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The protein E2F is a transcription factor that binds to DNA to stimulate the synthesis of proteins necessary for cell division. When E2F is bound to the RB protein, however, it cannot bind to DNA. Thus, when functioning normally, the RB protein prevents a cell from dividing by binding to E2F. When RB is absent or inactivated, that restraint is lost, and E2F is constantly available to trigger cell division.
The p53 gene
The p53 protein was discovered in 1979. It resides in the nucleus, where it regulates cell proliferation and cell death. In particular, it prevents cells with damaged DNA from dividing or, when damage is too great, promotes apoptosis. Cells exposed to mutagens (chemicals or radiation capable of mutating the DNA) need time to repair any genetic damage they sustain so that they do not copy errors into the DNA of their daughter cells. When mutations occur, normal levels of the p53 protein rise, which slows the transition of the cell cycle from the G1 phase to the S phase. That extra time allows DNA repair mechanisms to effectively restore the DNA sequences to normal. The brakes on the cell cycle—high p53 levels—are then removed, and the cell proceeds to divide.
If there is a large amount of genetic damage, p53 triggers a series of biochemical reactions that cause the cell to self-destruct. Total functional inactivation of the p53 gene will cause genetic damage to accumulate in the cell and will also fail to set off apoptosis in severely injured cells.
Both radiation therapy and chemotherapy can kill tumor cells by stimulating apoptosis. Some tumors that have lost p53 function are more resistant to therapy because of the cells’ diminished capacity to trigger cell death. (See Diagnosis and treatment of cancer: Therapeutic strategies.)
Inactivation of the p53 gene occurs through mutation of one allele, and loss of the other accounts for 70 percent of cases of colon carcinoma, 30 to 50 percent of cases of breast cancer, and 50 percent of cases of lung cancer. In two other types of cancer, inactivation of the p53 gene occurs not through mutation and loss of the alleles but through binding of the p53 protein with another protein (called an antagonist) that disables p53 function. One such antagonist, called MDM2, is involved in sarcomas. Other antagonists are the “early proteins” produced by cancer-causing strains of the human papillomavirus (see Cancer-causing agents: Human papillomaviruses).
Other tumor suppressor genes
Other tumor suppressor genes that have been discovered through the study of familial cancers include the BRCA1 and BRCA2 genes, which are associated with about 5 percent of hereditary breast cancers (see BRCA mutation); the APC gene, linked to familial adenomatous polyposis coli (a hereditary form of colorectal cancer that causes thousands of polyps to form in the colon, some of which can become cancerous); the WT1 gene, involved in Wilms tumor of the kidney; the VHL gene, associated with kidney cancer and von Hippel-Lindau disease; and the NF1 and NF2 genes, responsible for certain forms of neurofibromatosis.
Tumor suppressor genes discovered through the study of hereditary cancers also play a role in sporadic cancers. For example, hereditary melanoma is associated with a loss of function of the tumor suppressor gene called MTS1 (from multiple tumor suppressor), which also goes awry in a variety of sporadic tumors. MTS1 codes for a protein called p16. When functioning properly, the p16 protein prevents the cell cycle from progressing from the G1 stage to the S stage through an interaction with the RB protein. In cells in which p16 function is lost, the transition from G1 to S is not slowed. That transition point in the cell cycle seems to be extremely important to cellular health, since about 80 percent of human tumors exhibit a problem there.
DNA repair defects
DNA repair mechanisms are involved in maintaining the integrity of DNA, which often acquires errors during replication. The gene products that oversee the maintenance of DNA integrity help to detect the damage and activate and direct the repair machinery, thereby disabling mutagenic molecules before they permanently damage the DNA. In general, those genes, referred to as the “caretakers of the genome,” behave similarly to tumor suppressor genes. When the cellular mechanisms that repair errors in the DNA are damaged—through acquired or inherited alterations—the rate of genetic mutation increases by several orders of magnitude.
Defects in two mismatch repair genes, called MSH2 and MLH1, underlie one of the most-common syndromes of inherited cancer susceptibility, hereditary nonpolyposis colon cancer. That form of colorectal cancer accounts for 15 to 20 percent of all colon cancer cases. Inherited or acquired alterations in the mismatch repair genes allow mutations—specifically point mutations and changes in the lengths of simple sequence repetitions—to accumulate rapidly (behavior referred to as a mutator phenotype). Since that defect is inherited by all the cells in the body, it is not known why some organs are more susceptible to cancer development than others.
Another type of repair system that can malfunction is one that corrects defects inflicted on DNA by ultraviolet radiation, a major constituent of sunlight (see Cancer-causing agents: Radiation). That kind of radiation damage involves the fusion of two nucleotide bases called pyrimidines to form a “pyrimidine dimer.” Normally, the repair system removes the dimer from the DNA and replaces it with two undamaged nucleotides. Malfunction of the repair pathway, on the other hand, is responsible for two inherited disorders, xeroderma pigmentosum and Cockayne syndrome.
Apoptosis and cancer development
Many cells undergo programmed cell death, or apoptosis, during fetal development. Apoptosis also may occur when a cell becomes damaged or deregulated, as is the case during tumor development and other pathological processes. Thus, when functioning properly, the body can induce apoptosis to rid itself of cancer cells.
Not all cancer cells succumb in that manner, however. Some find ways to escape apoptosis. Two mutations identified in human tumors lead to a loss of programmed cell death. One mutation inactivates the p53 gene, which normally can trigger apoptosis. The second mutation affects a proto-oncogene called BCL-2, which codes for a protein that blocks cell suicide. When mutated, the BCL-2 gene produces excessive amounts of the BCL-2 protein, which prevents the apoptosis program from being activated. Malignant lymphomas that stem from B lymphocytes exhibit this BCL-2 behavior. The alteration of the BCL-2 gene is caused by a chromosomal translocation that keeps the gene in a permanent “on” position. Loss of p53 function protects cells from only certain kinds of suicide, whereas the BCL-2 alteration completely blocks access to apoptosis.
The blocking of apoptosis is thought to be an important mechanism in tumor generation. That mutation also may contribute to the development of tumors that are resistant to radiation and drug therapies, most of which destroy cancer cells by inducing apoptosis in them. If some cells within a tumor are unable to commit suicide, they will survive treatment and proliferate, creating a tumor refractory to therapy of this type. In this way apoptosis-inducing therapies may actually select for cancer cells resistant to apoptosis.
Telomeres and the immortal cell
Immortalization is another way that cells escape death. Normal cells have a limited capacity to replicate, and so they age and die. The processes of aging and dying are regulated in part by telomeres, which, once reduced to a certain size through repeated cell divisions, cause the cell to reach a crisis point. The cell is then prevented from dividing further and dies.
That form of growth control appears to be inactivated by oncogenic expression or tumor suppression activity. In cells undergoing malignant transformation, telomeres do shorten, but, as the crisis point nears, a formerly quiescent enzyme called telomerase becomes activated. This enzyme prevents the telomeres from shortening further and thereby prolongs the life of the cell.
Most malignant tumors—including breast, colon, prostate, and ovarian cancers—exhibit telomerase activity, and the more advanced the cancer, the greater the frequency of detectable telomerase in independent samples. If cell immortality contributes to the growth of most cancers, telomerase would appear to be an attractive target for therapy.
Cancer stem cells
In normal tissues, the numbers of cells are carefully regulated, and the constant replenishment of cells is left to a specialized cell called the tissue stem cell. A property of tissue stem cells is that they divide infrequently, and when they divide, one daughter is a stem cell and the other daughter differentiates and replicates several times, giving rise to differentiated progeny. This division of labor—preserving the replicative potential (stem cell) and carrying out the specific functions of the organ (differentiated cells)—is mimicked in tumors, but in a less-organized fashion.
Cancer stem cells have been unequivocally identified in some tumor systems and are important because if they are not eradicated, no matter how many tumor cells are killed by therapy, the tumor will come back. Whereas the “stemness” of a cell in normal tissues is a stable characteristic, there is evidence that in cancer, stemness is less permanent and can be acquired or shed by proliferative tumor cells.
Invasion and metastasis
Histopathologists long observed that when epithelial cells from a cancer invade surrounding membranes, effecting their escape from the tumor site, they often become elongated or spindly. Molecules known as E-cadherin, which changes cell-to-cell adhesion in epithelium, and N-cadherin, which favors cell migration, have been found to be under expressed and overexpressed in invading cancer cells. In addition, a series of important control circuits that operate at the cellular level during the normal development of the embryo and in wound healing are exploited by tumor cells to implement a program of invasion and distant spread. This so-called “epithelial-mesenchymal transition program” relies on a number of powerful transcription factors, which are stimulated by factors in the tumor cell environment and are capable of regulating the expression of the molecules that drive invasion and metastasis. Nontumor stromal cells (a type of connective tissue cell) can also stimulate the expression of those factors, and they are in part responsible for invasion at the edge of the tumor cell mass, the zone where tumor cells and host stroma interact extensively. In some instances inflammatory cells of the host immune system play a similar role in facilitating invasion.
For metastatic cancer cells to be clinically significant, they must grow and cause symptoms at the site that they have colonized. Single tumor cells from a distant tumor can be found in a patient’s bone marrow, yet they may never proliferate and cause problems. To grow as a distant deposit, cells need to find suitable “soil” conditions in the target organ, such as the presence of growth-stimulating signals. In contrast, deprivation of nutrients or growth suppression by immune cells may keep colonies of tumor cells dormant for significant lengths of time.
