What Causes Cancer?
Cancer is caused by a combination of genetic and epigenetic factors. Genetic factors include mutations, both germ line and somatic, and polymorphisms. Mutations substantially change the expression levels, activities, or functions of encoded proteins. Many childhood cancers, and a minority of adult cancers, are caused by germ-line mutations—inherited mutations that are present in the DNA of every cell in the organism. By contrast, most adult cancers are caused by somatic (non-germ-line) mutations—mutations acquired by a somatic cell during development, maturation or, most commonly, adulthood. On the other hand, polymorphisms—minor sequence variations that only subtly change protein expression, activity, or function—rarely cause disease, but can predispose individuals to develop diseases, including cancer. Individuals within a species differ, despite a common genome, largely because most genes exist in multiple forms (polymorphisms) that differ by one or a few nucleotides. Perhaps the best known example is the ApoE4 variant of the ApoE gene, which predisposes individuals to Alzheimer's disease. Polymorphisms that are thought to predispose individuals to developing cancer occur in genes that control cell growth, differentiation, or apoptosis, or enzymes that metabolize carcinogens or anticarcinogens.
Epigenetic factors that cause cancer include reversible changes to DNA, such as DNA methylation or posttranslational modification of DNA-associated proteins, such as histones. Such changes generally alter the compaction of chromatin (DNA plus associated proteins), which can have profound effects on gene expression. In addition, the tissue structure and hormonal milieu in which a potential cancer cell exists can strongly influence whether, and to what extent, it progresses to form a malignant tumor. The influence of tissue structure may be particularly important for the development of late-life cancers.
Cancer-causing mutations. Cancer-causing mutations range from single base changes (point mutations) to gross rearrangements, losses, and/ or amplifications of large regions of chromosomes. The latter mutations generally occur when cancer cells develop genomic instability. What are the targets of cancer-causing mutations? Given the features of cancer cells—abnormal growth, resistance to apoptosis, loss of differentiation, and genomic instability—there are many genes that, when mutated, can contribute to malignant transformation. In general, these genes fall into either of two categories: oncogenes and tumor suppressor genes.
Oncogenes. Oncogenes are mutant forms of normal cellular genes termed proto-oncogenes. Proto-oncogenes generally encode proteins (proto-oncoproteins) that stimulate cell proliferation, regulate apoptosis, or restrain differentiation. In normal cells, the activities of proto-oncoproteins are tightly regulated. Mutations that convert a proto-oncogene into an oncogene often render the encoded protein resistant to normal regulatory constraints, or cause the protein to be overexpressed. Mutations that convert proto-oncogenes to oncogenes generally result in a gain of function ; that is, the mutation confers new or supraphysiological properties to the protein. Such mutations are dominant because only one of the two gene copies need be mutant in order for the mutation to exert its effects.
Proto-oncoproteins include growth factors, growth-factor receptors and their signal transduction proteins, growth-stimulatory transcription factors, and antiapoptotic proteins. Activating mutations range from subtle point mutations to gross chromosome rearrangements that create novel chimeric proteins.
An example of a simple activating point mutation is illustrated by members of the RAS protooncogene family. RAS proteins bind GTP (guanosine triphosphate) in response to growth-factor receptor occupancy, whereupon they transduce a growth-stimulatory signal. Shortly thereafter, the intrinsic GTPase activity of the RAS proteins converts the bound GTP to GDP (guanosine diphosphate), thereby attenuating the growth signal. Oncogenic mutations in RAS tend to be point mutations that abolish GTPase activity, but not GTP binding, thereby causing a constitutively active growth signal. The other end of the spectrum is illustrated by the ABL proto-oncogene, which encodes a protein tyrosine kinase that promotes cell death in response to DNA damage. ABL is converted to an oncogene when a chromosome breakage and rejoining event translocates the ABL gene, which is located on chromosome 9, to the BCR gene on chromosome 22. This translocation produces a novel fusion protein, BCR-ABL, which is a highly active, unregulated protein kinase. In contrast to the normal ABL protein, the BCR-ABL protein inhibits apoptosis after DNA damage, thereby allowing damaged cells to survive and proliferate.
Oncogenic mutations can also simply increase proto-oncogene expression. Two examples are MYC and BCL2, which encode a transcription factor that stimulates cell-cycle progression and a protein that inhibits apoptosis, respectively. Occasionally, a translocation moves these proto-oncogenes to a chromosome region containing the immunoglobin genes. When this occurs in a pre-B lymphocyte, where the immunoglobin genes are highly transcribed, MYC and BCL2 are overexpressed. This, in turn, promotes uncontrolled cell proliferation in the case of MYC, or resistance to cell death in the case of BCL2.
Thus, some mutations cause activation or overexpression of proto-oncogenes, creating oncogenes with supraphysiological or new functions, which in turn promote cell growth or inhibit differentiation or cell death.
Tumor suppressor genes. Tumor suppressors inhibit cell growth, promote differentiation, or stimulate apoptosis. They also suppress genomic instability, allowing cells to sense or repair DNA damage. In contrast to the gain-of-function mutations that activate proto-oncogenes, oncogenic mutations in tumor suppressor genes generally delete or inactivate the gene (loss of function). In most cases, both gene copies must be inactivated before loss-of-function is obvious. Thus, oncogenic mutations in tumor suppressor genes tend to be recessive.
Tumor suppressors include growth inhibitors and their receptors and signal transducers, transcription factors, proapoptotic proteins, and proteins that sense or repair DNA damage. Inactivating mutations are often chromosome aberrations that delete large segments of DNA. However, more subtle mutations (for example, point mutations) can also inactivate tumor suppressors.
The most widely studied, and possibly most important, tumor suppressor genes are RB and TP53, which encode the pRB and p53 proteins. These proteins are at the heart of two major tumor-suppressor pathways, each comprised of many interacting proteins. They are critical for the control of cellular senescence and are mutated in over 80 percent of human cancers.
pRB is a nuclear protein that indirectly controls the transcription of many genes. pRB is phosphorylated by several protein kinases, most prominently cyclin-dependent kinases (CDKs). When underphosphorylated, as it is in nondividing cells, pRB prevents the initiation of DNA synthesis. pRB is progressively phosphorylated by CDKs as cells progress through G1 (the phase of the cell cycle that precedes the period of DNA synthesis (S phase)). Phosphorylated pRB is inactive and cannot prevent cell-cycle progression. Growth factors and inhibitors promote or prevent cell proliferation ultimately by controlling pRB phosphorylation. Many cancer cells have deletions or inactivating mutations in both copies of RB, and thus fail to arrest growth in response to growth-inhibitory signals. Some cancer cells lack pRB mutations, but harbor inactivating mutations in the p16 tumor suppressor or overexpress cyclins D or E; p16 inhibits the CDKs that phosphorylate pRB, while cyclins D and E stimulate these CDKs. Thus, most mammalian cancers harbor mutations in the pRB pathway such that pRB is either physically or functionally inactive.
Most mammalian cancers also harbor mutations in the p53 pathway, whose functions overlap and differ from those of the pRB pathway. p53 is a transcription factor that also halts cell-cycle progression—it is phosphorylated and stabilized in response to DNA damage, whereupon it induces genes that either halt progression into S phase and mitosis, stimulate repair, or induce apoptosis. Among the genes induced by p53 is the CDK inhibitor p21, providing an interaction between the p53 and pRB pathways. p53 plays a pivotal role in damage sensing and repair and is considered a guardian of the genome. Its function is abrogated by deletion (loss of function), but also by point mutations, which alter its properties as a transcription factor (gain of function). Many cancer cells harbor mutations in p53. Such cells fail to properly repair damaged DNA, but also fail to die. Consequently, they develop genomic instability, which accelerates mutation accumulation. Cancer cells that lack mutations in p53 generally have mutations in regulators of p53 expression or function.
Epigenetic factors and the cellular microenvironment. Nonmutational (epigenetic) events can also play a critical role in the development of cancer. Within cells, physiological modification of DNA—such as methylation of cytosine—can strongly influence gene expression. Methylated DNA is generally transcriptionally silent, largely because it is packaged into chromatin that is very compact. Loss of normal methylation can cause inappropriate proto-oncogene expression; conversely, inappropriate methylation can silence tumor suppressor genes.
Chromatin compaction is regulated largely by the presence of, and modifications to, histones and other DNA-binding proteins. These proteins are stripped from the DNA (and must be faithfully replaced) each time a cell undergoes DNA replication or during repair. Errors in replacement, or changes in cell physiology that alter the expression or modification of chromatin-compaction proteins, can also result in inappropriate proto-oncogene expression or silencing of tumor suppressor genes.
Outside the cell, the surrounding milieu or microenvironment can be a critical determinant of whether and how a cell harboring oncogenic mutations expresses itself. It has been known for several decades that tumor cells may develop into a fully malignant tumor, slow-growing and relatively benign tumor, or no tumor at all, depending on the tissue into which it is transplanted. It is now also known that all cells sense their microenvironment through specific receptors, including cell-surface receptors. Some of these receptors bind soluble growth factors and inhibitors, whereas others (integrins) bind extracellular matrix components. In some tumors, these receptors are mutated. Most frequently, however, tumor cells express an altered pattern of receptors and integrins.
Experiments have shown that by manipulating the cellular microenvironment, particularly the extracellular matrix, some tumor cells can be induced to lose their malignant properties, including their ability to form tumors in animals. Conversely, chronic disruption of the cellular microenvironment—for example, by cells that ectopically express a protease that degrades the extracellular matrix—can promote the development of cancer. Even apparently normal tissue contains cells that harbor potentially oncogenic mutations. Such cells are prevented from progressing to more malignant phenotypes by the normal microenvironment, while disruption of the microenvironment allows such cells to express their oncogenic potential. Thus, the microenvironment within a tissue can be a powerful tumor-suppressive mechanism that, in many cases, is dominant over oncogenic mutations.
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