant gene that confers susceptibility to tumor development (Figure 15.33).

Figure 15.33

Inheritance of retinoblastoma. Susceptibility to retinoblastoma is transmitted to approximately 50% of offspring. Affected and normal indivi- duals are indicated by purple and green symbols, respectively.

Although susceptibility to retinoblastoma is transmitted as a dominant trait, inheritance of the susceptibility gene is not sufficient to transform a normal retinal cell into a tumor cell. All retinal cells in a patient inherit the susceptibility gene, but only a small fraction of these cells give rise to tumors. Thus, tumor development requires additional events beyond inheritance of tumor susceptibility. In 1971, Alfred Knudson proposed that the development of retinoblastoma requires two mutations, which are now known to correspond to the loss of both of the functional copies of the tumor susceptibility gene (the Rb tumor suppressor gene) that would be present on homologous chromosomes of a normal diploid cell (Figure 15.34). In inherited retinoblastoma, one defective copy of Rb is genetically transmitted. The loss of this single Rb copy is not by itself sufficient to trigger tumor development, but retinoblastoma almost always develops in these individuals as a result of a second somatic mutation leading to the loss of the remaining normal Rb allele. Noninherited retinoblastoma, in contrast, is rare, since its development requires two independent somatic mutations to inactivate both normal copies of Rb in the same cell.

Figure 15.34

Mutations of Rb during retinoblastoma development. In hereditary retinoblastoma, a defective copy of the Rb gene (Rb - ) is inherited from the affected parent. A second somatic mutation, which inactivates the single normal Rb + copy in a retinal cell, then (more. )

The functional nature of the Rb gene as a negative regulator of tumorigenesis was initially indicated by observations of chromosome morphology. Visible deletions of chromosome 13q14 were found in some retinoblastomas, suggesting that loss (rather than activation) of the Rb gene led to tumor development (Figure 15.35). Gene-mapping studies further indicated that tumor development resulted from loss of normal Rb alleles in the tumor cells, consistent with the function of Rb as a tumor suppressor gene. Isolation of the Rb gene as a molecular clone in 1986 then firmly established that Rb is consistently lost or mutated in retinoblastomas. Gene transfer experiments also demonstrated that introduction of a normal Rb gene into retinoblastoma cells reverses their tumorigenicity, providing direct evidence for the activity of Rb as a tumor suppressor.

Figure 15.35

Rb deletions in retinoblastoma. Many retinoblastomas have deletions of the chromosomal locus (13q14) that contains the Rb gene.

Although Rb was identified in a rare childhood cancer, it is also involved in some of the more common tumors of adults. In particular, studies of the cloned gene have established that Rb is lost or inactivated in many bladder, breast, and lung carcinomas. The significance of the Rb tumor suppressor gene thus extends beyond retinoblastoma, apparently contributing to development of a substantial fraction of more common human cancers. In addition, as noted earlier in this chapter, the Rb protein is a key target for the oncogene proteins of several DNA tumor viruses, including SV40, adenoviruses, and human papillomaviruses, which bind to Rb and inhibit its activity (Figure 15.36). Transformation by these viruses thus results, at least in part, from inactivation of Rb at the protein level rather than from mutational inactivation of the Rb gene.

Figure 15.36

Interaction of Rb with oncogene proteins of DNA tumor viruses. The oncogene proteins of several DNA tumor viruses (e.g., SV40 T antigen) induce transformation by binding to and inactivating Rb protein.

Characterization of Rb as a tumor suppressor gene served as the prototype for the identification of additional tumor suppressor genes that contribute to the development of many different human cancers (Table 15.5). Some of these genes were identified as the causes of rare inherited cancers, playing a role similar to that of Rb in hereditary retinoblastoma. Other tumor suppressor genes have been identified as genes that are frequently deleted or mutated in common noninherited cancers of adults, such as colon carcinoma. In either case, it appears that most tumor suppressor genes are involved in the development of both inherited and noninherited forms of cancer. Indeed, mutations of some tumor suppressor genes appear to be the most common molecular alterations leading to human tumor development.

Table 15.5

The second tumor suppressor gene to have been identified is p53, which is frequently inactivated in a wide variety of human cancers, including leukemias, lymphomas, sarcomas, brain tumors, and carcinomas of many tissues, including breast, colon, and lung. In total, mutations of p53 may play a role in up to 50% of all cancers, making it the most common target of genetic alterations in human malignancies. It is also of interest that inherited mutations of p53 are responsible for genetic transmission of a rare hereditary cancer syndrome, in which affected individuals develop any of several different types of cancer. In addition, the p53 protein (like Rb) is a target for the oncogene proteins of SV40, adenoviruses, and human papillomaviruses.

Like p53, the INK4 and PTEN tumor suppressor genes are very frequently mutated in several common cancers, including lung cancer, prostate cancer, and melanoma. Two other tumor suppressor genes (APC and MADR2) are frequently deleted or mutated in colon cancers. In addition to being involved in noninherited cases of this common adult cancer, inherited mutations of the APC gene are responsible for a rare hereditary form of colon cancer, called familial adenomatous polyposis. Individuals with this condition develop hundreds of benign colon adenomas (polyps), some of which almost inevitably progress to malignancy. Inherited mutations of two other tumor suppressor genes, BRCA1 and BRCA2, are responsible for hereditary cases of breast cancer, which account for 5 to 10% of the total breast cancer incidence.

Additional tumor suppressor genes have been implicated in the development of brain tumors, pancreatic cancers, and basal cell skin carcinomas, as well as in several rare inherited cancer syndromes, such as Wilms' tumor. The number of identified tumor suppressor genes is rapidly expanding, and the characterization of these genes remains an active area of cancer research.

Essay on Tumor Suppressor Genes | Cancer | Diseases | Biology

Read this essay to examine the nature of tumor suppressor genes and the ways in which their loss can lead to cancer. Also learn about the roles played by all the types of gene mutations, along with non-mutational changes, in converting normal cells into cancer cells.

1. Essay on Tumor Suppressor Genes: (Around 4000 Words)

Roles in Cell Proliferation and Cell Death:

By definition, tumor suppressors are genes whose loss or inactivation can lead to cancer, a condition characterized by increased cell proliferation and decreased cell death. It is therefore logical to suspect that the normal function of a tumor suppressor gene would be the opposite—namely, to inhibit cell proliferation or promote cell death—and so the loss of such functions would cause increased cell proliferation or decreased cell death.

i. Cell Fusion Experiments Provided the First Evidence for the Existence of Tumor Suppressor Genes:

The first indication that cells might contain genes whose loss is associated with the development of cancer came from experiments using a technique called cell fusion. In 1960, a research team in Paris headed by Georges Barski discovered that cells of two different types grown in culture will occasionally fuse together to form hybrid cells containing the chromosomes of both original cell types.

Shortly thereafter Henry Harris reported that cell fusion can be artificially induced by treating cells with inactivated forms of a particular type of virus called Sendai virus. Treatment with the virus causes the plasma membranes of two cells to fuse with each other, creating a combined cell in which the nuclei of the two original cells share the same cytoplasm.

When the cell subsequently divides, the two separate nuclei break down and a single new nucleus is formed that contains chromosomes derived from both of the original cells. Such a cell, containing a nucleus with chromosomes derived from two different cells, is called a hybrid cell.

Experiments in which cancer cells were fused with normal cells provided some important early insights into the genetic basis for the abnormal behavior of cancer cells. Based on our current understanding of oncogenes, you might expect that the hybrid cells created by fusing cancer cells with normal cells would have acquired oncogenes from the original cancer cell and would therefore exhibit uncontrolled proliferation, just like a cancer cell.

In fact, that is not what usually happens the fusion of cancer cells with normal cells almost always yields hybrid cells that initially behave like the normal parent and do not form tumors (Figure 1). Such results, first reported in the late 1960s, pro­vided the earliest evidence that normal cells contain genes that can suppress tumor growth and reestablish normal controls on cell proliferation.

Although fusing cancer cells with normal cells gener­ally yields hybrid cells that lack the ability to form tumors, it does not mean that these cells are normal.

When they are allowed to grow for extended periods in culture, the hybrid cells often revert back to the malig­nant, uncontrolled behavior of the original cancer cells. Reversion to malignant behavior is associated with the loss of certain chromosomes, suggesting that these particular chromosomes contain genes that had been suppressing the ability to form tumors. Such observa­tions eventually led to the naming of the lost genes as “tumor suppressor genes.”

As long as hybrid cells retain both sets of original chromosomes—that is, chromosomes derived from both the cancer cells and the normal cells—the ability to form tumors is suppressed. Tumor suppression is even observed when the original cancer cells possess an oncogene, such as a mutant RAS gene, that is actively expressed in the hybrid cells.

This means that tumor suppressor genes located in the chromosomes of normal cells are able to overcome the effects of a RAS oncogene present in a cancer cell chromosome. The ability to form tumors only reappears after the hybrid cell loses a chromosome containing a critical tumor suppressor gene.

ii. Studies of Inherited Chromosomal Defects and Loss of Heterozygosity have Led to the Identification of Several Dozen Tumor Suppressor Genes:

Although cell fusion experiments provided early evidence for the existence of tumor suppressor genes, identifying these genes did not turn out to be a simple task. By definition, the existence of a tumor suppressor gene only becomes evident after its function has been lost. How do scientists go about identifying something whose very existence is unknown until it disappears?

One approach is based on the fact that defects in tumor suppressors are responsible for several hereditary cancer syndromes. Members of cancer-prone families often inherit a defective tumor suppressor gene from one parent, thereby elevating their cancer risk because a single mutation in the other copy of that tumor suppressor gene can then lead to cancer.

Microscopic examination of cells obtained from individuals in such families sometimes reveals the existence of gross chromosomal defects. For example, certain individuals with familial retinoblastoma exhibit a deleted segment in a specific region of one copy of chromosome 13, not just in cancer cells but in all cells of the body.

To determine whether a tumor suppressor is located in the region that has undergone deletion, scientists have simply examined retinoblastoma cells to see which gene has become mutated in the comparable region of the second copy of chromosome 13.

The loss of tumor suppressor genes is not restricted to hereditary cancers. These genes may also be lost or inacti­vated through random mutations that strike a particular target tissue, leading to the mutation or loss of both copies of the same gene.

You might think that the most straight­forward way for that to happen would be through two independent mutations randomly occurring in sequence. However, the mutation rate for any given gene is about one in a million per cell division, so the chance of two independent mutations affecting two copies of the same gene is extremely remote.

After a single copy of a tumor suppressor gene has undergone mutation, a more efficient approach for disrupting the remaining normal copy is through a phe­nomenon known as loss of heterozygosity, so named because the initial state, in which one abnormal and one normal gene copy are present, is called the heterozygous state.

Getting rid of the remaining normal copy therefore causes the heterozygous state to be lost. Loss of heterozygosity is more common than you might expect whereas individual gene mutations arise at a rate of one in a million per gene per cell division, loss of heterozygosity is as frequent as once in a thousand cell divisions and tends to affect large regions of DNA encompassing hundreds of different genes.

Figure 2 illustrates several ways in which loss of het­erozygosity may arise. In one mechanism, called mitotic nondisjunction, the two duplicated copies of a given chro­mosome fail to separate (disjoin) at the time of mitosis, so both copies go to one daughter cell and the other daughter cell receives no copies.

As seen in Figure 2b, the latter cell will no longer be heterozygous for any genes contained on the missing chromosome. A second mechanism involves mitotic recombination, in which homologous chromosomes exchange DNA sequences when they line up during the process of mitosis. Figure 2c shows how such an exchange could lead to loss of heterozygosity.

A third mechanism, called gene conversion, occurs when the DNA molecules from two homologous chromosomes line up next to each other and copy base sequence information from one to the other.

In this way, a DNA region that was originally present in two different versions in the two members of a homolo­gous pair of chromosomes can be made identical by copying DNA sequence information from one chromo­some to the other chromosome (Figure 2d).

The existence of the preceding mechanisms means that if a cell happens to acquire a random mutation that inactivates one copy of a tumor suppressor gene, loss of heterozygosity might either replace the normal copy with the defective version or remove it entirely. Loss of heterozygosity usually affects hundreds of neighboring genes simultaneously, making it relatively easy to detect.

You simply analyze a large number of known genes, searching for those that are present in two different versions in the normal cells of a cancer patient but are present in only one version in the same person’s cancer cells. When genes exhibiting this behavior are detected, it is likely that they lie near a tumor suppressor gene whose loss of heterozygosity is actually responsible for the cancerous growth.

Geneticists have performed thousands of searches looking for chromosomal regions that exhibit loss of heterozygosity in cancer cells. This approach, along with the study of chromosomal defects associated with hereditary cancer syndromes, has led to the identification of several dozen tumor suppressor genes.

iii. The RB Tumor Suppressor Gene Produces a Protein that Restrains Passage through the Restriction Point:

The first tumor suppressor gene to be isolated and characterized was the RB gene. The protein produced by the RB gene, called the Rb protein (or simply Rb), restrains cell proliferation in the absence of growth factors. The Rb protein normally exerts this action by halting the cell cycle at the restriction point.

In cells that have been exposed to an appropriate growth factor, however, signaling pathways trigger the production of Cdk-cyclin complexes that catalyze the phosphorylation of Rb. Phosphorylated Rb can no longer exert its inhibitory effects and so the cells are free to pass through the restriction point and into S phase.

The molecular mechanism by which Rb exerts this control over the restriction point is summarized in Figure 3. Prior to phosphorylation, Rb binds to the E2F transcription factor, a protein that (in the absence of bound Rb) activates the transcription of genes coding for enzymes and other proteins required for initiating DNA replication.

As long as the Rb protein remains bound to E2F, the E2F molecule is inactive and these genes stay silent, thereby preventing cells from entering into S phase. However, in a cell that has been stimulated to divide (e.g., by the addition of growth factors), the activation of growth signaling pathways leads to the production of Cdk-cyclin complexes that catalyze the phosphorylation of Rb. Phosphorylation abolishes the ability of Rb to bind to E2F, thus allowing E2F to activate the transcription of genes whose products are required for entry into S phase.

Because the normal purpose of Rb is to halt the cell cycle in the absence of growth factors, RB mutations that lead to the loss or inactivation of the Rb protein remove this restraining influence on the cell cycle and lead to excessive proliferation. Such mutations leading to a loss of Rb function are observed in some hereditary as well as environmentally caused forms of cancer. Certain cancer viruses also disrupt Rb function.

For example, the human papillomavirus (HPV), has an oncogene that codes for the E7 on co-protein, which binds to Rb. When bound to E7, the Rb protein cannot perform its normal function of restraining passage through the restriction point and cell proliferation therefore proceeds unchecked, even in the absence of growth factors. Cancers triggered by a loss of Rb func­tion can thus arise in two fundamentally different ways- through mutations that delete or disrupt both copies of the RB gene and through the action of viral oncopro­teins that bind to and inactivate the Rb protein.

The p53 Tumor Suppressor Gene Produces a Protein that Prevents Cells with Damaged DNA from Proliferating:

Since the discovery of the RB gene in the mid-1980s, dozens of additional tumor suppressor genes have been identified (Table 1). One of the most important is the p53 gene (also called TP53 in humans), which produces the p53 protein. The p53 gene is mutated in a broad spectrum of different tumor types, and almost half of the close to the ten million people diagnosed worldwide with cancer each year will have p53 mutations, making it the most commonly mutated gene in human cancers (Figure 4).

The p53 protein is sometimes called the “guardian of the genome” because of the central role that it plays in protecting cells from the effects of DNA damage. Figure 5 illustrates how this function is performed.

When cells are exposed to DNA-damaging agents, such as ion­izing radiation or toxic chemicals, the damaged DNA triggers the activation of an enzyme called ATM kinase, which catalyzes the phosphorylation of p53 and several other target proteins. Phosphorylation of p53 by the ATM kinase prevents it from interacting with Mdm2, a protein that would otherwise mark p53 for destruction by linking it to a small protein called ubiquitin.

Mdm2 is one of numerous proteins in the cell, called ubiquitin ligases that attach ubiquitin molecules to a specific set of proteins. As shown in Figure 6, the normal function of ubiquitin is to direct molecules to the proteasome, the cell’s main protein destruction machine.

After p53 has been phos­phorylated by ATM in response to DNA damage, the Mdm2 ubiquitin ligase can no longer attach ubiquitin chains to p53. As a result, the p53 protein accumulates in cells containing damaged DNA rather than being degraded by the ubiquitin-mediated proteasome pathway.

The accumulating p53 in turn activates two types of events- cell cycle arrest and cell death. Both responses are based on the ability of p53 to act as a transcription factor that binds to DNA and activates specific genes. Among the targeted genes is the gene coding for the p21 protein, a member of a class of molecules called Cdk inhibitors because they block the activity of Cdk-cyclin complexes.

The p21 protein inhibits the Cdk-cyclin complex that would normally phosphorylate Rb, thereby halting the cell cycle at the restriction point and providing time for the DNA damage to be repaired. At the same time, p53 also activates the production of DNA repair enzymes.

If the damage cannot be successfully corrected, p53 then acti­vates genes that produce proteins involved in triggering cell death by apoptosis. A key protein in this pathway, called Puma (“p53 up-regulated modulator of apoptosis”), promotes apoptosis by binding to and inactivating the Bcl2 protein, a normally occurring inhibitor of apoptosis.

By triggering cell cycle arrest or cell death in response to DNA damage, the p53 protein prevents genetically altered cells from proliferating and passing the damage on to future cell generations. Mutations that disrupt p53 function therefore increase cancer risk because they permit cells with damaged DNA to survive and reproduce.

For example, individuals who inherit a mutant p53 gene from one parent have an elevated risk of developing cancer because they only require one additional mutation to inactivate the second copy of the gene. This high-risk hereditary condition is called the Li-Fraumeni syndrome.

Most p53 mutations, however, are not inherited they are caused by exposure to DNA-damaging chemicals and radiation. To cite but two examples, carcinogenic chemicals in tobacco smoke have been found to trigger point mutations in the p53 gene of lung cells, and the ultraviolet radiation in sunlight has been shown to cause p53 mutations in skin cells.

When exposure to carcinogenic chemicals or radia­tion creates mutations in the p53 gene, you might expect that both copies of the gene would need to be inactivated before functional p53 protein would be lost. In some cases, however, mutation of one copy of the p53 gene may be sufficient to disrupt the p53 protein, even when the other copy of the gene is normal.

The apparent explanation is that the p53 molecule is constructed from four protein chains bound together to form a tetramer. As shown in Figure 7, the presence of even one mutant chain in such a tetramer can be enough to prevent the p53 protein from functioning normally. When a muta­tion in one copy of the p53 gene causes the p53 protein to be inactivated in this way, even in the presence of a normal copy of the gene, it is called a dominant negative mutation.

Mutating the p53 gene is not the only mechanism for disrupting p53 function the p53 protein can also be targeted directly by certain viruses. For example, human papillomavirus—whose E7 oncoprotein inactivates the Rb protein—produces another molecule, called the E6 oncoprotein, which binds to and targets the p53 protein for destruction.

The ability of human papillomavirus to cause cancer is therefore linked to its capacity to block the action of proteins produced by both the RB and p53 tumor suppressor genes.

The APC Tumor Suppressor Gene Codes for a Protein that Inhibits the Wnt Signaling Pathway:

The next tumor suppressor to be discussed is, like the p53 gene, a frequent target for cancer-causing mutations in this case, however, cancers arise mainly in one organ, namely the colon. The gene in question, called the APC gene, is the tumor suppressor. Individuals with this con­dition inherit a defective APC gene that causes thousands of polyps to grow in the colon and imparts a nearly 100% risk of developing colon cancer for individ­uals who live to the age of 60.

Although familial adenomatous polyposis is quite rare, accounting for less than 1% of all colon cancers, APC mutations are also associated with the more common forms of colon cancer that arise in people with no family history of the disease. In fact, recent studies suggest that roughly two-thirds of all colon cancers involve APC mutations.

The APC gene codes for a protein involved in the Wnt pathway, a signaling mechanism that plays a prominent role in activating cell proliferation during embryonic devel­opment. As shown in Figure 8, the central component of the Wnt pathway is a protein called β-catenin. Normally, β-catenin is prevented from functioning by a multi-protein destruction complex that consists of the APC protein com­bined with the proteins axin and glycogen synthase kinase 3 (GSK3).

When assembled in such an APC-axin-GSK3 complex, GSK3 catalyzes the phosphorylation of β- catenin. The phosphorylated β-catenin then becomes a target for a ubiquitin ligase that attaches it to ubiquitin, thereby marking the phosphorylated β-catenin for degra­dation by proteasomes. The net result is a low concentration of β-catenin, which makes the Wnt pathway inactive.

The Wnt pathway is turned on by signaling molecules called Wnt proteins, which bind to and activate cell surface Wnt receptors. The activated receptors stimulate a group of proteins that inhibit the axin-APC-GSK3 destruction complex and thereby prevent the degradation of β-catenin. The accumulating β-catenin then enters the nucleus and interacts with transcription factors that activate a variety of genes, including some that stimulate cell proliferation.

Mutations causing abnormal activation of the Wnt pathway have been detected in numerous cancers. Most of them are loss-of-function mutations in the APC gene that are either inherited or, more commonly, triggered by environmental carcinogens. The resulting absence of func­tional APC protein prevents the axin-APC-GSK3 complex from assembling and β-catenin therefore accumulates, locking the Wnt pathway in the on position and sending the cell a persistent signal to divide.

iv. The PTEN Tumor Suppressor Gene Codes for a Protein that Inhibits the PI3K-Akt Signaling Pathway:

Cell proliferation is controlled through an interconnected network of pathways with numerous branches and shared components. A good example is provided by growth factors that activate the Ras-MAPK pathway. When a growth factor binds to a receptor that activates Ras-MAPK signaling, the receptor usually activates several other path­ways at the same time.

One of these additional pathways, called the PI3K-Akt pathway, involves an enzyme called phosphatidylinositol 3-kinase (abbreviated as PI 3-kinase or PI3K). As shown in Figure 9, PI 3-kinase undergoes activation when it binds to phosphorylated tyrosines found in receptors that have been stimulated by growth factor binding.

A similar mech­anism is involved in triggering the Ras-MAPK pathway. PI 3-kinase then catalyzes the addition of a phosphate group to a plasma membrane lipid called PIP2 (phosphatidylinositol-4, 5-bisphosphate), which converts PIP2 into PIP3 (phosphatidylinositol-3, 4, 5-trisphosphate).

PIP3 in turn recruits protein kinases to the inner surface of the plasma membrane, leading to phosphorylation and activation of a protein kinase called Akt. Through its ability to catalyze the phosphorylation of several key target proteins, Akt suppresses apoptosis and inhibits cell cycle arrest. The net effect of the PI3K-Akt signaling pathway is therefore to promote cell survival and proliferation.

Dysfunctions in PI3K-Akt signaling have been detected in a number of different cancers. For example, AKT gene amplification occurs in some ovarian and pan­creatic cancers, and a v-akt oncogene coding for a mutant Akt protein is present in an animal retrovirus that causes thymus cancers in mice. In such cases, excessive produc­tion or activity of the Akt protein leads to hyperactivity of the PI3K-Akt pathway and hence an enhancement of cell proliferation and survival.

Conversely, inhibitors of PI3K-Akt signaling can function as tumor suppressors. A prominent example is PTEN, an enzyme that removes a phosphate group from PIP3 and thus abolishes its ability to activate Akt. In cells that are not being stimulated by growth factors, the intra­cellular concentration of PIP3 is kept low by the action of PTEN and the PI3K-Akt pathway is therefore inactive.

When loss-of-function mutations disrupt the ability to produce PTEN, the cell cannot degrade PIP3 efficiently and its concentration rises. The accumulating PIP3 in turn activates Akt, thereby leading to enhanced cell prolifera­tion and survival (even in the absence of growth factors). Mutations that reduce PTEN activity are found in up to 50% of prostate cancers and glioblastomas, 35% of uterine endometrial cancers, and to varying extents in ovarian, breast, liver, lung, kidney, thyroid, and lymphoid cancers.

v. Some Tumor Suppressor Genes Code for Components of the TGFβ-Smad Signaling Pathway:

Growth factors are usually thought of as being molecules that stimulate cell proliferation, but some growth factors have the opposite effect: They inhibit cell proliferation. An example is transforming growth factor β (TGFβ), a protein that may either stimulate or inhibit cell prolifera­tion, depending on the cell type and context. TGFβ is especially relevant for tumor development because it is a potent inhibitor of epithelial cell proliferation, and roughly 90% of human cancers are carcinomas—that is, cancers of epithelial origin.

TGFβ exerts its inhibitory effects on cell prolifera­tion through the TGFβ-Smad pathway illustrated in Figure 10. The first step in this pathway is the binding of TGFβ to a cell surface receptor. Like many other growth factor receptors, the receptors for TGFβ catalyze protein phosphorylation reactions, although in this case the amino acids serine and threonine rather than tyrosine are phosphorylated.

TGFβ binds to two types of recep­tors, called type I and type II receptors, located on the surface of its target cells. Upon binding of TGFβ, type II receptors phosphorylate type I receptors. The type I receptors then phosphorylate a class of proteins known as Smads, which bind to an additional protein (a “co- Smad”) and move into the nucleus.

Once inside the nucleus, the Smad complex activates the expression of genes that inhibit cell proliferation. Two key genes produce the p15 protein and the p21 protein, which both function as Cdk inhibitors.

The p15 and p21 proteins halt progression through the cell cycle by inhibiting the Cdk-cyclin complexes whose actions are required for passing through key transition points in the cycle.

Components of the TGFβ-Smad signaling pathway are frequently inactivated in human cancers. For example, loss-of-function mutations in the TGFβ receptor are common in colon and stomach cancers, and occur in some cancers of the breast, ovary, and pancreas as well.

Loss-of-function mutations in Smad proteins are likewise observed in a variety of cancers, including 50% of all pancreatic cancers and about 30% of colon cancers. Such evidence indicates that the genes coding for TGFβ recep­tors and Smads both qualify as tumor suppressors.

vi. One Gene Produces Two Tumor Suppressor Proteins: p16 and ARF:

Thus far, this article has described the relationship between tumor suppressor genes and several signaling pathways for inhibiting cell proliferation or promoting cell death. The next tumor suppressor to be covered, known as the CDKN2A gene, exhibits the rather unusual property of coding for two different proteins that act independently on two of these pathways, the Rb pathway and the p53 pathway.

How does the CDKN2A gene produce two entirely different tumor suppressor proteins? Because the genetic code is read three bases at a time, changing the start point by one or two nucleotides will completely change the message contained in a base sequence.

For example, the sequence AAAGGGCCC can be read in three different reading frames starting from the first, second, or third base—that is, starting as AAA-GGG . . ., AAG- GGC …, or AGG-GCC …, respectively. A shift in the normal reading frame usually creates a garbled message that does not code for a functional protein. In the ease of the CDKN2A gene, however, a shift in the reading frame leads to the production of an alternative protein that is fully functional.

The first of the two proteins produced by the CDKN2A gene is the pl6 protein (also called INK4a), a Cdk inhibitor that suppresses the activity of the Cdk- cyclin complex that normally phosphorylates the Rb protein. Loss-of-function mutations affecting p16 lead to excessive Cdk-cyclin activity and inappropriate Rb phosphorylation. Since the phosphorylated form of Rb cannot restrain the cell cycle at the restriction point, the net result is a loss of cell cycle control.

The second protein produced by the CDKN2A gene is called the ARF (for Alternative Reading Frame) protein. Although they are produced by the same gene, p16 and ARF are completely different proteins exhibiting no sequence similarity. Whereas p16 is a Cdk inhibitor, ARF binds to and promotes the degradation of Mdm2, the ubiquitin ligase that normally targets p53 for destruction by tagging it with ubiquitin (see Figures 5 and 6).

By pro­moting the degradation of Mdm2, ARF facilitates the stabilization and accumulation of p53. Conversely, loss- of-function mutations affecting ARF interfere with the ability of p53 to accumulate and perform its function in triggering cell cycle arrest and cell death.

The CDKN2A gene therefore influences cell prolifera­tion and survival through two independent proteins: the p16 protein, which is required for proper Rb signaling, and the ARF protein, which is required for proper p53 signaling (Figure 11).

Loss-of-function mutations in CDKN2A have been observed in numerous human cancers, including 15% to 30% of all cancers originating in the breast, lung, pancreas, and bladder. Deletion of both copies of the CDKN2A gene, which leads to complete absence of both the p16 and ARF proteins, is common in such cases.

2. Essay on Tumor Suppressor Genes: (Around 2500 Words)

Roles in DNA Repair and Genetic Stability:

Although they are involved in a variety of different signaling pathways, the tumor suppressor genes discussed thus far share a fundamental feature in common. They produce proteins whose normal function is to inhibit cell proliferation and survival. Loss-of-function mutations in such genes therefore have the opposite effect, namely increased cell proliferation and survival.

A second group of tumor suppressors act through their effects on DNA repair and the maintenance of chromosome integrity. Unlike genes that exert direct effects on cell proliferation and whose inactivation can lead directly to tumor formation, the inactivation of genes involved in DNA main­tenance and repair acts indirectly by permitting an increased mutation rate for all genes. This increased mutation rate in turn increases the likelihood that alterations will arise in other genes that directly affect cell proliferation.

The terms gatekeepers and caretakers are used to distinguish between these two classes of tumor suppressor genes. The tumor suppressors described in the first part of this article, which exert direct effects on cell proliferation and survival, are considered to be “gatekeepers” because the loss of such genes directly opens the gates to tumor formation.

Tumor suppressors involved in DNA mainte­nance and repair, on the other hand, are “caretakers” that preserve the integrity of the genome and whose inactiva­tion leads to mutations in other genes (including gatekeepers) that actually trigger the development of cancer. We will examine the functions of some of these caretaker genes.

i. Genes Involved in Excision and Mismatch Repair Help Prevent the Accumulation of Localized DNA Errors:

Cancer cells accumulate mutations at rates that can be hundreds or even thousands of times higher than normal. This condition, called genetic instability, does not by itself disrupt the normal controls on cell proliferation.

In fact, most of the mutations that arise in genetically unstable cells are likely to be harmful mutations that hinder cell survival. But elevated mutation rates also increase the probability that occasional mutations will arise that allows cells to escape from the normal constraints on cell proliferation and survival.

Cells that randomly incur such mutations will tend to outgrow their neigh­bors, an important first step in the development of cancer. Increased mutation rates also facilitate tumor progression in which cells acquire additional traits—for example, faster growth rate, increased invasiveness, ability to survive in the bloodstream, resistance to immune attack, ability to grow in other organs, resistance to drugs, and evasion of death-triggering mechanisms—that allow cancers to become increasingly more aggressive.

Genetic instability occurs in several different forms that differ in their underlying mechanisms. The simplest type is caused by defects in the DNA repair mechanisms that cells use for correcting localized errors involving one or a few nucleotides. These localized errors typically arise either from exposure to DNA- damaging agents or from base-pairing mistakes that take place during DNA replication.

There are two types of repair mechanisms employed for correcting such errors. Excision repair, is capable of repairing abnormal bases created by exposure to DNA-damaging agents, and mismatch repair, is used for correcting inappropriately paired bases that arise spontaneously during DNA replication.

Individuals who inherit loss-of-function mutations involving genes required for either of these repair mecha­nisms exhibit an increased cancer risk. For example, inherited mutations in excision repair genes cause xeroderma pigmentosum, a hereditary cancer syndrome involving an extremely high risk for skin cancer.

In a similar fashion, inherited mutations in genes coding for proteins involved in mismatch repair are responsible for hereditary nonpolyposis colon cancer (HNPCC), a heredi­tary syndrome associated with a high risk for colon cancer.

Although both of these hereditary syndromes involve a striking increase in cancer risk, xeroderma pigmentosum exhibits a recessive pattern of inheritance and HNPCC exhibits a dominant pattern of inheritance. In other words, inheriting an elevated cancer risk requires two defective copies of an excision repair gene but only one defective copy of a mismatch repair gene.

The reason for this difference appears to be related to how many steps are required to create genetic instability in the two cases (Figure 12). In a person who inherits a single defective mismatch repair gene all that is required to start accumulating DNA errors at a high rate is for the second copy of the gene to undergo mutation. This second “hit” will immediately permit uncorrected errors to accumulate during normal DNA replication because of the absence of mismatch repair.

In contrast, if a person were to inherit a single defective excision repair gene, subsequent mutation of the second copy of the gene would debilitate excision repair but would not immediately lead to the accumulation of mutations.

A third step, namely exposure to a DNA-damaging agent such as ultraviolet light, is needed to actually create the mutations. Thus more steps are needed to create genetic instability involving excision repair than is the case for mismatch repair.

Inherited mutations in genes required for excision or mismatch repair create a dramatic increase in the risk for certain hereditary cancers, but mutations in these two classes of genes are less important for most nonhereditary forms of cancer.

Nonetheless, mutations in excision or mismatch repair have been detected in about 15% of colon cancers and in several other kinds of cancer as well, suggesting that deficiencies in DNA repair occasionally contribute to the genetic instabilities observed in non- hereditary cancers.

Proteins Produced by the BRCA1 and BRCA2 Genes Assist in the Repair of Double-Strand DNA Breaks:

Another type of genetic instability exhibited by cancer cells involves their tendency to acquire gross abnormali­ties in chromosome structure and number. Such chromosomal instabilities can be caused by defects in a variety of different tumor suppressors, including the BRCA1 and BRCA2 genes.

Women who inherit a muta­tion in one of the BRCA genes typically exhibit a lifetime cancer risk of 40% to 80% for breast cancer and 15% to 65% for ovarian cancer. The BRCA1 and BRCA2 genes were initially thought to exert their effects directly on cell proliferation, but later studies revealed that they produce proteins involved in pathways for sensing DNA damage and performing the necessary repairs.

The two BRCA tumor suppressor genes code for large nuclear proteins that bear little resemblance to one another. An early clue regarding their cellular role came from the observation that cells deficient in either of the BRCA proteins exhibit large numbers of chromosomal abnormalities, including broken chromosomes and chromosomal translocations.

The apparent reason for these abnormalities is that the two BRCA proteins are involved in the process by which cells repair double-strand breaks in DNA. Double-strand breaks are more difficult to repair than single-strand breaks because with single-strand breaks, the remaining strand of the DNA double helix remains intact and can serve as a template for aligning and repairing the defective strand.

In contrast, double-strand breaks completely cleave the DNA double helix into two separate fragments and the repair machinery is therefore con­fronted with the problem of identifying the correct two fragments and rejoining their broken ends without losing any nucleotides.

The two main ways of repairing double-strand breaks are nonhomologous end-joining and homologous recombination. Of the two mechanisms, homologous recombination is less prone to error because it uses the DNA present in the unbroken homologous chromosome to serve as a template for guiding the repair of the DNA from the broken chromosome.

Repairing double-strand breaks by homologous recombination is a complex process that requires the participation of a large number of different proteins, including BRCA1 and BRCA2. The pathway is activated by the same ATM kinase whose role in detecting and responding to DNA damage was introduced earlier in this article (see Figure 5).

We have already seen that in response to DNA damage, the ATM kinase catalyzes the phosphorylation of the p53 protein, which then halts the cell cycle to permit time for repair to occur. The ATM kinase also phosphorylates and activates more than a dozen additional proteins involved in cell cycle control and DNA repair, including BRCA1 and other molecules required for repairing double-strand breaks.

Figure 13 shows that the mechanism for repairing double-strand breaks by homologous recombination involves two main phases. First, a group of proteins called the Rad50 exonuclease complex removes nucleotides from one strand of the broken end of a DNA double helix to expose a single-stranded segment on the opposite strand.

In the second phase, a multi-protein assembly called the Rad51 repair complex carries out a “strand invasion” reaction in which the exposed single-stranded DNA segment at the end of the broken DNA molecule displaces one of the two strands of the intact DNA molecule being used as a template.

In this step, Rad51 first coats the single-stranded DNA the coated strand then invades and moves along the target DNA double helix until it reaches a complementary sequence. Once it has been located, the complementary sequence is used as a template for guiding repair of the broken DNA.

Although their roles are not completely understood, the BRCA1 and BRCA2 proteins are both required for efficient repair of double-strand breaks. BRCA2 binds tightly to and controls the activity of Rad51, the central protein responsible for carrying out strand invasion during repair by homologous recombination.

BRCA1 is associated with both the Rad50 exonuclease complex and the Rad51 repair complex. Moreover, it is known that ATM phosphorylates BRCA1 in response to DNA damage, suggesting that BRCA1 plays an early role in activating the pathway for repairing double-strand breaks.

Cells deficient in either BRCA1 or BRCA2 are extremely sensitive to carcinogenic agents that produce double-strand DNA breaks. In such cells, double-strand breaks can only be repaired by error-prone mechanisms, such as non-homologous end-joining, that lead to broken, rearranged, and translocated chromosomes. The resulting chromosomal instability is thought to play a large role in the cancer risks exhibited by women who inherit BRCA1 or BRCA2 mutations.

Mutations in Genes that Influence Mitotic Spindle Behavior can Lead to Chromosomal Instabilities:

We have just seen how broken and translocated chromo­somes arise in cancer cells as a result of mutations that disrupt tumor suppressor genes needed for repairing double-strand DNA breaks. Another chromosomal abnormality frequently observed in cancer cells is the tendency for whole chromosomes to be lost or gained, thereby leading to aneuploid cells that possess an abnormal number of chromosomes (Figure 14).

The various mechanisms that underlie the development of aneuploidy are just beginning to be unraveled, but evidence already points to the existence of tumor suppressor genes whose loss contributes to this type of chromosomal instability.

To explain how these tumor suppressors work, we first need to review the normal mechanisms used by cells for sorting and parceling out chromosomes during cell division. In a normal cell cycle, chromosomal DNA is first replicated during S phase to create duplicate copies of each chromosome, and the duplicate copies are then separated into the two new cells formed by the subse­quent mitotic cell division.

Accurate separation of the duplicated chromosomes is accomplished by attaching the chromosomes to the mitotic spindle, which separates and moves the chromosomes in a way that ensures that each new cell receives a complete set of chromosomes (Figure 15).

A critical moment occurs at the end of metaphase, when the chromosomes line up at the center of the mitotic spindle just before being parceled out to the two new cells. If chromosome movement toward opposite spindle poles were to begin before the chromosomes is all attached to the spindle, a newly forming cell might receive extra copies of some chromosomes and no copies of others.

To protect against this possible danger, cells possess a control mechanism called the spindle checkpoint that monitors chromosome attachment to the spindle and prevents chromosome movement from beginning until all chromo­somes are properly attached. In the absence of such a mechanism, there would be no guarantee that each newly forming cell would receive a complete set of chromosomes (see Figure 15, bottom right).

The key to the spindle checkpoint is the anaphase- promoting complex, a multiprotein complex that triggers the onset of anaphase—the stage of mitosis when the chromosomes move toward opposite poles of the mitotic spindle.

As shown in Figure 16a, the anaphase-promoting complex initiate’s chromosome movement by activating separase, an enzyme that breaks down proteins called cohesins that hold the duplicated chromosomes together. As long as they are joined together by cohesins, the dupli­cated chromosomes cannot separate from each other and move toward opposite spindle poles.

To prevent premature separation, chromosomes that are not yet attached to the mitotic spindle send a “wait” signal that inhibits the anaphase-promoting complex, thereby blocking the activation of separase. The “wait” signal is transmitted by proteins that are members of the Mad and Bub families.

The Mad and Bub proteins bind to chromosomes that are unattached to the mitotic spindle and are converted into a Mad-Bub multiprotein complex, which inhibits the anaphase-promoting complex by blocking the action of one of its essential activators, the Cdc20 protein (see Figure 16b).

After the chromosomes have all become attached to the spindle, the Mad and Bub proteins are no longer converted into this inhibitory complex and the anaphase-promoting complex is free to initiate the onset of anaphase.

Mutations that cause the loss or inactivation of Mad or Bub proteins have been linked to certain types of cancer, which indicates that genes coding for some of the Mad and Bub proteins behave as tumor suppressor genes. A lack of Mad or Bub proteins caused by loss-of-function mutations in these tumor suppressor genes disrupts the “wait” mechanism and impedes the ability of the spindle checkpoint to operate properly.

Under such conditions, chromosome movement toward the spindle poles begins before all the chromosomes are properly attached to the mitotic spindle. The result is a state of chromosomal instability in which cell division creates aneuploid cells lacking some chromosomes and possessing extra copies of others.

Another route to chromosomal instability involves the mechanism responsible for assembling the mitotic spindle. Formation of a mitotic spindle requires two small structures called centrosomes, one located at each end of the spindle (see Figure 15). Centrosomes promote the assembly of the spindle microtubules, which form in the space between the two centrosomes. Cancer cells often possess extra centrosomes and therefore produce aberrant mitotic spindles.

In Figure 17, we see a cancer cell with three centrosomes that have assembled a spindle with three poles. Multipolar spindles containing three or more poles, which are rare in normal tissues but common in cancer cells, contribute to the development of aneuploidy because they cannot sort the two sets of chromosomes accurately. Cells produced by mitosis involving an abnormal spindle will often be missing certain chromo­somes and thus will lack any tumor suppressor genes that the missing chromosomes would normally possess.

3. Essay on Tumor Suppressor Genes: (Around 2000 Words)

Role of Mutation and Non-Mutation in Converting Normal Cells into Cancer Cells:

Mutations in cancer-related genes, and the genetic insta­bility that facilitates the accumulation of such mutations, are centrally involved in the mechanisms by which cancers arise.

Yet one cannot explain the behavior of a malignant tumor by pointing solely to gene mutations. The final part of this article will provide a broad overview of the role played not just by mutations but also by non-mutational changes in converting normal cells into cancer cells.

i. Cancers Vary in their Gene Expression Profiles:

Mutations that create oncogenes or disrupt the function of tumor suppressor genes are central to the development of cancer, but they do not explain all the cellular changes that accompany the conversion of normal cells into cancer cells.

Many of the properties exhibited by cancer cells are triggered not by gene mutations, but by switching on (or off) the expression of normal genes, thereby leading to increases (or decreases) in the production of hundreds of different proteins. The term epigenetic change is employed when referring to such alterations that are based on changing the expression of a gene rather than mutating it.

Measuring epigenetic changes requires techniques that can monitor the expression of thousands of genes simultaneously. One very powerful tool is the DNA microarray, a fingernail-sized, thin chip of glass or plastic that has been spotted at fixed locations with thousands of DNA fragments corresponding to various genes of interest.

A single microarray may contain 10,000 or more spots, each representing a different gene. To determine which genes are being expressed in any given cell popula­tion, one begins by extracting molecules of messenger RNA (mRNA), which represent the products of gene transcription. The mRNA is then copied with reverse transcriptase, an enzyme that makes single-stranded DNA copies that are complementary in sequence to each mRNA.

The resulting single-stranded DNA (called cDNA for complementary DNA) is then attached to a fluorescent dye. When the microarray is bathed with the fluorescent cDNA, each cDNA molecule binds or hybridizes by complementary base-pairing to the spot containing the specific gene to which it corresponds.

Figure 18 illustrates how DNA microarrays can be used to create a gene expression profile that compares the patterns of gene expression in cancer cells and a corre­sponding population of normal cells. In this particular example, two fluorescent dyes are used: a red dye to label cDNAs derived from cancer cells and a green dye to label cDNAs derived from the corresponding normal cells.

When the red and green cDNAs are mixed together and placed on a DNA microarray, the red cDNAs bind to genes expressed in cancer cells and the green cDNAs bind to genes expressed in normal cells.

Red spots therefore repre­sent higher expression of a gene in cancer cells, green spots represent higher expression of a gene in normal cells, yellow spots (caused by a mixture of red and green fluorescence) represent genes whose expression is roughly the same, and black spots (absence of fluorescence) repre­sent genes expressed in neither cell type.

Thus the relative expression of thousands of genes in cancer and normal cells can be compared by measuring the intensity and color of the fluorescence of each spot. Such analyses have revealed that the expression of hundreds of different genes is typically altered in cancer cells compared with normal cells of the same tissue. Moreover, significant variations in gene expression are often detected when the same type of cancer is examined in different patients.

The changes in gene expression commonly exhibited by cancer cells arise in several difference ways. One well- documented mechanism involves epigenetic silencing by DNA methylation, a process in which methyl groups are attached to the base C in DNA at sites where it is located adjacent to the base G.

In vertebrate DNA, these -CG- sequences are preferentially located near the beginning of genes (about half of all human genes are associated with -CG- sites). When -CG- sequences undergo methylation, the transcription of adjacent genes is inhibited or “silenced.”

Most -CG- sites are un-methylated in normal cells, but extensive methylation is often seen in cancer cells, where it leads to the inappropriate silencing of a variety of different genes. Tumor suppressor genes are frequently among the genes to be silenced by this mechanism.

In fact, the tumor suppressor genes of cancer cells are inactivated by epigenetic silencing at least as often as they are inactivated by DNA mutation. Loss of gene function through inappropriate methylation may therefore be as important to cancer cells as mutation induced loss of function.

ii. Colon Cancer Illustrates How a Stepwise Series of Mutations can Lead to Malignancy:

Cancer arises via a multistep process in which cellular properties gradually change over time as mutations confer new traits that impart selective advantages to the cells in which they arise.

Now that we have described the main classes of cancer-related genes and the molecular path­ways in which they participate, it is appropriate to return to the concept of multistep carcinogenesis to see how a specific sequence of gene mutations can lead to cancer.

Current estimates indicate that there are more than 100 different oncogenes and several dozen tumor sup­pressor genes. For cancer to arise, it is rarely sufficient to have a defect in just one of these genes, nor is it necessary for a large number to be involved.

Instead, each type of cancer tends to be characterized by a small handful of mutations involving the inactivation of tumor suppressor genes as well as the conversion of proto-oncogenes into oncogenes. In other words, creating a cancer cell usually requires that the brakes on cell growth (tumor suppressor genes) be released and the accelerators for cell growth (oncogenes) be activated.

This principle is nicely illustrated by the stepwise progression toward malignancy observed in colon cancer. Scientists have isolated DNA from a large number of colon cancer patients and examined it for the presence of mutations. The most common pattern to be detected is the presence of a KRAS oncogene (a member of the RAS gene family) accompanied by loss-of-function mutations in the tumor suppressor genes APC, p53, and SMAD4.

Rapidly growing colon cancers tend to exhibit all four genetic alterations, whereas benign tumors have only one or two, suggesting that mutations in the four genes occur in a stepwise fashion that correlates with increasingly aggressive behavior.

As shown in Figure 19, the earliest mutation to be routinely detected is loss of function of the APC gene, which frequently occurs in small polyps before cancer has even arisen. Mutations in KRAS tend to be seen when the polyps get larger, and mutations in SMAD4 and p53 usually appear as cancer finally begins to develop.

These mutations, however, do not always occur in the same sequence or with the same exact set of genes. For example, APC mutations are found in about two-thirds of all colon cancers, which means that the APC gene is normal in one out of every three cases.

Analysis of tumors containing normal APC genes has revealed that many of them possess oncogenes that produce an abnormal, hyperactive form of β-catenin, a protein that—like the APC protein—is involved in Wnt signaling (see Figure 8).

Because APC inhibits the Wnt pathway and β-catenin stimulates it, mutations leading to the loss of APC and mutations that create hyperactive forms of β-catenin have the same basic effect- Both enhance cell proliferation by increasing the activity of the Wnt pathway.

Another pathway frequently disrupted in colon cancer is the TGFβ-Smad pathway, which inhibits rather than stim­ulates epithelial cell proliferation. Loss-of-function mutations in genes coding for components of this pathway, such as the TGFβ receptor or Smad4, are commonly detected in colon cancers. Such mutations disrupt the growth-inhibiting activity of the TGFβ-Smad pathway and thereby contribute to enhanced cell proliferation.

Overall, the general principle illustrated by the various colon cancer mutations is that different tumor suppressor genes and oncogenes can affect the same pathway, and it is the disruption of particular signaling pathways that is important in cancer cells rather than the particular gene mutations through which the disruption is achieved (Table 2).

iii. The Various Causes of Cancer can be brought Together into a Single Model:

Colon cancer illustrates how normal cells can be converted into cancer cells by a small number of genetic changes, each affecting a particular pathway and conferring some type of selective advantage. Of course, colon cancer is just one among dozens of different human cancers, and the few genes commonly mutated in colon cancer are only a tiny fraction of the more than 100 different oncogenes and tumor suppressor genes.

When various kinds of tumors are compared, it is found that different combinations of gene mutations can lead to cancer and that each type of cancer tends to exhibit its own characteristic mutation patterns.

Despite this variability, a number of shared principles are apparent in the various routes to cancer. An overview is provided by the model illustrated in Figure 20, which begins with the four main causes of cancer: chemicals, radiation, infectious agents, and heredity.

Each of these four factors contributes to the development of malig­nancy. While the details may differ, the bottom line is that one way or another, each of the four causes of cancer leads to DNA alterations.

In the case of either viruses that introduce specific oncogenes into cells or cancer syndromes that arise from inherited gene defects, the DNA alterations involve a specific gene. Most of the DNA mutations induced by carcinogens, on the other hand, are random. The higher the dose and potency of the carcinogen, the greater the DNA damage and therefore the greater the probability that a random mutation will disrupt a critical gene.

But critical genes (proto-oncogenes and tumor suppressor genes) represent only a tiny fraction of the chromosomal DNA, so the random nature of mutation means that luck plays a significant role if two people are exposed to the same dose of a carcinogen, one may develop cancer while the other does not simply because random mutations happen to damage a critical proto-oncogene or tumor suppressor gene in the unlucky individual.

The random nature of mutation contributes to the long period of time that is usually required for cancer to develop. Moreover, when DNA repair mechanisms and DNA damage checkpoints are operating properly, many mutations are either repaired or the cells containing them are destroyed by apoptosis. Taken together, such consider­ations may help explain why cancer is largely a disease of older age.

For cancer to develop, cells need to gradually accumulate a stepwise series of appropriate mutations involving the inactivation of tumor suppressor genes as well as the conversion of proto-oncogenes into oncogenes.

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Benign Tumors of Peripheral Nerves

Benign peripheral nerve sheath tumors differ from other soft tissue tumors in several important respects. Most soft tissue tumors arise from mesodermally derived tissue and display a range of features consonant with that lineage. Nerve sheath tumors arise from tissues considered to be of neuroectodermal or neural crest origin and display a range of features that mirrors the various elements of the nerve (e.g., Schwann cell, perineurial cell). Whereas most soft tissue tumors only seem to be encapsulated by virtue of the compression of surrounding tissues against their advancing border, benign nerve sheath tumors arising in a nerve are completely surrounded by epineurium or perineurium and therefore have a true capsule , a feature that facilitates their enucleation. Finally, benign nerve sheath tumors represent the most important group of benign soft tissue lesions in which malignant transformation is an acknowledged phenomenon. Sarcomas develop in neurofibromas in a subset of patients with neurofibromatosis 1, thereby providing an excellent model in which to study the molecular pathway of malignant transformation.

This chapter discusses the two principal benign nerve sheath tumors, schwannoma and neurofibroma, their associated syndromes, and the more recently recognized perineurioma. Schwannomas recapitulate in a more or less consistent fashion the appearance of the differentiated Schwann cell, whereas neurofibromas display a spectrum of cell types ranging from the Schwann cell to the fibroblast. Schwannomas and neurofibromas are distinctive lesions that can be reproducibly distinguished from one another, in most instances, by their pattern of growth, cellular composition, associated syndromes, and cytogenetic alterations ( Table 26.1 ). Perineuriomas mirror the barrier (perineurial) cell of the nerve sheath, as recognized by certain characteristic ultrastructural and immunophenotypic features.

Schwannoma Neurofibroma
Age 20-50 yr 20-40 yr younger in NF1
Common locations Head and neck flexor portion of extremities less often retroperitoneum and mediastinum Cutaneous nerves deep locations in NF1
Encapsulation Usually Usually not
Growth patterns Encapsulated tumor with Antoni A and B areas plexiform type uncommon Localized, diffuse, and plexiform patterns
Associated syndromes Most lesions sporadic some NF2 and schwannomatosis, rarely NF1 Most lesions sporadic some NF1
S-100 protein and SOX10 immunostain Strong and uniform Variable staining of cells
Malignant transformation Exceptionally rare Rare in sporadic cases but occurs in 2%–3% of NF1 patients

Normal Anatomy

The peripheral nervous system consists of nervous tissue outside the brain and spinal cord and includes somatic and autonomic nerves, end-organ receptors, and supporting structures. It develops when axons lying close to one another grow out from the neural tube and are gradually invested with Schwann cells. Schwann cells arise from the neural crest, a group of cells that arise from and lie lateral to the neural tube and underneath the ectoderm of the developing embryo. The major peripheral nerve trunks form by fusion and division of segmental spinal nerves and contain mixtures of sensory, motor, and autonomic elements.

In the fully developed nerve, a layer of connective tissue or epineurium surrounds the entire nerve trunk ( Fig. 26.1 ). This structure varies in size, depending on the location of the nerve, and is composed of a mixture of collagen and elastic fibers along with mast cells. Several nerve fascicles lie within the confines of the epineurium, and each in turn is surrounded by a well-defined sheath known as the perineurium . The outer portion of the perineurium consists of layers of connective tissue, and the inner portion is represented by a multilayered, concentrically arranged sheath of flattened cells. The perineurium, which is continuous with the pia-arachnoid of the central nervous system, represents the principal diffusion barrier for the peripheral nerve. Unlike the Schwann cell, the perineurial cell is a mesodermal derivative sharing an immunophenotype with the cells of the pia-arachnoid (S-100 protein negative epithelial membrane antigen [EMA], GLUT1, and claudin-1 positive). Ultrastructurally, perineurial cells form close junctions with each other and have basal lamina along the endoneurial and perineurial aspects of the cell, features not encountered in the ordinary fibroblast and Schwann cell.

Despite the undoubted importance of the investing connective tissue, the critical supporting element is the Schwann cell . It provides mechanical protection for the axon, produces and maintains the myelin sheath, and serves as a tube to guide regenerating nerve fibers. Ultrastructurally, the Schwann cell is easily identified by its intimate relation to its axons and by a continuous basal lamina that coats the surface of the cell facing the endoneurium. In routine preparations, it is difficult to distinguish the axon from the myelin sheath. This distinction, however, is easily accomplished with special stains. Silver stains selectively stain the axon ( Fig. 26.2 ), whereas stains such as Luxol fast blue stain myelin. The variation in diameter of the axon and myelin sheath can be appreciated with these stains. In general, moderately or heavily myelinated fibers correspond to sensory and motor fibers with fast conduction speeds, whereas lightly myelinated or unmyelinated fibers correspond to autonomic fibers with slower conduction speeds. Ultrastructurally, the cytoplasm of the axon is characterized by numerous cytoplasmic filaments, slender mitochondria, and a longitudinally oriented endoplasmic reticulum. Nissl substance, a feature of the nerve cell body, is not present in the axoplasm. In addition, small vesicles are observed occasionally they may represent packets of neurotransmitter substance en route to the nerve terminal.

Traumatic (Amputation) Neuroma

Traumatic neuroma is an exuberant, but nonneoplastic, proliferation of a nerve occurring in response to injury or surgery. Under ideal circumstances, the ends of a severed nerve reestablish continuity by an orderly growth of axons from proximal to distal stump through tubes of proliferating Schwann cells. However, if close apposition of the ends of a nerve is not maintained, or if there is no distal stump, a disorganized proliferation of the proximal nerve gives rise to a neuroma. Symptomatic neuromas are usually the result of surgery, notably amputation. Occasionally, other surgical procedures, such as cholecystectomy, have been implicated in their pathogenesis. A rare form of traumatic neuroma is seen in rudimentary (supernumerary) digits that undergo autoamputation in utero. These lesions appear as raised nodules on the ulnar surface of the proximal fifth finger and contain a disordered proliferation of nerves similar to a conventional traumatic neuroma ( Fig. 26.3 ).

Clinically, the neuroma presents as a firm nodule that is occasionally tender or painful. Strangulation of the proliferating nerve by scar tissue, local trauma, and infection may explain the pain. Grossly, the lesions are circumscribed, white-gray nodules seldom exceeding 5 cm in diameter they are located in continuity with the proximal end of the injured or transected nerve. They consist of a haphazard proliferation of nerve fascicles, including axons with their investitures of myelin, Schwann cells, and fibroblasts. The fascicles are usually less well myelinated than the parent nerve and are embedded in a background of collagen ( Fig. 26.4 ).

Traumatic neuromas are sometimes confused with solitary circumscribed neuromas (palisaded encapsulated neuromas) and neurofibromas. Participation of all elements of the nerve fascicles and identification of a damaged nerve distinguish a traumatic neuroma from neurofibroma . In areas where the fascicles are small and the matrix is poorly collagenized and highly myxoid, the similarity to neurofibroma may be striking ( Fig. 26.5 ) and therefore may require identification of subtler clues, such as the characteristic collagen bundles of neurofibroma. Solitary circumscribed neuromas arise exclusively in the skin, predominantly in women they consist of a more circumscribed, orderly arrangement of nerve fascicles.

Treatment of traumatic neuromas is partly prophylactic. After traumatic nerve injury, an attempt should be made to reappose the ends of the severed nerve so that regeneration of the proximal end proceeds down the distal trunk in an orderly manner. Once a neuroma has formed, removal is indicated when it becomes symptomatic or when it must be distinguished from recurrent tumor in a patient who has had cancer-related surgery. Simple excision of the lesion and reembedding the proximal nerve stump in an area away from the old scar constitute the conventional therapy.

Mucosal Neuroma

Germline-activating mutations of the RET proto-oncogene are responsible for several familial syndromes, including multiple endocrine neoplasia (MEN) 2b (or IIB) (thyroid carcinoma, pheochromocytoma, and mucosal neuromas). Patients with this disease develop characteristic neuromas of the mucosal surfaces of the lips, mouth, eyelids, and intestines. Because mucosal neuromas may represent an early manifestation of this life-threatening syndrome, recognition of these lesions is of more than academic interest. The lesions manifest during the first few decades of life and present as multiple nodules of varying size, which may result in diffuse enlargement of the affected area.

Focally, the lesions are notable for the irregular, tortuous bundles of nerve with a prominent perineurium that lie scattered throughout the submucosa of the oral cavity ( Fig. 26.6 ). The nerves and perineurium may be distinguished by a prominent degree of myxoid change. In the gastrointestinal (GI) tract, both submucosal and myenteric plexus appear hyperplastic, with an increase in all elements of the plexus, including Schwann cells, neurons, and ganglion cells ( Fig. 26.7 ).

Pacinian Neuroma

Pacinian neuroma refers to localized hyperplasia or hypertrophy of the pacinian corpuscles, which occurs after trauma and usually produces pain. Typically, it develops on the digits, where it produces a localized mass. Pacinian neuromas range in appearance from small nodules attached to the nerve by a slender stalk to one or more contiguous subepineural nodules ( Fig. 26.8 ). Histologically, it consists of mature pacinian corpuscles that are increased in size or number (or both) and are often associated with degenerative changes and fibrosis of the adjacent nerve. The principal problem in the differential diagnosis is the distinction of these lesions from a normal pacinian body, which can achieve a size sufficient to be visualized macroscopically. For example, normal pacinian bodies can be identified in the abdominal cavity, where they are occasionally misinterpreted as tumor implants. We have also seen pacinian bodies in the stomach, an unexpected location where they are easily mistaken for a neural tumor. In pacinian neuromas the structures usually are larger than 1.5 mm in diameter. In general, a pacinian neuroma is diagnosed when the histologic features described previously are associated with a discrete pain-producing mass. Pacinian neuromas should not be confused with “pacinian neurofibromas,” a term loosely used to describe a heterogeneous group of lesions that probably includes neurofibroma, congenital nevi, perineurioma, and nerve sheath myxoma.

Solitary Circumscribed Neuroma (Palisaded Encapsulated Neuroma)

The solitary circumscribed neuroma, also known as “palisaded encapsulated neuroma,” can be conceptualized as a hyperplastic expansion of Schwann cells and axons of a cutaneous peripheral nerve. The term solitary circumscribed neuroma is now preferred for these tumors, since they may be neither palisaded nor encapsulated. Although slow to gain acceptance because of some similarity to the schwannoma, it has distinct clinical features. Solitary circumscribed neuromas develop as a small, asymptomatic nodule in the area of the face of adult patients. Rare cases on the distal extremities have been reported. Males and females are involved equally. Affected patients do not display manifestations of neurofibromatosis 1 or MEN-2b.

Histologically, one or more circumscribed or encapsulated nodules occupy the deep dermis and subcutaneous tissues ( Fig. 26.9 ). In some cases the nodules form clublike extensions into the subcutaneous tissue or may even have a plexiform architecture. They consist of a solid proliferation of Schwann cells and lack the variety of stromal changes (e.g., myxoid change, hyalinization) that may be encountered in schwannomas and neurofibromas ( Fig. 26.10 ). Although superficially these neuromas may resemble schwannomas, particularly if minor degrees of nuclear palisading are noted, they differ by the presence of axons, best demonstrated with silver stains or neurofilament protein immunohistochemistry (IHC), that traverse the lesion in close association with the Schwann cells. Schwannomas may contain axons, but they are typically located peripherally, immediately underneath the capsule.

In most instances, simple excision of solitary circumscribed neuroma has proved curative. In contrast to a traumatic neuroma, these lesions are encapsulated, more uniform appearing, and unassociated with a damaged nerve.

Morton Neuroma (Morton Metatarsalgia)

Morton interdigital neuroma is not a true tumor but rather a fibrosing process of the plantar digital nerve that results in paroxysmal pain in the sole of the foot, usually between the heads of the third and fourth metatarsals and less often between the second and third. The pain typically commences with exercise, is alleviated by rest, and may radiate into the toes or leg. In some cases, a small area of point tenderness can be defined, although generally no mass can be palpated. Theories to explain this condition have included chronic trauma, ischemia, and bursitis. Evidence favors that Morton neuroma is a nerve entrapment syndrome caused by impingement on the plantar digital nerve by the deep transverse intermetatarsal ligament or by the adjacent metatarsal heads. Because women are affected more often than men, the wearing of ill-fitting high-heeled shoes has been incriminated in the pathogenesis of this condition. Lesions histologically similar to Morton neuroma are sometimes seen in relation to nerves in the hand, where they are undoubtedly related to chronic occupational or recreational injury.

At surgery, the characteristic lesion is a firm fusiform enlargement of the plantar digital nerve at its bifurcation point. In advanced cases, the nerve may be firmly attached to the adjacent bursa and soft tissue. Although grossly the lesion resembles a traumatic neuroma or neurofibroma, it is different histologically. Proliferative changes characterize traumatic neuromas, whereas degenerative changes are the hallmark of Morton neuroma. Edema, fibrosis, and demyelinization occur within the nerve ( Fig. 26.11A ). Hyalinization of endoneurial vessels is also present in some cases ( Fig. 26.11B ). Elastic fibers are diminished in the center of the lesions but are increased at its periphery, where they have a bilaminar appearance similar to the elastic fibers in an elastofibroma. As the lesion progresses, the fibrosis becomes marked and envelops the epineurium and perineurium concentrically and may even extend into the surrounding tissue. Although conservative treatment such as orthopedic footwear and corticosteroid injections are first-line measures, the most successful therapy is removal of the affected nerve segment.

Nerve Sheath Ganglion Cysts

Rarely, ganglion cysts occur in intraneural locations. These lesions present as tender masses with pain or numbness in the distribution of the affected nerve. Most of these lesions are located in the external popliteal nerve at the head of the fibula, which suggests that a particular type of injury or irritation leads to their development. The nerve exhibits localized swelling that corresponds to myxoid change with secondary cyst formation. In some cases, however, the unlined cysts dominate the histologic picture and cause marked displacement of the nerve fascicles toward one side of the sheath ( Fig. 26.12 ). This lesion, like its soft tissue counterpart, represents a degenerative process rather than a neoplasm. The myxoid zones in these lesions have caused confusion with the so-called nerve sheath myxoma, a true neoplasm probably of Schwann cell origin, which is quite distinct from nerve sheath ganglion. Therapy of a nerve sheath ganglion cyst consists of local excision, although decompression is acceptable if the integrity of the nerve is threatened.

Neuromuscular Choristoma (Neuromuscular Hamartoma, Benign Triton Tumor)

Tumors composed of skeletal muscle and neural elements are collectively referred to as Triton tumors in accord with an early hypothesis concerning their histogenesis (see Chapter 27 ). The best recognized of these mosaic tumors is the malignant peripheral nerve sheath tumor (MPNST) with rhabdomyoblastic differentiation (malignant Triton tumor), although combinations such as rhabdomyosarcoma with ganglion cells (ectomesenchymoma) also occur. Benign lesions composed of neural and skeletal muscle differentiation are rare and are represented principally by the neuromuscular choristoma and the neurofibroma with a rhabdomyomatous component.

Of the fewer than 50 cases from the literature, the majority occurred in young children as solitary masses involving large nerve trunks, particularly the brachial and sciatic. Tumors arising from the cranial nerves also occur, but usually present during adult life. The case described by O’Connell and Rosenberg presented as multiple lesions outside the nerve. Because of their strategic locations, neurologic symptoms are prominent. Magnetic resonance imaging (MRI) may be helpful in diagnosis because these lesions typically present as fusiform expansions of the involved nerve, with T1 and T2 signal intensities similar to normal skeletal muscle, minimal interposed adipose tissue, and absent gadolinium enhancement. Grossly, the lesions simulate a benign nerve sheath tumor. The tumors are multinodular masses subdivided by fibrous bands into smaller nodules or fascicles. Each fascicle is composed of highly differentiated skeletal muscle fibers that vary in size but are often larger than normal. Intimately associated with the skeletal muscle and sharing the same perimysial sheath are both small myelinated and nonmyelinated nerves ( Fig. 26.13 ). IHC studies for neural and muscle markers highlight the close juxtaposition of both components. Smooth muscle is rarely present.

Several reports attest to the association between neuromuscular choristoma and deep fibromatosis. In some cases the lesions are noted simultaneously, whereas in others the fibromatosis supervenes months to years after the initial biopsy of the choristoma. In four of five cases studied by Carter et al., both the neuromuscular choristoma and the fibromatosis possessed mutations in CTNNB1 , with identical mutations in three patients. It was suggested that the unique monomelic distribution of neuromuscular choristomas pointed toward a postzygotic somatic event within an ectomesenchymal precursor, with CTNNB1 mutation and abnormal β-catenin signaling resulting in the abnormal combination of nerve and skeletal muscle that characterize these lesions. Biopsy appears to be the inciting factor in the development of fibromatoses in patients with neuromuscular choristoma, and it should not be performed in patients with radiographically typical lesions. A similar phenomenon may occur in another fibromatosis precursor, Gardner-associated fibroma.


Neurofibromas may assume one of three growth patterns: localized, diffuse, or plexiform. The localized form is seen most often as a superficial, solitary tumor in normal individuals. Diffuse and plexiform neurofibromas have a close association with neurofibromatosis 1 (NF1), the latter almost pathognomonic of the disease, as discussed later.

Localized (Sporadic) Neurofibroma

Localized neurofibromas occur most often as sporadic lesions in patients who do not have NF1. Their exact incidence is unknown because of the difficulty in excluding the diagnosis of NF1 in some patients, such as young persons, in whom the initial presentation of the disease may be a solitary neurofibroma, or patients who have no affected family members. Despite these problems, it appears that sporadic neurofibromas outnumber those occurring in NF1 by a considerable margin.

Clinical Findings

Localized sporadic neurofibromas, like their inherited counterparts, affect the genders equally. Most develop in persons between ages 20 and 30 years. Because most are superficial lesions of the dermis or subcutis, they are found evenly distributed over the body surface. They grow slowly as painless nodules that produce few symptoms. Grossly, they are glistening tan-white tumors that lack the secondary degenerative changes common to schwannomas. If they arise in major nerves, they expand the structure in a fusiform fashion, and normal nerves can be seen entering and exiting from the mass ( Fig. 26.14 ). If this lesion remains confined by the epineurium, it has a true capsule. More frequently, these tumors arise in small nerves and readily extend into soft tissue. These tumors appear circumscribed but not encapsulated.

Microscopic Findings

Histologically, neurofibromas vary, depending on their content of cells, stromal mucin, and collagen ( Figs. 26.15 to 26.18 ). In its most characteristic form, neurofibromas contain interlacing bundles of elongated cells with wavy, darkly stained nuclei. The cells are intimately associated with wirelike strands of collagen that have been likened to shredded carrots. Small to moderate amounts of mucoid material separate the cells and collagen. The stroma of the tumor is dotted with mast cells, lymphocytes, and rarely xanthoma cells. Less frequently, neurofibromas are highly cellular and consist of Schwann cells set in a uniform collagen matrix devoid of mucosubstances ( Fig. 26.16 ). The cells may be arranged in short fascicles, whorls, or even a storiform pattern. In certain respects, these cellular neurofibromas resemble Antoni A areas of a schwannoma. Unlike schwannomas, however, neurofibromas are not encapsulated and lack a clear partition into two zones. Moreover, small neurites can usually be demonstrated throughout these tumors. Least commonly, neurofibromas are highly myxoid and therefore often confused with myxomas this form of neurofibroma usually occurs on the extremities. These hypocellular neoplasms contain pools of acid mucopolysaccharide with widely spaced Schwann cells. In contrast to the cells of myxoma, neurofibroma cells usually have a greater degree of orientation. The vascularity is also more prominent, and with careful searching, features of specific differentiation (e.g., pseudomeissnerian bodies) may be found. Rare variations in neurofibromas are epithelioid change of the Schwann cells and skeletal muscle ( Fig. 26.19 ). Extraordinarily rare cases contain benign glands or rosettes. S-100 protein and SOX10 can be identified in these tumors but stain only a subset of cells, in keeping with the observation that neurofibromas contain a mixed population of cells (see Fig. 26.18 ).

Although solitary neurofibromas are not associated with the same incidence of malignant change as their inherited counterparts, the exact risk is unknown. It is probably vanishingly small. Simple excision of these tumors is considered adequate therapy.

Neurofibromatosis 1 (NF1)

Neurofibromatosis, also termed von Recklinghausen disease for the German pathologist who described the disease in 1882, was formerly considered a single disease but is now known to be at least two clinically and genetically distinct diseases. The more common disease, formerly known as the “peripheral” form of neurofibromatosis, is designated neurofibromatosis 1 (NF1), whereas the less common disease, formerly known as the “central” form, is designated neurofibromatosis 2 (NF2) (bilateral vestibular schwannoma).

A common genetic disease, NF1 affects 1 in every 3500 individuals. It is inherited as an autosomal dominant trait with a high rate of penetrance. Because only half the patients with NF1 have affected family members, the disease in the remaining patients represents new mutations. The mutation rate, estimated at 10 −4 per gamete per generation, is among the highest for a dominantly inherited trait. About 80% of new mutations are of paternal origin.

NF1 is caused by deletions, insertions, stop mutations, amino acid substitutions, and splicing mutations in the NF1 gene, a tumor suppressor gene located in the pericentromeric region of chromosome 17. Spanning a distance of 300 kb and containing at least 60 exons, it is one of the largest human genes, an observation that likely explains its high mutation rate. It encodes an approximately 2800–amino acid protein known as neurofibromin , several isoforms of which are differentially expressed in tissues such as brain, neurons, and peripheral nerve. A small portion of neurofibromin possesses sequence homology to the RAS GTPase-activating protein (RAS-GAP) family of proteins that inactivate RAS. Loss of NF1 gene expression therefore results in increased RAS activity, cell proliferation, and tumorigenesis. Increased RAS-GTP results in increased Raf kinase–mediated signaling, which in turn activates a signaling cascade involving MEK kinase and the Erk1 and Erk 2 isoforms of MAPK, causing cell proliferation. Increased RAS-GTP also activates the mTOR pathway, which protects cells from apoptosis. Neurofibromin has other functions as well. For example, neurofibromin positively regulates cyclic AMP, which in turn modulates astrocytic growth and differentiation in the brain. Neurofibromas in patients with NF1 are composed chiefly of neurofibromin-deficient Schwann cells. Understanding these additional signaling pathways will likely begin to explain the protean manifestations of the disease.

Clinical Findings

Although, in principle, diagnosis of NF1 should be possible through genetic testing, the large size of the gene and the myriad of mutations have precluded this. Instead, a protein truncation assay to screen for stop mutations has been devised. Unfortunately, it detects only two-thirds of cases and does not predict severity of the disease. More recently, deep sequencing of all 60 NF1 exons, copy number analyses, and screening for intronic splicing site mutations have been reported to identify 95% of presumed NF1 mutations. Some commercial laboratories are also now performing complete sequencing of the entire NF1 gene Longo et al., however, report that this approach has only been successful in 75% to 85% of candidate cases, for unclear reasons. Therefore the diagnosis of NF1 is still at least in part dependent on identification of the cardinal signs of the disease, two or more of which must be present to establish the diagnosis ( Box 26.1 ).

NF1 is diagnosed in an individual with two or more of the following signs or factors:

Six or more café au lait macules: >5 mm in greatest diameter in prepubertal individuals >15 mm in greatest diameter in postpubertal individuals

Two or more neurofibromas of any type or one plexiform neurofibroma

Freckling in the axillary or inguinal region

Two or more Lisch nodules (iris hamartomas)

A distinctive osseous lesion such as sphenoid dysplasia or thinning of long bone cortex with or without pseudoarthrosis

First-degree relative (parent, sibling, offspring) with NF1 by the above criteria

The severity of the disease varies widely from patient to patient and from family to family. Because of the complexity of the disease and size of the gene, it has been difficult to perform precise genotypic-phenotypic correlations. Only in patients with extremely severe forms of the disease who harbor large deletions have such correlations been possible. It is therefore likely that genetic modifiers outside the NF1 locus play a role in disease symptoms. Complete gene deletions are associated with severe symptoms of NF1, a large number of neurofibromas, and significantly higher lifetime risk for MPNST, whereas mutations at the 3’ end of the gene correlate with familial spinal neurofibromatosis. Segmental forms of neurofibromatosis may be explained by somatic mosaicism.

In the typical patient, NF1 becomes evident within the first few years of life when café au lait spots develop. These pigmented macular lesions resemble freckles, especially during the early stage when they are small. Typically, they become much larger and darker with age and occur mainly on unexposed surfaces of the body ( Fig. 26.20 ). One of the most characteristic locations for café au lait spots is the axilla ( axillary freckle sign ). Pathologically, the spots are characterized by an increase in melanin pigment in the basal layer of the epidermis. In adults, only lesions larger than 1.5 cm are considered café au lait spots for purposes of diagnosis. Because the number of café au lait spots increases with age, and more than 90% of patients with neurofibromatosis have these lesions, their number serves as a useful guideline when making the diagnosis. Not only do these lesions herald the onset of the disease, but in older patients they often give some indication as to the form and severity of the disease. For instance, patients with few café au lait spots tend to have either (1) late onset of palpable neurofibromas, (2) localization of neurofibromas to one segment of the body, or (3) NF2.

Neurofibromas, the hallmark of the disease, make their appearance during childhood or adolescence after the café au lait spots. The time course varies greatly some tumors emerge at birth, and others appear during late adult life ( Fig. 26.21 ). They may be found in virtually any location and in rare cases may be restricted to one area of the body ( segmental neurofibromatosis ). Unusual symptoms have been related to the presence of these tumors in various organs such as the GI tract. The tumors are usually slowly growing lesions. Acceleration of their growth rate has been noted during pregnancy and at puberty. A sudden increase in the size of one lesion should always suggest malignant change.

In addition to peripheral neurofibromas, patients with NF1 also develop central nervous system (CNS) tumors, including optic nerve glioma, astrocytoma, and a variety of heterotopias. Vestibular schwannoma, the hallmark of NF2, is virtually never encountered in NF1. Unusual bright objects are detected by T2-weighted MRI in the brain in more than 60% of patients with NF1 and are thought to provide some indication of the degree of cognitive dysfunction.

Pigmented hamartomas of the iris ( Lisch nodules ) may also be found. These asymptomatic lesions are not present in normal individuals or in those with NF2 ( Figs. 26.22 and 26.23 ). Although Lisch nodules cannot be correlated with other specific manifestations of NF1, they are helpful for establishing the diagnosis.

Skeletal abnormalities occur in almost 40% of patients with NF1. They include erosive defects secondary to impingement by soft tissue tumors and primary defects, such as scalloping of the vertebra, congenital bowing of long bones with pseudoarthrosis, unilateral orbital malformations, and cystic osteolytic lesions. The intraosseous cystic lesions were previously believed to be skeletal neurofibromas, but most of these lesions have the histologic appearance of nonossifying fibroma or fibrous cortical defect, characterized by fascicles of fibroblasts arranged in short, intersecting fascicles (sometimes in a storiform pattern) and punctuated with occasional giant cells.

Vascular abnormalities, specifically vascular stenoses, secondary to proliferation of intimal cells, are a significant cause of premature death from renovascular hypertension or stroke. Gynecomastia-like changes (pseudogynecomastia) consisting of stromal hyalinization with nerve fibers and fibroblasts, some of which are multinucleated, have been reported in young males with the disease. In addition to these well-recognized signs and symptoms, NF1 is associated with diverse symptoms not clearly referable to the presence of tumors. They include disorders of growth, sexual maturation, and cognition and abnormalities of the lung. Patients with NF1 are also prone to develop nonneural tumors, notably pheochromocytoma, myelogenous leukemia, and multifocal gastrointestinal stromal tumor (GIST).

Variants of NF1

In addition to classic NF1, there appear to be variant forms in which the features are atypical or incomplete. They include (1) segmental NF manifesting as neurofibromas in a segmental distribution caused by somatic mosaicism of NF1 mutations, (2) gastrointestinal NF, (3) familial spinal NF, and (4) familial café au lait spots.

Pathologic Findings

Several types of neurofibroma occur with NF1 and are distinguished on the basis of their gross and microscopic appearance.

Localized Neurofibroma

Localized neurofibroma is the most common type encountered, but it is histologically the least characteristic because identical lesions also occur on a sporadic basis. These tumors are typically located in the dermis and subcutis but may be located in deep soft tissue as well. The tumors are larger than solitary neurofibromas. Large pendulous tumors of the skin were referred to as fibroma molluscum in the early literature.

Histologically, these tumors are no different from solitary neurofibromas and embrace a spectrum from highly cellular to highly myxoid tumors. When malignant transformation occurs, it is usually in deeply situated lesions (see later).

Plexiform Neurofibroma

Plexiform neurofibroma is pathognomonic of NF1, provided that the definition of a plexiform neurofibroma is stringent ( Figs. 26.24 to 26.27 ). Plexiform neurofibromas always develop during early childhood, often before the cutaneous neurofibromas have fully developed. Those plexiform neurofibromas involving an entire extremity give rise to the condition known as elephantiasis neuromatosa, in which the extremity is enlarged ( Fig. 26.28 ). The overlying skin is loose, redundant, and hyperpigmented, and the underlying bone may be hypertrophied, a phenomenon probably related to the increased vascular supply to the limb. Macroscopically, plexiform neurofibromas are large lesions that affect large segments of a nerve, distorting it and contorting it into a “bag of worms” ( Fig. 26.29 ). Smaller lesions, which simply have a plexiform pattern when viewed microscopically rather than macroscopically, should not be interpreted as plexiform neurofibromas for purposes of establishing the diagnosis of NF1.

Microscopically, the lesion consists of a tortuous mass of expanded nerve branches, as seen when cut in various planes of section. In the early stages, the nerves may simply have an increase in the endoneurial matrix material, resulting in a wide separation of the small nerve fascicles ( Fig. 26.30 ). With continued growth, the cells spill out of the nerves into soft tissue, creating a diffuse backdrop of neurofibromatous tissue ( Fig. 26.31 ), so that NF1 lesions can have both plexiform and diffuse areas. Plexiform neurofibromas, like localized neurofibromas, may display nuclear atypia. Because these lesions are at greatest risk to undergo malignant transformation, care should be paid to lesions displaying heightened cellularity and atypia. The sequence of histologic changes and the inherent problems are discussed later. Occasionally, plexiform neurofibromas contain small schwannian nodules resembling a miniature schwannoma such lesions have been described as “hybrid schwannoma-neurofibromas” (see Hybrid Benign Peripheral Nerve Sheath Tumors, later).

Diffuse Neurofibroma

Diffuse neurofibroma is an uncommon but distinctive form that occurs principally in children and young adults. A subset of patients with this lesion also has neurofibromatosis.

Clinically, this tumor is most common in the head and neck region and presents as a plaquelike elevation of the skin. On cut section, the entire subcutis between superficial fascia and dermis is thickened by firm, grayish tissue ( Fig. 26.32 ). As its name implies, this form of neurofibroma is poorly defined and spreads extensively along connective tissue septa and between fat cells. Despite its infiltrative growth, it does not destroy but rather envelops the normal structures that it encompasses, in much the same way as dermatofibrosarcoma protuberans (DFSP) ( Fig. 26.33 ). It differs from the conventional neurofibroma in that it has a uniform matrix of fine fibrillary collagen. The Schwann cells, which lie suspended in the matrix, are usually less elongated than those of conventional neurofibromas and have short fusiform or even round contours. Usually the cellularity is low in diffuse neurofibromas ( Fig. 26.34 ), but occasionally it is high enough to suggest the possibility of a round cell sarcoma ( Fig. 26.35 ). The tumor contains clusters of pseudomeissnerian body–like structures, a characteristic feature of this lesion that serves to distinguish it from the superficial aspect of DFSP ( Fig. 26.39 ). Some diffuse neurofibromas consist of a rather complex arrangement of several mesenchymal elements in addition to the neurofibromatous tissue ( Figs. 26.36 to 26.40 ). These tumors, which seem to be more common in neurofibromatosis, consist of neurofibromatous tissue admixed with mature fat or large ectatic vessels. The latter structures are so striking at times that they eclipse the neural component and can result in the erroneous impression of exuberant granulation tissue. Nuclear palisading may occasionally be present in diffuse neurofibromas. Extremely rarely, diffuse neurofibroma may progress to MPNST.

Pigmented Neurofibroma

About 1% of all neurofibromas contain melanin-bearing pigmented cells. Most occur in patients with NF1 and are of the diffuse type, although some have features of both diffuse and plexiform types ( Fig. 26.41 ). The pigment is not usually appreciated on gross examination and requires histologic examination. The pigmented cells, which are dendritic or epithelioid in shape, are dispersed throughout the tumors but tend to cluster and localize toward the superficial portions of the lesion ( Fig. 26.42 ). They express both S-100 protein and melanin markers, in contrast to the surrounding nonpigmented cells, which express S-100 protein only. Because of the diffuse pattern of growth, these lesions may recur, but metastasis has not been recorded.

These lesions should be distinguished from pigmented forms of DFSP ( Bednar tumor ), a tumor that in the past was sometimes referred to as a storiform pigmented neurofibroma . The uniform fibroblastic cells, repetitive storiform pattern, and lack of S-100 protein immunoreactivity seen in pigmented DFSP usually make this distinction apparent. The distinction between congenital pigmented nevi with neuroid features and pigmented neurofibroma is less clear-cut. The lack of a junctional or superficial nevoid component supports the diagnosis of a pigmented neurofibroma over that of a congenital neuroid nevus.

Malignant Change in Neurofibromas

In a subset of NF1 patients, an MPNST emerges from a preexisting neurofibroma, typically a deep-seated plexiform lesion ( Figs. 26.43 and 26.44 ). The histologic demarcation between a neurofibroma with atypical histologic features and a low-grade MPNST is difficult because, in effect, these lesions represent a histologic continuum (see Figs. 26.45 to 26.48 ). Furthermore, in neurofibromas that have undergone malignant transformation, it is common to see neurofibroma with a range of atypical features adjacent to areas of frank MPNST. To date, no large study has correlated the number and degree of atypical features in neurofibromas with either outcome or molecular alterations. Because progression of neurofibromas to MPNST is associated with additional mutational events (see later), IHC for p16/CDKN2A (lost in MPNST), Ki67 (high in MPNST), p53 (overexpressed in MPNST), EGFR (amplified in MPNST), and H3K27me3 (lost in 50%–60% of MPNSTs) can be of some assistance in this often challenging distinction. However, there is significant overlap in the expression patterns of these proteins in atypical neurofibromatous neoplasms and MPNSTs, and findings with these markers must always be correlated with light microscopy.

A small study with short-term follow-up by Lin et al. suggested that cellularity, atypia, and low levels of mitotic activity were still associated with good outcome others reported similar findings. Some believe the presence of mitotic figures in an otherwise innocuous neurofibroma is insufficient for a diagnosis of malignancy, but mitotic activity and cellularity seem to covary it is unusual to encounter a mitotically active neurofibroma without some increase in cellularity. The following discussion represents a general approach to this problem. In the final analysis, although labels are convenient, borderline neurofibromatous lesions require careful sampling, dialogue with the clinician, and potentially complete removal, depending on the clinical setting. A recent consensus paper by Miettinen et al., proposing the term “atypical neurofibromatous neoplasm of uncertain biologic potential” (ANNUBP) for some of these tumors, discusses many of these difficult issues. Our own approach to these difficult lesions is similar to that advocated in this consensus statement.

The term neurofibroma should be used for conventional neurofibromas, including those with nuclear atypia only ( Fig. 26.45 ). The latter, as an isolated focal or diffuse change, is common in neurofibromas and does not correlate with malignancy. It is thought to be a degenerative phenomenon, akin to the changes that may be seen in “ancient” schwannoma, symplastic leiomyomas, and symplastic glomus tumors. Although some use the term “atypical neurofibroma” for these lesions, we strongly discourage this term because it could be misconstrued as reflecting concern about malignancy.

The term neurofibroma with atypical features (or “atypical neurofibromatous neoplasm of uncertain biologic potential”) is used for neurofibromas that have any combination of cellularity, nuclear atypia, and mitotic activity, but fall short of the minimum criteria for a diagnosis of low-grade MPNST ( Fig. 26.46 ). This category excludes lesions characterized by nuclear atypia only, as described previously. In general, these lesions are recognized first at low-power magnification, which shows areas having greater cellularity and a more pronounced fascicular growth pattern than seen in ordinary neurofibroma. These areas are the best places to then look for cytologic atypia, in particular monotonous, hyperchromatic cells or pleomorphic cells, as well as mitotic activity. Extensive scrutiny of otherwise typical-appearing neurofibromas for scattered mitotic figures is generally counterproductive, in our experience. Miettinen et al. proposed labeling as “ANNUBP” the tumors showing at least two of the following features: (1) cytologic atypia, (2) loss of neurofibroma architecture, (3) high cellularity, and/or (4) mitotic activity of more than 1 figure per 50 high-power fields but less than 3 figures per 10 hpf.

We recommend reserving the diagnosis of “low-grade MPNST arising in neurofibroma” for cases that show generalized nuclear atypia, diffuse cellularity, and low levels of mitotic activity ( Figs. 26.47 and 26.48 ). Nuclear atypia consists of nuclear enlargement and hyperchromatism. Some require that nuclear enlargement should be at least three times the size of a normal Schwann cell nucleus. The recent consensus paper suggested that the term low-grade MPNST be applied to tumors fulfilling criteria for ANNUBP and displaying 3 to 9 mitotic figures per 10 hpf, although it was recognized that this represented a purely empirical approach. It should be recognized that no outcome-based data support these mitotic figure–based cutoffs.


Unlike solitary neurofibromas, those encountered in neurofibromatosis cause significant morbidity. The large number of lesions usually makes surgical therapy impossible. Therefore, surgery has traditionally been reserved for lesions that are large, painful, or located in strategic areas where continued expansion would compromise organ function. Even after attempted complete excision of these lesions, clinical recurrences occasionally develop, a phenomenon related to the poorly defined nature of the tumors. Targeted therapies may therefore prove to be extremely important. Treatment of plexiform neurofibromas with cis -retinoic acid, a maturational agent, and interferon-α, an antiangiogenic factor, have shown growth stabilization in a majority of patients. Some patients have also responded to thalidomide, known to have antiangiogenic properties.

A problem of greater importance is that of malignant transformation. The exact incidence is difficult to determine and has been estimated at 2% to 29% of patients with NF1, but seems dependent on the severity of disease among the population studied. A large follow-up study of a nationwide cohort of 212 Danish patients with neurofibromatosis found nine sarcomas and 16 gliomas but noted the tumors occurred in the proband group (84 patients), who by definition required hospitalization and were probably more severely affected by the disorder. The authors suggest that the natural history of neurofibromatosis may be more accurately reflected by the largest group of patients, relatives of the probands (128 patients) who did not require hospitalization and whose prognosis may have been better than previously thought. Both groups, however, had decreased survival rate after 40 years compared with the general population. A more recent study by Evans et al. documented an 8% to 13% lifetime risk for MPNST, and de Raedt et al. identified an association between large genomic deletions and malignancy in NF1 patients. The latter suggests that certain mutations may be more closely linked to the risk for malignant transformation. In general, patients with NF1 and MPNST have had the disease for many years and present with rapid enlargement or pain in a preexisting neurofibroma. Both symptoms, especially rapid enlargement, should always lead to biopsy. Unfortunately, the prognosis is poor for patients developing an MPNST in this setting (see Chapter 27 ).

With the identification of the NF1 gene in 1990, it has become possible to examine the molecular events underlying tumorigenesis in this disease. Because conventional mice knockout models in which NF1 is completely inactivated (NF1 −/− ) prove lethal in utero, conditional mice knockout models in which Schwann cell–specific NF1 is inactivated have been used. In this system, Zhu et al. have shown that Schwann cell–specific knockout mice (NF1 −/− ) develop Schwann cell hyperplasias but rarely neurofibromas, whereas Schwann cell–specific knockout mice having one mutant and one wild-type allele (NF1 +/− ) readily develop plexiform neurofibromas containing NF1 +/− mast cells. These observations have led to the hypothesis that neurofibromin-deficient Schwann cells (NF1 −/− ) require other haploinsufficient (NF1 +/− ) cells (e.g., mast cells, fibroblasts) in the microenvironment for tumorigenesis. Progression of neurofibromas to MPNST requires additional mutational events involving mitogenic and cell cycle regulatory pathways. Mutations in P53 , INK4 (p16 INK4a and p14 ARF genes), p27 kip1 , and amplification of EGFR have been reported in MPNSTs and suggest a synergistic effect with neurofibromatosis.


Schwannoma is an encapsulated nerve sheath tumor consisting of two components: a highly ordered cellular component (Antoni A area) and a loose myxoid component (Antoni B area). The presence of encapsulation and the two types of Antoni areas plus uniformly intense immunostaining for S-100 protein and SOX10 distinguish schwannoma from neurofibroma.

Clinical Findings

Schwannomas occur at all ages but are most common in persons 20 to 50 years old. They affect the genders in about equal numbers. The tumors have a predilection for the head, neck, and flexor surfaces of the upper and lower extremities. Consequently, the spinal roots and the cervical, sympathetic, vagus, peroneal, and ulnar nerves are most often affected. Deeply situated tumors predominate in the posterior mediastinum and the retroperitoneum. Schwannomas are usually solitary sporadic lesions. In a population-based study of schwannomas, about 90% were sporadic, 3% occurred in patients with NF2, 2% in those with schwannomatosis, and 5% in association with multiple meningiomas in patients with or without NF2. Rarely, schwannomas occur as part of NF1. About 60% of sporadic and NF2-associated schwannomas have inactivating mutations of the NF2 gene. These events are small frameshift mutations that occur throughout the coding sequence and predict a truncated product. Usually these mutations are accompanied by inactivation of the remaining wild-type allele on 22q. In about one-third of tumors, there is a loss of 22q without detectable mutations, and the remaining tumors seem to have no detectable NF2 alteration. Nevertheless, all schwannomas, whether sporadic or syndromic, lack the protein product merlin. This suggests that schwannomas with apparent intact NF2 gene have either undetectable mutations or epigenetic modification of the gene.

Schwannoma is a slowly growing tumor usually present several years before diagnosis. When it involves small nerves, it is freely movable except for a single point of attachment. In large nerves, the tumor is movable except along the long axis of the nerve, where the attachment restricts mobility. Pain and neurologic symptoms are uncommon unless the tumor becomes large. In some cases the patient is vaguely aware that the tumor waxes and wanes in size, a phenomenon that might be related to fluctuations in the amount of cystic change in the lesion. Of particular significance is the posterior mediastinal schwannoma , which often originates from or extends into the vertebral canal. Such lesions, termed dumbbell tumors or hourglass tumors, pose difficult management problems because patients may develop profound neurologic difficulties.

Gross Findings

Because these tumors arise in nerve sheaths, schwannomas are surrounded by a true capsule consisting of the epineurium. Depending on the size of the involved nerve, the appearance of the tumor varies. Tumors of small nerves may resemble neurofibromas because of their fusiform shape, and they often eclipse or obliterate the nerve of origin. In large nerves the tumors present as eccentric masses over which the nerve fibers are splayed.

On cut section these tumors have a pink, white, or yellow appearance and usually measure less than 5 cm ( Figs. 26.49 and 26.50 ). Tumors in the retroperitoneum and mediastinum are considerably larger. As a result, these tumors are more likely to manifest secondary degenerative changes such as cystification and calcification (see later, ancient schwannoma).

Mapping the chromosome 17p tumor suppressor locus

In the late 1980s, our group mapped regions of chromosomal loss in colorectal cancer to identify the locations of tumor suppressor genes. The highest frequency loss involved the short arm of chromosome 17 (17p), which occurred in >75% of colorectal carcinomas ( Reichmann et al., 1981 Muleris et al., 1985 Fearon et al., 1987 Vogelstein et al., 1988). Sporadic colorectal cancers posed a significant challenge compared to hereditary cancer predisposition syndromes like retinoblastoma where small constitutional deletions narrowed down the target area for analysis. To more precisely localize the candidate tumor suppressor, we performed Southern blots with a panel of 20 different polymorphic markers on 17p to evaluate loss of heterozygosity (LOH) in 58 paired samples of colorectal carcinoma and matched normal colorectal tissues. This analysis identified a minimal common region of deletion shared among all tumors in which any LOH was observed. This region encompassed approximately half of 17p ( Baker et al., 1989). With today’s genomic maps, we can estimate that the common region of deletion spanned >12.5 megabase pairs of DNA and contained

577 genes, including 480 protein-coding genes. Relative to today, genomic maps in 1988 were extremely sparse and much of the genome could be considered uncharted territory in terms of the density and identity of genes. Identifying the tumor suppressor gene within this area was a daunting prospect, and we did not consider it likely when we started this project in the mid-80’s that the gene could actually be identified within a time-frame consistent with a pre-doctoral thesis. Remember that at the time (1985), oncogenes were already known but tumor suppressor genes were mythical beasts, predicted to exist but not yet sighted.


Patients with neurofibromatosis type 1 (NF1), one of the most common genetic disease affecting the nervous system, develop multiple neurofibromas that can transform into aggressive sarcomas known as malignant peripheral nerve sheath tumors (MPNSTs). Studies of human tumors and newly developed transgenic mouse models indicate that Schwann cells are the primary neoplastic cell type in neurofibromas and MPNSTs and that development of these peripheral nerve sheath tumors involves mutations of multiple tumor suppressor genes. However, it is widely held that tumor suppressor mutations alone are not sufficient to induce peripheral nerve sheath tumor formation and that dysregulated growth factor signaling cooperates with these mutations to promote neurofibroma and MPNST tumorigenesis. In Part I of this review, we discussed findings demonstrating that a loss of NF1 tumor suppressor gene function in neoplastic Schwann cells is a key early step in neurofibroma formation and that progression from neurofibroma to MPNST is associated with abnormalities of additional tumor suppressor genes, including p53, INK4A, and p27 kip1 . In Part II of this review, we consider evidence that dysregulated signaling by specific growth factors and growth factor receptors promotes the proliferation, migration, and survival of neoplastic Schwann cells in neurofibromas and MPNSTs.

EdCaN - learning resources for nurses

The terms 'tumour' and 'neoplasm' are often used interchangeably to describe an abnormal mass of tissue that results from excessive cell proliferation. The term tumour has its origins in the Latin word tumere, meaning 'to swell' and is used to describe an abnormal mass of tissue with no useful bodily function. Neoplasm comes from the Ancient Greek neo (new) and plasma (formation) and refers to the pathological formation and growth of abnormal tissue. Both of these terms may be used to describe and classify either a benign or a malignant growth. 7

Benign growths

A benign growth does not usually threaten life unless it interferes with vital structures, tissues or organs. Benign growths are generally composed of masses of cells that closely resemble the normal cells composing the tissue in which they are found. Benign tumours perform no useful bodily function and treatment or removal is usually curative. 10, 11

Malignant growths

A malignant growth is composed of cells of atypical structure and function when compared to the healthy cells surrounding them. A malignant tumour, reflecting the Latin origin of the term malignans, meaning to be wicked or to act maliciously, is capable of invading other tissues and, if untreated, usually results in death. Thus, cancer is a malignant disease and the masses of abnormal cells that form a cancer may be termed a malignant tumour or malignant neoplasm. 10, 11

Learning activities

Access a current text and construct a table that compares and contrasts the characteristics of benign and malignant tumours.

Develop an evidence based response for a person affected by benign brain tumour who asks the following two questions:


  1. Garmann

    Yes indeed. It happens.

  2. Stoner

    Perhaps I will refuse))

  3. Mekhi

    Sorry for interfering, there is a suggestion that we should take a different route.

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