Also called tumorigenesis, carcinogenesis is the molecular process by which cancer develops.
The development of cancer is a complicated process in which a large number of factors interact to disrupt normal cell growth and division. Cancer can be caused by a number of internal factors such as heredity, immunology, and hormones as well as external factors such as chemicals, viruses, diet, and radiation. Although attention is often focused on environmental chemicals (such as asbestos and coal tar) as a cause of cancer, only 5% of cancers can be linked to chemical exposure. We now know that the chief causes of cancer are lifestyle factors such as diet, cigarette smoke, alcohol, and sun exposure. In fact, dietary factors are associated with 35% of all human cancers and cigarette smoke for another 30%.
Whatever the cause of cancer, its development is a multi-stage process involving damage to the genetic material of cells (deoxyribonucleic acid, or DNA). This damage occurs in genes regulating normal cell growth and division. Because several stages or several mutations are required for cancer to develop, there is usually a long latent period before cancer appears.
Agents that cause cancer (carcinogens) can be classified as genotoxic or nongenotoxic (also referred to as epigenetic). Genotoxins cause irreversible genetic damage or mutations by binding to DNA. Genotoxins include chemical agents like N-methyl-N-nitrosourea (MNU) or non-chemical agents such as ultraviolet light and ionizing radiation. After the carcinogen enters the body, the body makes an attempt to eliminate it through a process called biotransformation (a series of reactions in which the chemical structure of a compound is altered). The purpose of these reactions is to make the carcinogen more water-soluble so that it can be removed from the body. But these reactions can also convert a less toxic carcinogen into a more toxic one. Certain viruses can also act as carcinogens by interacting with DNA.
Nongenotoxins do not directly affect DNA but act in other ways to promote growth. These include hormones and some organic (carbon-based) compounds.
Stages of carcinogenesis
Cancer develops through four definable stages: initiation, promotion, progression and malignant conversion. These stages may progress over many years. The first stage, initiation, involves a change in the genetic makeup of a cell. This may occur randomly or when a carcinogen interacts with DNA causing damage. This initial damage rarely results in cancer because the cell has in place many mechanisms to repair damaged DNA. However, if repair does not occur and the damage to DNA is in the location of a gene that regulates cell growth and proliferation, DNA repair, or a function of the immune system, then the cell is more prone to becoming cancerous.
During promotion, the mutated cell is stimulated to grow and divide faster and becomes a population of cells. Eventually a benign tumor becomes evident. In human cancers, hormones, cigarette smoke, or bile acids are substances that are involved in promotion. This stage is usually reversible as evidenced by the fact that lung damage can often be reversed after smoking stops.
The progression phase is less well understood. During progression, there is further growth and expansion of the tumor cells over normal cells. The genetic material of the tumor is more fragile and prone to additional mutations. These mutations occur in genes that regulate growth and cell function such as oncogenes, tumor suppressor genes, and DNA mismatch-repair genes. These changes contribute to tumor growth until conversion occurs, when the growing tumor becomes malignant and possibly metastatic. Many of these genetic changes have been identified in the development of colon cancer and thus it has become a model for studying multi-stage carcinogenesis.
Normal cell proliferation is controlled by growth factors and cytokines (mediating proteins) that act on the cell membrane, triggering a cascade of biochemical signals (a process called signal transduction). These signals control, among others, the genes that regulate cell growth and division. Oncogenes are altered forms of normal cellular genes called proto-oncogenes that are involved in this cascade of events. They may mutate spontaneously, through interaction with viruses, or by chemical or physical means.
When a proto-oncogene is altered to become an oncogene, the pathway of cell growth and proliferation become altered. This may lead to the abnormal growth of cells (neoplastic transformation). More than 100 oncogenes have been identified. An example of an oncogene is the K-ras gene that is mutated in colon cancer cells.
Genes are the means by which a cell produces proteins, each of which have a very specific role. A mutated gene can cause overproduction of a protein, underproduction of a protein, or alteration of a protein that may be unable to carry out its purpose. Oncogenes typically produce more of their protein product when mutated, while tumor suppressor genes typically produce less of their protein product when mutated.
Tumor suppressor genes
Both the activation of oncogenes and the inactivation of tumor suppressor genes appear to be necessary for cancer to occur. Tumor suppressor genes are typically associated with cell growth and differentiation and cell suicide (apoptosis). More than a dozen tumor suppressor genes have been identified. Proteins produced by tumor suppressor genes typically inhibit a cell from reproducing during times when growth is inappropriate such as during DNA repair; they are considered the "brakes" of the cell.
Mutations that inactivate the tumor suppressor gene p53 are the most common mutations seen in human cancers, accounting for about 50%. Carcinomas of the breast, colon, stomach, bladder and testis; melanoma ; and soft tissue sarcoma all are linked to p53 mutations. The p53 protein is found in the nucleus of the cell and regulates cell functions such as cell growth, DNA repair, and apoptosis. The most notable role for p53 is to halt cell growth to allow the cell time to repair damaged DNA. If p53 is mutated, it loses this function, apoptosis does not occur, and unregulated cell growth results. In Li-Fraumeni syndrome a mutation of the p53 gene is inherited. This puts the individual at a high risk for a number of cancers such as early onset breast carcinoma, childhood sarcomas , and other tumors. Other tumor suppressor genes include the retinoblastoma gene and the DCC gene that is mutated in colon cancer.
DNA mismatch-repair genes
This more recently discovered class of cancer susceptibility genes is associated with the genetic instability of cancer cells that allows for multiple mutations to occur. This instability hastens the course of cancer. The normal function of these genes is to repair damage to the DNA. Mutations in DNA mismatch-repair genes are most notable in hereditary non-polyposis colorectal cancer (HNPCC).
Apoptosis, also called cell suicide, refers to the death of a damaged cell. It is not random but occurs in cells with damaged DNA. When a cell becomes mutated and does not repair itself, it can be sacrificed to prevent that mutation from being passed on to the next generation of cells. Inhibition of apoptosis can be an essential step in carcinogenesis. Two genes involved in apoptosis are the tumor suppressor gene p53 and the bcl-2 proto-oncogene.
Colon cancer has become a model for studying multi-stage carcinogenesis. Four distinct sequential mutations have been described in the development of colon cancer. These are mutations of the APC (adenomatous polyposis coli), K-ras, DCC (deleted in colon cancer), and p53 genes. With each mutation, progressive changes are seen in the colonic epithelium (the cells on the internal surface of the colon).
Mutation of APC typically occurs early and is sometimes inherited. Mutations in APC lead to dysplasia (abnormalities in adult cells) or polyp formation (usually benign growths on the surface of mucous membranes). These polyps can remain dormant for many decades. When one cell in this polyp develops a second mutation, in the K-ras gene, it grows at a faster rate resulting in a larger tumor or intermediate adenoma . Subsequent mutations in DCC and p53 lead to late adenoma and finally carcinoma.
These mutations result in both the overexpression of oncogenes and the deletion of anti-oncogenes, the combination of which results in cancer. This is, however, just a model and not all genes are altered in all cases of colon cancer; additional mutations are likely. Individuals with the hereditary predisposition to colon cancer known as familial adenomatous polyposis (FAP) typically have inherited mutations of the APC gene, the first step of colon cancer. Only 15% of colon cancer cases are due to hereditary factors, however, with 85% due to sporadic mutations.
Kinzler, Kenneth W., and Bert Vogelstein. "Colorectal Tumors."In The Genetic Basis of Human Cancer. Volgelstein, B., and K. Kinzler, eds. New York: McGraw-Hill, 1998.
McKinnell, Robert G., Ralph E. Parchment, Alan O. Perantoni, and G. Barry Pierce. The Biological Basis of Cancer. New York: Cambridge University Press, 1998.
Templeton, Dennis J., and Robert A. Weinberg. "Principles of Cancer Biology" In Clinical Oncology. Murphy, G., W. Lawrence, and R. Lenhard, eds. Atlanta: The American Cancer Society, 1995.
Weinberg, Robert A. One Renegade Cell: How Cancer Begins. New York: Basic Books, 1998.
Weinstein, I. Bernard. "Disorders in Cell Circuitry During Multistage Carcinogenesis: The Role of Homeostasis." Carcinogenesis 21 (2000): 857-64.
Mellors, Robert C. "Etiology of Cancer: Carcinogenesis." Neoplasia Weill Medical College of Cornell University. July 1999. 27 June 2001 <http://edcenter.med.cornell.edu/CUMC_PathNotes/Neoplasia/Neoplasia_04.html>.
Cindy L. A. Jones, Ph.D.
—A process of cell death performed by a damaged cell.
—A change to a more mature phenotype or appearance.
—A abnormal appearance of cells caused by cancer.
—A cancerous or invasive tumor.
—A tumor with the ability to break off and grow in a distant location.
—A change in the genetic code that can be inherited or acquired.
—A gene involved in normal cell growth that when mutated can lead to unregulated cell growth or cancer.
—Reproduction of a cell. It differs from growth in that it is a change in number rather than size.
Tumor suppressor gene
—A gene involved in slowing down cell growth so that if inactivated allows growth to progress without control.
"Carcinogenesis." Gale Encyclopedia of Cancer. . Encyclopedia.com. (August 19, 2017). http://www.encyclopedia.com/medicine/encyclopedias-almanacs-transcripts-and-maps/carcinogenesis
"Carcinogenesis." Gale Encyclopedia of Cancer. . Retrieved August 19, 2017 from Encyclopedia.com: http://www.encyclopedia.com/medicine/encyclopedias-almanacs-transcripts-and-maps/carcinogenesis
Although there are many different forms of cancer, the basic multistage process by which various tumors develop is similar for all cancers. This process is called carcinogenesis. Carcinogenesis begins when carcinogens (cancer-causing substances) damage the DNA in a cell (e.g., a genetic mutation) and/or cause changes in other cell components or cell activities that can predispose them to cancer. These altered cells look normal, but they grow faster than the surrounding normal cells—a stage called hyperplasia. In time (often years), another mutation occurs: the mutated cells grow excessively and appear abnormal in shape and orientation. This stage is called dysplasia, and the cells are called premalignant lesions. After more time, a third mutation occurs. The cells now become more abnormal in rate of growth and appearance, and a tumor develops. If the tumor does not break through the boundaries between tissues, it is "in situ" cancer. In situ tumors can develop further mutations, break through tissue boundaries, and invade surrounding tissues; at this stage, they become malignant tumors that can send cells throughout the body to establish new tumors (metastasis). During the development of a malignant tumor, DNA damage occurs as an accumulation of mutations in as many as six or more genes.
Two types of genes, proto-oncogenes and tumor suppressor genes, play important roles in tumor development. A proto-oncogene codes for proteins that stimulate cell division. When a mutation occurs in a proto-oncogene, it can become a carcinogenic oncogene that causes these proteins to be overactive, resulting in the formation of large numbers of cells. In contrast, tumor suppressor genes code for proteins that inhibit cell division. When a mutation occurs in a tumor suppressor gene, the inhibitory proteins may not function properly, and inappropriate growth of cells remains unchecked. Mutated forms of other genes, such as those that help regulate the invasion of surrounding tissues and metastasis, also may contribute to tumor development. Some people inherit certain cancer-related gene mutations, and these people may be at risk for early development of cancer.
Carcinogenesis can be initiated by chemical agents (e.g., tobacco smoke, pesticides, certain metals); physical agents (e.g., ionizing radiation, ultraviolet [UV] radiation, mineral fibers such as asbestos); and viruses (e.g., Epstein-Barr virus, hepatitis B and C viruses, human papillomavirus). In addition to cancer-causing agents from the environment, highly reactive oxygen-containing molecules that can damage DNA are formed continuously in the body (e.g., endogenously) as a result of biochemical reactions. Other endogenous mutagenic mechanisms also exist. The relative importance of environmental agents versus endogenous molecules in causing the genetic mutations that contribute to carcinogenesis is a matter of debate.
Once inside the body, most chemical carcinogens are metabolized; that is, they are transformed in some way by the body's physical and chemical processes. Chemical carcinogens can be converted into highly reactive compounds that can damage DNA and other cell components, or they can be detoxified and thus prevented from doing cellular damage. The metabolic fate of chemical carcinogens is linked to the activities of particular enzymes—protein molecules in the body that help chemical reactions occur but are not themselves changed in the reactions. The activities of these enzymes can differ among individuals because of the occurrence of genetic polymorphisms (different forms of the genes that code for the enzymes) and the differing activities can either increase or decrease a person's susceptibility to environmental carcinogens. For instance, a higher risk of lung cancer is associated with certain polymorphic forms of the gene CYP1A1, which codes for an enzyme that acts on chemical carcinogens in tobacco smoke. Thus, even though genetic factors (e.g., polymorphisms, inherited mutations) and environmental factors (e.g., carcinogens, radiation, viruses) can make independent contributions to carcinogenesis, these factors also can interact to influence cancer development. A clear example of a gene-environment interaction is observed in people who have inherited a defective copy of the gene that directs the repair of DNA damaged by UV radiation; these people are more susceptible to sunlight-initiated skin cancers than people without the defective gene.
Hundreds of diverse chemicals have been tested to determine whether they are carcinogens, including air pollutants (e.g., gasoline vapors, carbon tetrachloride), water pollutants (e.g., chlorination byproducts), industrial materials (e.g., asbestos, polychlorinated biphenyls), pesticides (e.g., malathion, lindane), herbicides (e.g., chlorophenoxy compounds), pharmaceuticals (e.g., adriamycin, chloramphenicol), food additives (e.g., butylated hydroxytoluene [BHT], food coloring agents), and naturally occurring compounds in foods (e.g., aflatoxins, saffrole). Data for approximately 1,300 compounds tested in animal experiments can be found in the Carcinogenic Potency Database (http://potency.berkeley.edu/app14.html). It is difficult, however, to predict human cancer risk resulting from low-dose exposures based on information from animal experiments that use extremely high doses of chemicals; thus, the value of animal experiments for assessing human risk is still being debated.
(see also: Behavioral Determinants; Cancer; Carcinogen; Environmental Determinants of Health; Genes; Genetics and Health; Medical Genetics )
Holland, J. F.; Bast, R. C., Jr.; Morton, D. L.; Frei, E., III; Kule, D. W.; and Weichselbaum, R. R., eds. (1997). Cancer Medicine, 4th edition, Vol. 1. Baltimore: Williams & Wilkins.
Schottenfeld, D., and Fraumeni, J. F., Jr., eds. (1996). Cancer Epidemiology and Prevention, 2nd edition. New York: Oxford University Press.
"What You Need to Know about Cancer" (1996). Scientific American 275 (Spec. Issue, September).
"Carcinogenesis." Encyclopedia of Public Health. . Encyclopedia.com. (August 19, 2017). http://www.encyclopedia.com/education/encyclopedias-almanacs-transcripts-and-maps/carcinogenesis
"Carcinogenesis." Encyclopedia of Public Health. . Retrieved August 19, 2017 from Encyclopedia.com: http://www.encyclopedia.com/education/encyclopedias-almanacs-transcripts-and-maps/carcinogenesis
"carcinogenesis." A Dictionary of Nursing. . Encyclopedia.com. (August 19, 2017). http://www.encyclopedia.com/caregiving/dictionaries-thesauruses-pictures-and-press-releases/carcinogenesis
"carcinogenesis." A Dictionary of Nursing. . Retrieved August 19, 2017 from Encyclopedia.com: http://www.encyclopedia.com/caregiving/dictionaries-thesauruses-pictures-and-press-releases/carcinogenesis