Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abnormal cell division. Cell division is a physiological process that occurs in almost all tissues and under a variety of circumstances. Normally the balance between proliferation and programmed cell death, in the form of apoptosis, is maintained to ensure the integrity of tissues and organs. According to the prevailing accepted theory of carcinogenesis, the somatic mutation theory, mutations in DNA and epimutations that lead to cancer disrupt these orderly processes by disrupting the programming regulating the processes, upsetting the normal balance between proliferation and cell death. This results in uncontrolled cell division and the evolution of those cells by natural selection in the body. Only certain mutations lead to cancer whereas the majority of mutations do not.
Variants of inherited genes may predispose individuals to cancer. In addition, environmental factors such as carcinogens and radiation cause mutations that may contribute to the development of cancer. Finally random mistakes in normal DNA replication may result in cancer causing mutations. A series of several mutations to certain classes of genes is usually required before a normal cell will transform into a cancer cell. On average, for example, 15 "driver mutations" and 60 "passenger" mutations are found in colon cancers. Mutations in genes that regulate cell division, apoptosis (cell death), and DNA repair may result in uncontrolled cell proliferation and cancer.
Cancer is fundamentally a disease of regulation of tissue growth. In order for a normal cell to transform into a cancer cell, genes that regulate cell growth and differentiation must be altered. Genetic and epigenetic changes can occur at many levels, from gain or loss of entire chromosomes, to a mutation affecting a single DNA nucleotide, or to silencing or activating a microRNA that controls expression of 100 to 500 genes. There are two broad categories of genes that are affected by these changes. Oncogenes may be normal genes that are expressed at inappropriately high levels, or altered genes that have novel properties. In either case, expression of these genes promotes the malignant phenotype of cancer cells. Tumor suppressor genes are genes that inhibit cell division, survival, or other properties of cancer cells. Tumor suppressor genes are often disabled by cancer-promoting genetic changes. Finally Oncovirinae, viruses that contain an oncogene, are categorized as oncogenic because they trigger the growth of tumorous tissues in the host. This process is also referred to as viral transformation.
- 1 Causes
- 2 Cancer cell biology
- 3 Mechanisms
- 4 References
- 5 Further reading
Genetic and epigenetic
There is a diverse classification scheme for the various genomic changes that may contribute to the generation of cancer cells. Many of these changes are mutations, or changes in the nucleotide sequence of genomic DNA. There are also many epigenetic changes that alter whether genes are expressed or not expressed. Aneuploidy, the presence of an abnormal number of chromosomes, is one genomic change that is not a mutation, and may involve either gain or loss of one or more chromosomes through errors in mitosis. Large-scale mutations involve the deletion or gain of a portion of a chromosome. Genomic amplification occurs when a cell gains many copies (often 20 or more) of a small chromosomal region, usually containing one or more oncogenes and adjacent genetic material. Translocation occurs when two separate chromosomal regions become abnormally fused, often at a characteristic location. A well-known example of this is the Philadelphia chromosome, or translocation of chromosomes 9 and 22, which occurs in chronic myelogenous leukemia, and results in production of the BCR-abl fusion protein, an oncogenic tyrosine kinase. Small-scale mutations include point mutations, deletions, and insertions, which may occur in the promoter of a gene and affect its expression, or may occur in the gene's coding sequence and alter the function or stability of its protein product. Disruption of a single gene may also result from integration of genomic material from a DNA virus or retrovirus, and such an event may also result in the expression of viral oncogenes in the affected cell and its descendants.
DNA damage is considered to be the primary cause of cancer. More than 60,000 new naturally occurring DNA damages arise, on average, per human cell, per day, due to endogenous cellular processes (see article DNA damage (naturally occurring)).
Additional DNA damages can arise from exposure to exogenous agents. As one example of an exogenous carcinogeneic agent, tobacco smoke causes increased DNA damage, and these DNA damages likely cause the increase of lung cancer due to smoking. In other examples, UV light from solar radiation causes DNA damage that is important in melanoma, helicobacter pylori infection produces high levels of reactive oxygen species that damage DNA and contributes to gastric cancer, and the Aspergillus metabolite, aflatoxin, is a DNA damaging agent that is causative in liver cancer.
DNA damages can also be caused by endogenous (naturally occurring) agents. Macrophages and neutrophils in an inflamed colonic epithelium are the source of reactive oxygen species causing the DNA damages that initiate colonic tumorigenesis, and bile acids, at high levels in the colons of humans eating a high fat diet, also cause DNA damage and contribute to colon cancer.
Such exogenous and endogenous sources of DNA damage are indicated in the boxes at the top of the figure in this section. The central role of DNA damage in progression to cancer is indicated at the second level of the figure. The central elements of DNA damage, epigenetic alterations and deficient DNA repair in progression to cancer are shown in red.
A deficiency in DNA repair would cause more DNA damages to accumulate, and increase the risk for cancer. For example, individuals with an inherited impairment in any of 34 DNA repair genes (see article DNA repair-deficiency disorder) are at increased risk of cancer with some defects causing up to 100% lifetime chance of cancer (e.g. p53 mutations). Such germ line mutations are shown in a box at the left of the figure, with an indication of their contribution to DNA repair deficiency. However, such germline mutations (which cause highly penetrant cancer syndromes) are the cause of only about 1 percent of cancers.
The majority of cancers are called non-hereditary or "sporadic cancers". About 30% of sporadic cancers do have some hereditary component that is currently undefined, while the majority, or 70% of sporadic cancers, have no hereditary component.
In sporadic cancers, a deficiency in DNA repair is occasionally due to a mutation in a DNA repair gene, but much more frequently reduced or absent expression of DNA repair genes is due to epigenetic alterations that reduce or silence gene expression. This is indicated in the figure at the 3rd level from the top. For example, for 113 colorectal cancers examined in sequence, only four had a missense mutation in the DNA repair gene MGMT, while the majority had reduced MGMT expression due to methylation of the MGMT promoter region (an epigenetic alteration).
When expression of DNA repair genes is reduced, this causes a DNA repair deficiency. This is shown in the figure at the 4th level from the top. With a DNA repair deficiency, more DNA damages remain in cells at a higher than usual level (5th level from the top in figure), and these excess damages cause increased frequencies of mutation and/or epimutation (6th level from top of figure). Experimentally, mutation rates increase substantially in cells defective in DNA mismatch repair or in Homologous recombinational repair (HRR). Chromosomal rearrangements and aneuploidy also increase in HRR defective cells During repair of DNA double strand breaks, or repair of other DNA damages, incompletely cleared sites of repair can cause epigenetic gene silencing.
The somatic mutations and epigenetic alterations caused by DNA damages and deficiencies in DNA repair accumulate in field defects. Field defects are normal appearing tissues with multiple alterations (discussed in the section below), and are common precursors to development of the disordered and improperly proliferating clone of tissue in a cancer. Such field defects (second level from bottom of figure) may have multiple mutations and epigenetic alterations.
It is impossible to determine the initial cause for most specific cancers. In a few cases, only one cause exists; for example, the virus HHV-8 causes all Kaposi's sarcomas. However, with the help of cancer epidemiology techniques and information, it is possible to produce an estimate of a likely cause in many more situations. For example, lung cancer has several causes, including tobacco use and radon gas. Men who currently smoke tobacco develop lung cancer at a rate 14 times that of men who have never smoked tobacco, so the chance of lung cancer in a current smoker being caused by smoking is about 93%; there is a 7% chance that the smoker's lung cancer was caused by radon gas or some other, non-tobacco cause. These statistical correlations have made it possible for researchers to infer that certain substances or behaviors are carcinogenic. Tobacco smoke causes increased exogenous DNA damage, and these DNA damages are the likely cause of lung cancer due to smoking. Among the more than 5,000 compounds in tobacco smoke, the genotoxic DNA damaging agents that occur both at the highest concentrations and which have the strongest mutagenic effects are acrolein, formaldehyde, acrylonitrile, 1,3-butadiene, acetaldehyde, ethylene oxide and isoprene.
Using molecular biological techniques, it is possible to characterize the mutations, epimutations or chromosomal aberrations within a tumor, and rapid progress is being made in the field of predicting prognosis based on the spectrum of mutations in some cases. For example, up to half of all tumors have a defective p53 gene. This mutation is associated with poor prognosis, since those tumor cells are less likely to go into apoptosis or programmed cell death when damaged by therapy. Telomerase mutations remove additional barriers, extending the number of times a cell can divide. Other mutations enable the tumor to grow new blood vessels to provide more nutrients, or to metastasize, spreading to other parts of the body. However, once a cancer is formed it continues to evolve and to produce sub clones. For example, a renal cancer, sampled in 9 areas, had 40 ubiquitous mutations, 59 mutations shared by some, but not all regions, and 29 "private" mutations only present in one region.
The cells in which all these DNA alterations accumulate are difficult to trace, but two recent lines of evidence suggest that normal stem cells may be the cells of origin in cancers. First, there exists a highly positive correlation (Spearman’s rho = 0.81; P < 3.5 × 10−8) between the risk of developing cancer in a tissue and the number of normal stem cell divisions taking place in that same tissue. The correlation applied to 31 cancer types and extended across five orders of magnitude. This correlation means that if the normal stem cells from a tissue divide once, the cancer risk in that tissue is approximately 1X. If they divide 1,000 times, the cancer risk is 1,000X. And if the normal stem cells from a tissue divide 100,000 times, the cancer risk in that tissue is approximately 100,000X. This strongly suggests that the main reason we have cancer is that our normal stem cells divide, which implies that cancer originates in normal stem cells. Second, statistics show that most human cancers are diagnosed in aged people. A possible explanation is that cancers occur because cells accumulate damage through time. DNA is the only cellular component that can accumulate damage over the entire course of a life, and stem cells are the only cells that can transmit DNA from the zygote to cells late in life. Other cells cannot keep DNA from the beginning of life until a possible cancer occurs. This implies that most cancers arise from normal stem cells.
Contribution of field defects
The term "field cancerization" was first used in 1953 to describe an area or "field" of epithelium that has been preconditioned by (at that time) largely unknown processes so as to predispose it towards development of cancer. Since then, the terms "field cancerization" and "field defect" have been used to describe pre-malignant tissue in which new cancers are likely to arise.
Field defects have been identified in association with cancers and are important in progression to cancer. However, it was pointed out by Rubin that "the vast majority of studies in cancer research has been done on well-defined tumors in vivo, or on discrete neoplastic foci in vitro. Yet there is evidence that more than 80% of the somatic mutations found in mutator phenotype human colorectal tumors occur before the onset of terminal clonal expansion…" More than half of somatic mutations identified in tumors occurred in a pre-neoplastic phase (in a field defect), during growth of apparently normal cells. It would also be expected that many of the epigenetic alterations present in tumors may have occurred in pre-neoplastic field defects.
In the colon, a field defect probably arises by natural selection of a mutant or epigenetically altered cell among the stem cells at the base of one of the intestinal crypts on the inside surface of the colon. A mutant or epigenetically altered stem cell may replace the other nearby stem cells by natural selection. This may cause a patch of abnormal tissue to arise. The figure in this section includes a photo of a freshly resected and lengthwise-opened segment of the colon showing a colon cancer and four polyps. Below the photo there is a schematic diagram of how a large patch of mutant or epigenetically altered cells may have formed, shown by the large area in yellow in the diagram. Within this first large patch in the diagram (a large clone of cells), a second such mutation or epigenetic alteration may occur so that a given stem cell acquires an advantage compared to other stem cells within the patch, and this altered stem cell may expand clonally forming a secondary patch, or sub-clone, within the original patch. This is indicated in the diagram by four smaller patches of different colors within the large yellow original area. Within these new patches (sub-clones), the process may be repeated multiple times, indicated by the still smaller patches within the four secondary patches (with still different colors in the diagram) which clonally expand, until stem cells arise that generate either small polyps or else a malignant neoplasm (cancer). In the photo, an apparent field defect in this segment of a colon has generated four polyps (labeled with the size of the polyps, 6mm, 5mm, and two of 3mm, and a cancer about 3 cm across in its longest dimension). These neoplasms are also indicated (in the diagram below the photo) by 4 small tan circles (polyps) and a larger red area (cancer). The cancer in the photo occurred in the cecal area of the colon, where the colon joins the small intestine (labeled) and where the appendix occurs (labeled). The fat in the photo is external to the outer wall of the colon. In the segment of colon shown here, the colon was cut open lengthwise to expose the inner surface of the colon and to display the cancer and polyps occurring within the inner epithelial lining of the colon.
If the general process by which sporadic colon cancers arise is the formation of a pre-neoplastic clone that spreads by natural selection, followed by formation of internal sub-clones within the initial clone, and sub-sub-clones inside those, then colon cancers generally should be associated with, and be preceded by, fields of increasing abnormality reflecting the succession of premalignant events. The most extensive region of abnormality (the outermost yellow irregular area in the diagram) would reflect the earliest event in formation of a malignant neoplasm.
In experimental evaluation of specific DNA repair deficiencies in cancers, many specific DNA repair deficiencies were also shown to occur in the field defects surrounding those cancers. The Table, below, gives examples for which the DNA repair deficiency in a cancer was shown to be caused by an epigenetic alteration, and the somewhat lower frequencies with which the same epigenetically caused DNA repair deficiency was found in the surrounding field defect.
|Cancer||Gene||Frequency in Cancer||Frequency in Field Defect||Reference|
|Head and Neck||MGMT||54%||38%|||
|Head and Neck||MLH1||33%||25%|||
|Head and Neck||MLH1||31%||20%|||
Some of the small polyps in the field defect shown in the photo of the opened colon segment may be relatively benign neoplasms. Of polyps less than 10mm in size, found during colonoscopy and followed with repeat colonoscopies for 3 years, 25% were unchanged in size, 35% regressed or shrank in size while 40% grew in size.
Cancers are known to exhibit genome instability or a mutator phenotype. The protein-coding DNA within the nucleus is about 1.5% of the total genomic DNA. Within this protein-coding DNA (called the exome), an average cancer of the breast or colon can have about 60 to 70 protein altering mutations, of which about 3 or 4 may be "driver" mutations, and the remaining ones may be "passenger" mutations. However, the average number of DNA sequence mutations in the entire genome (including non-protein-coding regions) within a breast cancer tissue sample is about 20,000. In an average melanoma tissue sample (where melanomas have a higher exome mutation frequency) the total number of DNA sequence mutations is about 80,000. These high frequencies of mutations in the total nucleotide sequences within cancers suggest that often an early alteration in the field defect giving rise to a cancer (e.g. yellow area in the diagram in the preceding section) is a deficiency in DNA repair. Large field defects surrounding colon cancers (extending to about 10 cm on each side of a cancer) are found to frequently have epigenetic defects in 2 or 3 DNA repair proteins (ERCC1, XPF and/or PMS2) in the entire area of the field defect. When expression of DNA repair genes is reduced, DNA damages accumulate in cells at a higher than normal level, and these excess damages cause increased frequencies of mutation and/or epimutation. Mutation rates strongly increase in cells defective in DNA mismatch repair or in homologous recombinational repair (HRR). A deficiency in DNA repair, itself, can allow DNA damages to accumulate, and error-prone translesion synthesis past some of those damages may give rise to mutations. In addition, faulty repair of these accumulated DNA damages may give rise to epimutations. These new mutations and/or epimutations may provide a proliferative advantage, generating a field defect. Although the mutations/epimutations in DNA repair genes do not, themselves, confer a selective advantage, they may be carried along as passengers in cells when the cell acquires an additional mutation/epimutation that does provide a proliferative advantage.
There are a number of theories of carcinogenesis and cancer treatment that fall outside the mainstream of scientific opinion, due to lack of scientific rationale, logic, or evidence base. These theories may be used to justify various alternative cancer treatments. They should be distinguished from those theories of carcinogenesis that have a logical basis within mainstream cancer biology, and from which conventionally testable hypotheses can be made.
Several alternative theories of carcinogenesis, however, are based on scientific evidence and are increasingly being acknowledged. Some researchers believe that cancer may be caused by aneuploidy (numerical and structural abnormalities in chromosomes) rather than by mutations or epimutations. Cancer has also been considered as a metabolic disease in which the cellular metabolism of oxygen is diverted from the pathway that generates energy (oxidative phosphorylation) to the pathway that generates reactive oxygen species (figure). This causes an energy switch from oxidative phosphorylation to aerobic glycolysis (Warburg's hypothesis) and the accumulation of reactive oxygen species leading to oxidative stress (oxidative stress theory of cancer). All these theories of carcinogenesis may be complementary rather than contradictory. Aberrant DNA methylation patterns – hypermethylation and hypomethylation compared to normal tissue – have been associated with a large number of human malignancies. (See DNA methylation in cancer)
A number of authors have questioned the assumption that cancers result from sequential random mutations as oversimplistic, suggesting instead that cancer results from a failure of the body to inhibit an innate, programmed proliferative tendency. A related theory developed by astrobiologists suggests that cancer is an atavism, an evolutionary throwback to an earlier form of multicellular life. The genes responsible for uncontrolled cell growth and cooperation between cancer cells are very similar to those that enabled the first multicellular life forms to group together and flourish. These genes still exist within the genome of more complex metazoans, such as humans, although more recently evolved genes keep them in check. When the newer controlling genes fail for whatever reason, the cell can revert to its more primitive programming and reproduce out of control. The theory is an alternative to the notion that cancers begin with rogue cells that undergo evolution within the body. Instead they possess a fixed number of primitive genes that are progressively activated, giving them finite variability. Another evolutionary theory puts the roots of cancer back to the origin of the eukarote (nucleated) cell by massive horizontal gene transfer, when the genomes of infecting viruses were cleaved (and thereby attenuated) by the host, but their fragments integrated into the host genome as immune protection. Cancer now originates when a rare somatic mutation recombines such fragments into a functional driver of cell proliferation.
Cancer cell biology
Often, the multiple genetic changes that result in cancer may take many years to accumulate. During this time, the biological behavior of the pre-malignant cells slowly change from the properties of normal cells to cancer-like properties. Pre-malignant tissue can have a distinctive appearance under the microscope. Among the distinguishing traits are an increased number of dividing cells, variation in nuclear size and shape, variation in cell size and shape, loss of specialized cell features, and loss of normal tissue organization. Dysplasia is an abnormal type of excessive cell proliferation characterized by loss of normal tissue arrangement and cell structure in pre-malignant cells. These early neoplastic changes must be distinguished from hyperplasia, a reversible increase in cell division caused by an external stimulus, such as a hormonal imbalance or chronic irritation.
The most severe cases of dysplasia are referred to as "carcinoma in situ." In Latin, the term "in situ" means "in place", so carcinoma in situ refers to an uncontrolled growth of cells that remains in the original location and has not shown invasion into other tissues. Nevertheless, carcinoma in situ may develop into an invasive malignancy and is usually removed surgically, if possible.
Just like a population of animals undergoes evolution, an unchecked population of cells also can undergo evolution. This undesirable process is called somatic evolution, and is how cancer arises and becomes more malignant.
Most changes in cellular metabolism that allow cells to grow in a disorderly fashion lead to cell death. However once cancer begins, cancer cells undergo a process of natural selection: the few cells with new genetic changes that enhance their survival or reproduction continue to multiply, and soon come to dominate the growing tumor, as cells with less favorable genetic change are out-competed. This is exactly how pathogens such as MRSA can become antibiotic-resistant (or how HIV can become drug-resistant), and the same reason why crop blights and pests can become pesticide-resistant. This evolution is why cancer recurrences will have cells that have acquired cancer-drug resistance (or in some cases, resistance to radiation from radiotherapy).
Biological properties of cancer cells
- Acquisition of self-sufficiency in growth signals, leading to unchecked growth.
- Loss of sensitivity to anti-growth signals, also leading to unchecked growth.
- Loss of capacity for apoptosis, in order to allow growth despite genetic errors and external anti-growth signals.
- Loss of capacity for senescence, leading to limitless replicative potential (immortality)
- Acquisition of sustained angiogenesis, allowing the tumor to grow beyond the limitations of passive nutrient diffusion.
- Acquisition of ability to invade neighbouring tissues, the defining property of invasive carcinoma.
- Acquisition of ability to build metastases at distant sites, the classical property of malignant tumors (carcinomas or others).
The completion of these multiple steps would be a very rare event without :
- Loss of capacity to repair genetic errors, leading to an increased mutation rate (genomic instability), thus accelerating all the other changes.
These biological changes are classical in carcinomas; other malignant tumors may not need to achieve them all. For example, tissue invasion and displacement to distant sites are normal properties of leukocytes; these steps are not needed in the development of leukemia. The different steps do not necessarily represent individual mutations. For example, inactivation of a single gene, coding for the p53 protein, will cause genomic instability, evasion of apoptosis and increased angiogenesis. Not all the cancer cells are dividing. Rather, a subset of the cells in a tumor, called cancer stem cells, replicate themselves and generate differentiated cells.
Cancer as a defect in cell interactions
Normally, once a tissue is injured or infected, damaged cells elicit inflammation, by stimulating specific patterns of enzyme activity and cytokine gene expression on surrounding cells. Discrete clusters of molecules are secreted, which act as mediators, inducing the activity of subsequent cascades of biochemical changes. Each cytokine binds to specific receptors on various cell types, and each cell type responds differently by altering the activity of intracellular signal transduction pathways, depending on the receptors that the cell expresses and the signaling molecules present inside the cell. Collectively, this reprogramming process induces a stepwise change in cell phenotypes, which will ultimately lead to restoration of tissue function and toward regaining essential structural integrity. A tissue can thereby heal, depending on the productive communication between the cells present at the site of damage, and the immune system. Key factor in healing is the regulation of cytokine gene expression, which enables complementary groups of cells to respond to inflammatory mediators in a manner that gradually produces essential changes in tissue physiology. Cancer cells have either permanent (genetic) or reversible (epigenetic) changes on their genome, which partly inhibit their communication with surrounding cells and with the immune system. Cancer cells do not communicate with their tissue microenvironment in a manner that protects tissue integrity; instead, the movement and the survival of cancer cells become possible in locations where they can impair tissue function. Cancer cells survive by rewiring signal pathways that normally protect the tissue from the immune system.
One example for rewiring of tissue function in cancer is the activity of transcription factor NF-κB. NF-κB activates the expression of numerous genes that are involved in the transition between inflammation and regeneration, which encode cytokines, adhesion factors, and other molecules that can change cell fate. This reprogramming of cellular phenotypes normally allows the development of a fully functional intact tissue. NF-κB activity is tightly controlled by multiple proteins, which collectively ensure that only discrete clusters of genes are induced by NF-κB in a given cell and at a given time. This tight regulation of signal exchange between cells, protects the tissue from excessive inflammation, and ensures that different cell types would gradually acquire complementary functions, and specific positions. Failure of this mutual regulation between genetic reprogramming and cell interactions allows cancer cells to give rise to metastasis. Cancer cells respond aberrantly to cytokines, and activate signal cascades that can protect them from the immune system.
The role of iodine in marine fishes (rich in iodine) and freshwater fishes (iodine-deficient) is not completely understood, but it has been reported that freshwater fishes are more susceptible to infectious and, in particular, neoplastic and atherosclerotic diseases, of marine fishes. Marine elasmobranch fishes such as sharks, stingrays etc. are much less affected by cancer than freshwater fishes, and therefore have stimulated medical research to better understand carcinogenesis so it can be useful in other animals and especially in humans.
In order for cells to start dividing uncontrollably, genes that regulate cell growth must be dysregulated. Proto-oncogenes are genes that promote cell growth and mitosis, whereas tumor suppressor genes discourage cell growth, or temporarily halt cell division to carry out DNA repair. Typically, a series of several mutations to these genes is required before a normal cell transforms into a cancer cell. This concept is sometimes termed "oncoevolution." Mutations to these genes provide the signals for tumor cells to start dividing uncontrollably. But the uncontrolled cell division that characterizes cancer also requires that the dividing cell duplicates all its cellular components to create two daughter cells. The activation of anaerobic glycolysis (the Warburg effect), which is not necessarily induced by mutations in proto-oncogenes and tumor suppressor genes, provides most of the building blocks required to duplicate the cellular components of a dividing cell and, therefore, is also essential for carcinogenesis.
Oncogenes promote cell growth through a variety of ways. Many can produce hormones, a "chemical messenger" between cells that encourage mitosis, the effect of which depends on the signal transduction of the receiving tissue or cells. In other words, when a hormone receptor on a recipient cell is stimulated, the signal is conducted from the surface of the cell to the cell nucleus to affect some change in gene transcription regulation at the nuclear level. Some oncogenes are part of the signal transduction system itself, or the signal receptors in cells and tissues themselves, thus controlling the sensitivity to such hormones. Oncogenes often produce mitogens, or are involved in transcription of DNA in protein synthesis, which creates the proteins and enzymes responsible for producing the products and biochemicals cells use and interact with.
Mutations in proto-oncogenes, which are the normally quiescent counterparts of oncogenes, can modify their expression and function, increasing the amount or activity of the product protein. When this happens, the proto-oncogenes become oncogenes, and this transition upsets the normal balance of cell cycle regulation in the cell, making uncontrolled growth possible. The chance of cancer cannot be reduced by removing proto-oncogenes from the genome, even if this were possible, as they are critical for growth, repair and homeostasis of the organism. It is only when they become mutated that the signals for growth become excessive.
One of the first oncogenes to be defined in cancer research is the ras oncogene. Mutations in the Ras family of proto-oncogenes (comprising H-Ras, N-Ras and K-Ras) are very common, being found in 20% to 30% of all human tumours. Ras was originally identified in the Harvey sarcoma virus genome, and researchers were surprised that not only is this gene present in the human genome but also, when ligated to a stimulating control element, it could induce cancers in cell line cultures.
Proto-oncogenes promote cell growth in a variety of ways. Many can produce hormones, "chemical messengers" between cells that encourage mitosis, the effect of which depends on the signal transduction of the receiving tissue or cells. Some are responsible for the signal transduction system and signal receptors in cells and tissues themselves, thus controlling the sensitivity to such hormones. They often produce mitogens, or are involved in transcription of DNA in protein synthesis, which create the proteins and enzymes is responsible for producing the products and biochemicals cells use and interact with.
Mutations in proto-oncogenes can modify their expression and function, increasing the amount or activity of the product protein. When this happens, they become oncogenes, and, thus, cells have a higher chance to divide excessively and uncontrollably. The chance of cancer cannot be reduced by removing proto-oncogenes from the genome, as they are critical for growth, repair and homeostasis of the body. It is only when they become mutated that the signals for growth become excessive. It is important to note that a gene possessing a growth-promoting role may increase carcinogenic potential of a cell, under the condition that all necessary cellular mechanisms that permit growth are activated. This condition includes also the inactivation of specific tumor suppressor genes (see below). If the condition is not fulfilled, the cell may cease to grow and can proceed to die. This makes knowledge of the stage and type of cancer cell that grows under the control of a given oncogene crucial for the development of treatment strategies.
Tumor suppressor genes
Tumor suppressor genes code for anti-proliferation signals and proteins that suppress mitosis and cell growth. Generally, tumor suppressors are transcription factors that are activated by cellular stress or DNA damage. Often DNA damage will cause the presence of free-floating genetic material as well as other signs, and will trigger enzymes and pathways that lead to the activation of tumor suppressor genes. The functions of such genes is to arrest the progression of the cell cycle in order to carry out DNA repair, preventing mutations from being passed on to daughter cells. The p53 protein, one of the most important studied tumor suppressor genes, is a transcription factor activated by many cellular stressors including hypoxia and ultraviolet radiation damage.
Despite nearly half of all cancers possibly involving alterations in p53, its tumor suppressor function is poorly understood. p53 clearly has two functions: one a nuclear role as a transcription factor, and the other a cytoplasmic role in regulating the cell cycle, cell division, and apoptosis.
However, a mutation can damage the tumor suppressor gene itself, or the signal pathway that activates it, "switching it off". The invariable consequence of this is that DNA repair is hindered or inhibited: DNA damage accumulates without repair, inevitably leading to cancer.
Mutations of tumor suppressor genes that occur in germline cells are passed along to offspring, and increase the likelihood for cancer diagnoses in subsequent generations. Members of these families have increased incidence and decreased latency of multiple tumors. The tumor types are typical for each type of tumor suppressor gene mutation, with some mutations causing particular cancers, and other mutations causing others. The mode of inheritance of mutant tumor suppressors is that an affected member inherits a defective copy from one parent, and a normal copy from the other. For instance, individuals who inherit one mutant p53 allele (and are therefore heterozygous for mutated p53) can develop melanomas and pancreatic cancer, known as Li-Fraumeni syndrome. Other inherited tumor suppressor gene syndromes include Rb mutations, linked to retinoblastoma, and APC gene mutations, linked to adenopolyposis colon cancer. Adenopolyposis colon cancer is associated with thousands of polyps in colon while young, leading to colon cancer at a relatively early age. Finally, inherited mutations in BRCA1 and BRCA2 lead to early onset of breast cancer.
Development of cancer was proposed in 1971 to depend on at least two mutational events. In what became known as the Knudson two-hit hypothesis, an inherited, germ-line mutation in a tumor suppressor gene would cause cancer only if another mutation event occurred later in the organism's life, inactivating the other allele of that tumor suppressor gene.
Usually, oncogenes are dominant, as they contain gain-of-function mutations, while mutated tumor suppressors are recessive, as they contain loss-of-function mutations. Each cell has two copies of the same gene, one from each parent, and under most cases gain of function mutations in just one copy of a particular proto-oncogene is enough to make that gene a true oncogene. On the other hand, loss of function mutations need to happen in both copies of a tumor suppressor gene to render that gene completely non-functional. However, cases exist in which one mutated copy of a tumor suppressor gene can render the other, wild-type copy non-functional. This phenomenon is called the dominant negative effect and is observed in many p53 mutations.
Knudson's two hit model has recently been challenged by several investigators. Inactivation of one allele of some tumor suppressor genes is sufficient to cause tumors. This phenomenon is called haploinsufficiency and has been demonstrated by a number of experimental approaches. Tumors caused by haploinsufficiency usually have a later age of onset when compared with those by a two hit process.
In general, mutations in both types of genes are required for cancer to occur. For example, a mutation limited to one oncogene would be suppressed by normal mitosis control and tumor suppressor genes, first hypothesised by the Knudson hypothesis. A mutation to only one tumor suppressor gene would not cause cancer either, due to the presence of many "backup" genes that duplicate its functions. It is only when enough proto-oncogenes have mutated into oncogenes, and enough tumor suppressor genes deactivated or damaged, that the signals for cell growth overwhelm the signals to regulate it, that cell growth quickly spirals out of control. Often, because these genes regulate the processes that prevent most damage to genes themselves, the rate of mutations increases as one gets older, because DNA damage forms a feedback loop.
Mutation of tumor suppressor genes that are passed on to the next generation of not merely cells, but their offspring, can cause increased likelihoods for cancers to be inherited. Members within these families have increased incidence and decreased latency of multiple tumors. The mode of inheritance of mutant tumor suppressors is that affected member inherits a defective copy from one parent, and a normal copy from another. Because mutations in tumor suppressors act in a recessive manner (note, however, there are exceptions), the loss of the normal copy creates the cancer phenotype. For instance, individuals that are heterozygous for p53 mutations are often victims of Li-Fraumeni syndrome, and that are heterozygous for Rb mutations develop retinoblastoma. In similar fashion, mutations in the adenomatous polyposis coli gene are linked to adenopolyposis colon cancer, with thousands of polyps in the colon while young, whereas mutations in BRCA1 and BRCA2 lead to early onset of breast cancer.
A new idea announced in 2011 is an extreme version of multiple mutations, called chromothripsis by its proponents. This idea, affecting only 2–3% of cases of cancer, although up to 25% of bone cancers, involves the catastrophic shattering of a chromosome into tens or hundreds of pieces and then being patched back together incorrectly. This shattering probably takes place when the chromosomes are compacted during normal cell division, but the trigger for the shattering is unknown. Under this model, cancer arises as the result of a single, isolated event, rather than the slow accumulation of multiple mutations.
Many mutagens are also carcinogens, but some carcinogens are not mutagens. Examples of carcinogens that are not mutagens include alcohol and estrogen. These are thought to promote cancers through their stimulating effect on the rate of cell mitosis. Faster rates of mitosis increasingly leave fewer opportunities for repair enzymes to repair damaged DNA during DNA replication, increasing the likelihood of a genetic mistake. A mistake made during mitosis can lead to the daughter cells' receiving the wrong number of chromosomes, which leads to aneuploidy and may lead to cancer.
Role of infections
Furthermore, many cancers originate from a viral infection; this is especially true in animals such as birds, but less so in humans. 12% of human cancers can be attributed to a viral infection. The mode of virally induced tumors can be divided into two, acutely transforming or slowly transforming. In acutely transforming viruses, the viral particles carry a gene that encodes for an overactive oncogene called viral-oncogene (v-onc), and the infected cell is transformed as soon as v-onc is expressed. In contrast, in slowly transforming viruses, the virus genome is inserted, especially as viral genome insertion is obligatory part of retroviruses, near a proto-oncogene in the host genome. The viral promoter or other transcription regulation elements, in turn, cause over-expression of that proto-oncogene, which, in turn, induces uncontrolled cellular proliferation. Because viral genome insertion is not specific to proto-oncogenes and the chance of insertion near that proto-oncogene is low, slowly transforming viruses have very long tumor latency compared to acutely transforming virus, which already carries the viral-oncogene.
Viruses that are known to cause cancer such as HPV (cervical cancer), Hepatitis B (liver cancer), and EBV (a type of lymphoma), are all DNA viruses. It is thought that when the virus infects a cell, it inserts a part of its own DNA near the cell growth genes, causing cell division. The group of changed cells that are formed from the first cell dividing all have the same viral DNA near the cell growth genes. The group of changed cells are now special because one of the normal controls on growth has been lost.
Depending on their location, cells can be damaged through radiation from sunshine, chemicals from cigarette smoke, and inflammation from bacterial infection or other viruses. Each cell has a chance of damage, a step on a path toward cancer. Cells often die if they are damaged, through failure of a vital process or the immune system; however, sometimes damage will knock out a single cancer gene. In an old person, there are thousands, tens of thousands or hundreds of thousands of knocked-out cells. The chance that any one would form a cancer is very low.
When the damage occurs in any area of changed cells, something different occurs. Each of the cells has the potential for growth. The changed cells will divide quicker when the area is damaged by physical, chemical, or viral agents. A vicious circle has been set up: Damaging the area will cause the changed cells to divide, causing a greater likelihood that they will suffer knock-outs.
This model of carcinogenesis is popular because it explains why cancers grow. It would be expected that cells that are damaged through radiation would die or at least be worse off because they have fewer genes working; viruses increase the number of genes working.
One concern is that we may end up with thousands of vaccines to prevent every virus that can change our cells. Viruses can have different effects on different parts of the body. It may be possible to prevent a number of different cancers by immunizing against one viral agent. It is likely that HPV, for instance, has a role in cancers of the mucous membranes of the mouth.
Certain parasitic worms are known to be carcinogenic. These include:
- Clonorchis sinensis (the organism causing Clonorchiasis) and Opisthorchis viverrini (causing Opisthorchiasis) are associated with cholangiocarcinoma.
- Schistosoma species (the organisms causing Schistosomiasis) is associated with bladder cancer.
Epigenetics is the study of the regulation of gene expression through chemical, non-mutational changes in DNA structure. The theory of epigenetics in cancer pathogenesis is that non-mutational changes to DNA can lead to alterations in gene expression. Normally, oncogenes are silent, for example, because of DNA methylation. Loss of that methylation can induce the aberrant expression of oncogenes, leading to cancer pathogenesis. Known mechanisms of epigenetic change include DNA methylation, and methylation or acetylation of histone proteins bound to chromosomal DNA at specific locations. Classes of medications, known as HDAC inhibitors and DNA methyltransferase inhibitors, can re-regulate the epigenetic signaling in the cancer cell.
Epimutations include methylations or demethylations of the CpG islands of the promoter regions of genes, which result in repression or de-repression, respectively of gene expression. Epimutations can also occur by acetylation, methylation, phosphorylation or other alterations to histones, creating a histone code that represses or activates gene expression, and such histone epimutations can be important epigenetic factors in cancer. In addition, carcinogenic epimutation can occur through alterations of chromosome architecture caused by proteins such as HMGA2. A further source of epimutation is due to increased or decreased expression of microRNAs (miRNAs). For example, extra expression of miR-137 can cause downregulation of expression of 491 genes, and miR-137 is epigenetically silenced in 32% of colorectal cancers>
Cancer stem cells
A new way of looking at carcinogenesis comes from integrating the ideas of developmental biology into oncology. The cancer stem cell hypothesis proposes that the different kinds of cells in a heterogeneous tumor arise from a single cell, termed Cancer Stem Cell. Cancer stem cells may arise from transformation of adult stem cells or differentiated cells within a body. These cells persist as a subcomponent of the tumor and retain key stem cell properties. They give rise to a variety of cells, are capable of self-renewal and homeostatic control. Furthermore, the relapse of cancer and the emergence of metastasis are also attributed to these cells. The cancer stem cell hypothesis does not contradict earlier concepts of carcinogenesis. The cancer stem cell hypothesis has been a proposed mechanism that contributes to tumour heterogeneity.
While genetic and epigenetic alterations in tumor suppressor genes and oncogenes change the behavior of cells, those alterations, in the end, result in cancer through their effects on the population of neoplastic cells and their microenvironment. Mutant cells in neoplasms compete for space and resources. Thus, a clone with a mutation in a tumor suppressor gene or oncogene will expand only in a neoplasm if that mutation gives the clone a competitive advantage over the other clones and normal cells in its microenvironment. Thus, the process of carcinogenesis is formally a process of Darwinian evolution, known as somatic or clonal evolution. Furthermore, in light of the Darwinistic mechanisms of carcinogenesis, it has been theorized that the various forms of cancer can be categorized as pubertarial and gerontological. Anthropological research is currently being conducted on cancer as a natural evolutionary process through which natural selection destroys environmentally inferior phenotypes while supporting others. According to this theory, cancer comes in two separate types: from birth to the end of puberty (approximately age 20) teleologically inclined toward supportive group dynamics, and from mid-life to death (approximately age 40+) teleologically inclined away from overpopulative group dynamics.
- Tomasetti C, Li L, Vogelstein B (23 March 2017). "Stem cell divisions, somatic mutations, cancer etiology, and cancer prevention". Science. 355 (6331): 1330–1334. doi:10.1126/science.aaf9011.
- Wood LD, Parsons DW, Jones S, Lin J, Sjöblom T, Leary RJ, et al. (November 2007). "The genomic landscapes of human breast and colorectal cancers". Science. 318 (5853): 1108–13. doi:10.1126/science.1145720. PMID 17932254.
- Knudson AG (November 2001). "Two genetic hits (more or less) to cancer". Nature Reviews. Cancer. 1 (2): 157–62. doi:10.1038/35101031. PMID 11905807.
- Fearon ER, Vogelstein B (June 1990). "A genetic model for colorectal tumorigenesis". Cell. 61 (5): 759–67. doi:10.1016/0092-8674(90)90186-I. PMID 2188735.
- Croce CM (January 2008). "Oncogenes and cancer". The New England Journal of Medicine. 358 (5): 502–11. doi:10.1056/NEJMra072367. PMID 18234754.
- Lim LP, Lau NC, Garrett-Engele P, Grimson A, Schelter JM, Castle J, Bartel DP, Linsley PS, Johnson JM (February 2005). "Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs". Nature. 433 (7027): 769–73. doi:10.1038/nature03315. PMID 15685193.
- Balaguer F, Link A, Lozano JJ, Cuatrecasas M, Nagasaka T, Boland CR, Goel A (August 2010). "Epigenetic silencing of miR-137 is an early event in colorectal carcinogenesis". Cancer Research. 70 (16): 6609–18. doi:10.1158/0008-5472.CAN-10-0622. PMC . PMID 20682795.
- Bernstein C, Prasad AR, Nfonsam V, Bernstein H. (2013). DNA Damage, DNA Repair and Cancer, New Research Directions in DNA Repair, Prof. Clark Chen (Ed.), ISBN 978-953-51-1114-6, InTech, http://www.intechopen.com/books/new-research-directions-in-dna-repair/dna-damage-dna-repair-and-cancer
- Kastan MB (April 2008). "DNA damage responses: mechanisms and roles in human disease: 2007 G.H.A. Clowes Memorial Award Lecture". Molecular Cancer Research. 6 (4): 517–24. doi:10.1158/1541-7786.MCR-08-0020. PMID 18403632.
- Cunningham FH, Fiebelkorn S, Johnson M, Meredith C (November 2011). "A novel application of the Margin of Exposure approach: segregation of tobacco smoke toxicants". Food and Chemical Toxicology. 49 (11): 2921–33. doi:10.1016/j.fct.2011.07.019. PMID 21802474.
- Kanavy HE, Gerstenblith MR (December 2011). "Ultraviolet radiation and melanoma". Seminars in Cutaneous Medicine and Surgery. 30 (4): 222–8. doi:10.1016/j.sder.2011.08.003. PMID 22123420.
- Handa O, Naito Y, Yoshikawa T (2011). "Redox biology and gastric carcinogenesis: the role of Helicobacter pylori". Redox Report. 16 (1): 1–7. doi:10.1179/174329211X12968219310756. PMID 21605492.
- Smela ME, Hamm ML, Henderson PT, Harris CM, Harris TM, Essigmann JM (May 2002). "The aflatoxin B(1) formamidopyrimidine adduct plays a major role in causing the types of mutations observed in human hepatocellular carcinoma". Proceedings of the National Academy of Sciences of the United States of America. 99 (10): 6655–60. doi:10.1073/pnas.102167699. PMC . PMID 12011430.
- Katsurano M, Niwa T, Yasui Y, Shigematsu Y, Yamashita S, Takeshima H, Lee MS, Kim YJ, Tanaka T, Ushijima T (January 2012). "Early-stage formation of an epigenetic field defect in a mouse colitis model, and non-essential roles of T- and B-cells in DNA methylation induction". Oncogene. 31 (3): 342–51. doi:10.1038/onc.2011.241. PMID 21685942.
- Bernstein C, Holubec H, Bhattacharyya AK, Nguyen H, Payne CM, Zaitlin B, Bernstein H (August 2011). "Carcinogenicity of deoxycholate, a secondary bile acid". Archives of Toxicology. 85 (8): 863–71. doi:10.1007/s00204-011-0648-7. PMC . PMID 21267546.
- Malkin D (April 2011). "Li-fraumeni syndrome". Genes & Cancer. 2 (4): 475–84. doi:10.1177/1947601911413466. PMC . PMID 21779515.
- Fearon ER (November 1997). "Human cancer syndromes: clues to the origin and nature of cancer". Science. 278 (5340): 1043–50. doi:10.1126/science.278.5340.1043. PMID 9353177.
- Lichtenstein P, Holm NV, Verkasalo PK, Iliadou A, Kaprio J, Koskenvuo M, Pukkala E, Skytthe A, Hemminki K (July 2000). "Environmental and heritable factors in the causation of cancer--analyses of cohorts of twins from Sweden, Denmark, and Finland". The New England Journal of Medicine. 343 (2): 78–85. doi:10.1056/NEJM200007133430201. PMID 10891514.
- Halford S, Rowan A, Sawyer E, Talbot I, Tomlinson I (June 2005). "O(6)-methylguanine methyltransferase in colorectal cancers: detection of mutations, loss of expression, and weak association with G:C>A:T transitions". Gut. 54 (6): 797–802. doi:10.1136/gut.2004.059535. PMC . PMID 15888787.
- Narayanan L, Fritzell JA, Baker SM, Liskay RM, Glazer PM (April 1997). "Elevated levels of mutation in multiple tissues of mice deficient in the DNA mismatch repair gene Pms2". Proceedings of the National Academy of Sciences of the United States of America. 94 (7): 3122–7. doi:10.1073/pnas.94.7.3122. PMC . PMID 9096356.
- Hegan DC, Narayanan L, Jirik FR, Edelmann W, Liskay RM, Glazer PM (December 2006). "Differing patterns of genetic instability in mice deficient in the mismatch repair genes Pms2, Mlh1, Msh2, Msh3 and Msh6". Carcinogenesis. 27 (12): 2402–8. doi:10.1093/carcin/bgl079. PMC . PMID 16728433.
- Tutt AN, van Oostrom CT, Ross GM, van Steeg H, Ashworth A (March 2002). "Disruption of Brca2 increases the spontaneous mutation rate in vivo: synergism with ionizing radiation". EMBO Reports. 3 (3): 255–60. doi:10.1093/embo-reports/kvf037. PMC . PMID 11850397.
- German J (March 1969). "Bloom's syndrome. I. Genetical and clinical observations in the first twenty-seven patients". American Journal of Human Genetics. 21 (2): 196–227. PMC . PMID 5770175.
- O'Hagan HM, Mohammad HP, Baylin SB (August 2008). Lee JT, ed. "Double strand breaks can initiate gene silencing and SIRT1-dependent onset of DNA methylation in an exogenous promoter CpG island". PLoS Genetics. 4 (8): e1000155. doi:10.1371/journal.pgen.1000155. PMC . PMID 18704159.
- Cuozzo C, Porcellini A, Angrisano T, Morano A, Lee B, Di Pardo A, Messina S, Iuliano R, Fusco A, Santillo MR, Muller MT, Chiariotti L, Gottesman ME, Avvedimento EV (July 2007). "DNA damage, homology-directed repair, and DNA methylation". PLoS Genetics. 3 (7): e110. doi:10.1371/journal.pgen.0030110. PMC . PMID 17616978.
- Villeneuve PJ, Mao Y (November 1994). "Lifetime probability of developing lung cancer, by smoking status, Canada". Canadian Journal of Public Health = Revue Canadienne De Sante Publique. 85 (6): 385–8. PMID 7895211.
- Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, et al. (March 2012). "Intratumor heterogeneity and branched evolution revealed by multiregion sequencing". The New England Journal of Medicine. 366 (10): 883–92. doi:10.1056/NEJMoa1113205. PMC . PMID 22397650.
- López-Lázaro M (August 2015). "Stem cell division theory of cancer". Cell Cycle. 14 (16): 2547–8. doi:10.1080/15384101.2015.1062330. PMC . PMID 26090957.
- López-Lázaro M (May 2015). "The migration ability of stem cells can explain the existence of cancer of unknown primary site. Rethinking metastasis". Oncoscience. 2 (5): 467–75. doi:10.18632/oncoscience.159. PMC . PMID 26097879.
- Tomasetti C, Vogelstein B (January 2015). "Cancer etiology. Variation in cancer risk among tissues can be explained by the number of stem cell divisions". Science. 347 (6217): 78–81. doi:10.1126/science.1260825. PMC . PMID 25554788.
- Slaughter DP, Southwick HW, Smejkal W (September 1953). "Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin". Cancer. 6 (5): 963–8. doi:10.1002/1097-0142(195309)6:5<963::AID-CNCR2820060515>3.0.CO;2-Q. PMID 13094644.
- Bernstein C, Bernstein H, Payne CM, Dvorak K, Garewal H (February 2008). "Field defects in progression to gastrointestinal tract cancers". review. Cancer Letters. 260 (1–2): 1–10. doi:10.1016/j.canlet.2007.11.027. PMC . PMID 18164807.
- Nguyen H, Loustaunau C, Facista A, Ramsey L, Hassounah N, Taylor H, Krouse R, Payne CM, Tsikitis VL, Goldschmid S, Banerjee B, Perini RF, Bernstein C (2010). "Deficient Pms2, ERCC1, Ku86, CcOI in field defects during progression to colon cancer". Journal of Visualized Experiments: JoVE (41): 1931. doi:10.3791/1931. PMC . PMID 20689513.
- Rubin H (March 2011). "Fields and field cancerization: the preneoplastic origins of cancer: asymptomatic hyperplastic fields are precursors of neoplasia, and their progression to tumors can be tracked by saturation density in culture". BioEssays. 33 (3): 224–31. doi:10.1002/bies.201000067. PMID 21254148.
- Tsao JL, Yatabe Y, Salovaara R, Järvinen HJ, Mecklin JP, Aaltonen LA, Tavaré S, Shibata D (February 2000). "Genetic reconstruction of individual colorectal tumor histories". Proceedings of the National Academy of Sciences of the United States of America. 97 (3): 1236–41. doi:10.1073/pnas.97.3.1236. PMC . PMID 10655514.
- Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA, Kinzler KW (March 2013). "Cancer genome landscapes". review. Science. 339 (6127): 1546–58. doi:10.1126/science.1235122. PMC . PMID 23539594.
- Shen L, Kondo Y, Rosner GL, Xiao L, Hernandez NS, Vilaythong J, Houlihan PS, Krouse RS, Prasad AR, Einspahr JG, Buckmeier J, Alberts DS, Hamilton SR, Issa JP (September 2005). "MGMT promoter methylation and field defect in sporadic colorectal cancer". Journal of the National Cancer Institute. 97 (18): 1330–8. doi:10.1093/jnci/dji275. PMID 16174854.
- Lee KH, Lee JS, Nam JH, Choi C, Lee MC, Park CS, Juhng SW, Lee JH (October 2011). "Promoter methylation status of hMLH1, hMSH2, and MGMT genes in colorectal cancer associated with adenoma-carcinoma sequence". Langenbeck's Archives of Surgery. 396 (7): 1017–26. doi:10.1007/s00423-011-0812-9. PMID 21706233.
- Svrcek M, Buhard O, Colas C, Coulet F, Dumont S, Massaoudi I, et al. (November 2010). "Methylation tolerance due to an O6-methylguanine DNA methyltransferase (MGMT) field defect in the colonic mucosa: an initiating step in the development of mismatch repair-deficient colorectal cancers". Gut. 59 (11): 1516–26. doi:10.1136/gut.2009.194787. PMID 20947886.
- Facista A, Nguyen H, Lewis C, Prasad AR, Ramsey L, Zaitlin B, Nfonsam V, Krouse RS, Bernstein H, Payne CM, Stern S, Oatman N, Banerjee B, Bernstein C (April 2012). "Deficient expression of DNA repair enzymes in early progression to sporadic colon cancer". Genome Integrity. 3 (1): 3. doi:10.1186/2041-9414-3-3. PMC . PMID 22494821.
- Paluszczak J, Misiak P, Wierzbicka M, Woźniak A, Baer-Dubowska W (February 2011). "Frequent hypermethylation of DAPK, RARbeta, MGMT, RASSF1A and FHIT in laryngeal squamous cell carcinomas and adjacent normal mucosa". Oral Oncology. 47 (2): 104–7. doi:10.1016/j.oraloncology.2010.11.006. PMID 21147548.
- Zuo C, Zhang H, Spencer HJ, Vural E, Suen JY, Schichman SA, Smoller BR, Kokoska MS, Fan CY (October 2009). "Increased microsatellite instability and epigenetic inactivation of the hMLH1 gene in head and neck squamous cell carcinoma". Otolaryngology--Head and Neck Surgery. 141 (4): 484–90. doi:10.1016/j.otohns.2009.07.007. PMID 19786217.
- Tawfik HM, El-Maqsoud NM, Hak BH, El-Sherbiny YM (2011). "Head and neck squamous cell carcinoma: mismatch repair immunohistochemistry and promoter hypermethylation of hMLH1 gene". American Journal of Otolaryngology. 32 (6): 528–36. doi:10.1016/j.amjoto.2010.11.005. PMID 21353335.
- Zou XP, Zhang B, Zhang XQ, Chen M, Cao J, Liu WJ (November 2009). "Promoter hypermethylation of multiple genes in early gastric adenocarcinoma and precancerous lesions". Human Pathology. 40 (11): 1534–42. doi:10.1016/j.humpath.2009.01.029. PMID 19695681.
- Wani M, Afroze D, Makhdoomi M, Hamid I, Wani B, Bhat G, Wani R, Wani K (2012). "Promoter methylation status of DNA repair gene (hMLH1) in gastric carcinoma patients of the Kashmir valley". Asian Pacific Journal of Cancer Prevention. 13 (8): 4177–81. doi:10.7314/APJCP.2012.13.8.4177. PMID 23098428.
- Agarwal A, Polineni R, Hussein Z, Vigoda I, Bhagat TD, Bhattacharyya S, Maitra A, Verma A (2012). "Role of epigenetic alterations in the pathogenesis of Barrett's esophagus and esophageal adenocarcinoma". International Journal of Clinical and Experimental Pathology. 5 (5): 382–96. PMC . PMID 22808291. Review.
- Hofstad B, Vatn MH, Andersen SN, Huitfeldt HS, Rognum T, Larsen S, Osnes M (September 1996). "Growth of colorectal polyps: redetection and evaluation of unresected polyps for a period of three years". Gut. 39 (3): 449–56. doi:10.1136/gut.39.3.449. PMC . PMID 8949653.
- Schmitt MW, Prindle MJ, Loeb LA (September 2012). "Implications of genetic heterogeneity in cancer". Annals of the New York Academy of Sciences. 1267: 110–6. doi:10.1111/j.1749-6632.2012.06590.x. PMC . PMID 22954224.
- Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J, et al. (February 2001). "Initial sequencing and analysis of the human genome". Nature. 409 (6822): 860–921. doi:10.1038/35057062. PMID 11237011.
- Yost SE, Smith EN, Schwab RB, Bao L, Jung H, Wang X, Voest E, Pierce JP, Messer K, Parker BA, Harismendy O, Frazer KA (August 2012). "Identification of high-confidence somatic mutations in whole genome sequence of formalin-fixed breast cancer specimens". Nucleic Acids Research. 40 (14): e107. doi:10.1093/nar/gks299. PMC . PMID 22492626.
- Berger MF, Hodis E, Heffernan TP, Deribe YL, Lawrence MS, Protopopov A, et al. (May 2012). "Melanoma genome sequencing reveals frequent PREX2 mutations". Nature. 485 (7399): 502–6. doi:10.1038/nature11071. PMC . PMID 22622578.
- Rasnick D, Duesberg PH (June 1999). "How aneuploidy affects metabolic control and causes cancer". The Biochemical Journal. 340 (3): 621–30. doi:10.1042/0264-6021:3400621. PMC . PMID 10359645.
- López-Lázaro M (March 2010). "A new view of carcinogenesis and an alternative approach to cancer therapy". Molecular Medicine. 16 (3–4): 144–53. doi:10.2119/molmed.2009.00162. PMC . PMID 20062820.
- Soto AM, Sonnenschein C (October 2004). "The somatic mutation theory of cancer: growing problems with the paradigm?". BioEssays. 26 (10): 1097–107. doi:10.1002/bies.20087. PMID 15382143.
- Davies PC, Lineweaver CH (February 2011). "Cancer tumors as Metazoa 1.0: tapping genes of ancient ancestors". Physical Biology. 8 (1): 015001. doi:10.1088/1478-3975/8/1/015001. PMC . PMID 21301065.
- Dean, Tim. "Cancer resembles life 1 billion years ago, say astrobiologists", Australian Life Scientist, 8 February 2011. Retrieved 15 February 2011.
- Sterrer, W (August 2016). "Cancer - Mutational Resurrection of Prokaryote Endofossils". Cancer Hypotheses. 1 (1): 1–15.
- Nowell PC (October 1976). "The clonal evolution of tumor cell populations". Science. 194 (4260): 23–8. doi:10.1126/science.959840. PMID 959840.
- Merlo LM, Pepper JW, Reid BJ, Maley CC (December 2006). "Cancer as an evolutionary and ecological process". Nature Reviews. Cancer. 6 (12): 924–35. doi:10.1038/nrc2013. PMID 17109012.
- Hanahan D, Weinberg RA (January 2000). "The hallmarks of cancer". Cell. 100 (1): 57–70. doi:10.1016/S0092-8674(00)81683-9. PMID 10647931.
- Cho RW, Clarke MF (February 2008). "Recent advances in cancer stem cells". Current Opinion in Genetics & Development. 18 (1): 48–53. doi:10.1016/j.gde.2008.01.017. PMID 18356041.
- Taniguchi K, Wu LW, Grivennikov SI, de Jong PR, Lian I, Yu FX, Wang K, Ho SB, Boland BS, Chang JT, Sandborn WJ, Hardiman G, Raz E, Maehara Y, Yoshimura A, Zucman-Rossi J, Guan KL, Karin M (March 2015). "A gp130-Src-YAP module links inflammation to epithelial regeneration". Nature. 519 (7541): 57–62. doi:10.1038/nature14228. PMC . PMID 25731159.
- You H, Lei P, Andreadis ST (December 2013). "JNK is a novel regulator of intercellular adhesion". Tissue Barriers. 1 (5): e26845. doi:10.4161/tisb.26845. PMC . PMID 24868495.
- Busillo JM, Azzam KM, Cidlowski JA (November 2011). "Glucocorticoids sensitize the innate immune system through regulation of the NLRP3 inflammasome". The Journal of Biological Chemistry. 286 (44): 38703–13. doi:10.1074/jbc.M111.275370. PMC . PMID 21940629.
- Wang Y, Bugatti M, Ulland TK, Vermi W, Gilfillan S, Colonna M (March 2016). "Nonredundant roles of keratinocyte-derived IL-34 and neutrophil-derived CSF1 in Langerhans cell renewal in the steady state and during inflammation". European Journal of Immunology. 46 (3): 552–9. doi:10.1002/eji.201545917. PMID 26634935.
- Siqueira Mietto B, Kroner A, Girolami EI, Santos-Nogueira E, Zhang J, David S (December 2015). "Role of IL-10 in Resolution of Inflammation and Functional Recovery after Peripheral Nerve Injury". The Journal of Neuroscience. 35 (50): 16431–42. doi:10.1523/JNEUROSCI.2119-15.2015. PMID 26674868.
- Seifert AW, Maden M (2014). "New insights into vertebrate skin regeneration". International Review of Cell and Molecular Biology. 310: 129–69. doi:10.1016/B978-0-12-800180-6.00004-9. PMID 24725426.
- Kwon MJ, Shin HY, Cui Y, Kim H, Thi AH, Choi JY, Kim EY, Hwang DH, Kim BG (December 2015). "CCL2 Mediates Neuron-Macrophage Interactions to Drive Proregenerative Macrophage Activation Following Preconditioning Injury". The Journal of Neuroscience. 35 (48): 15934–47. doi:10.1523/JNEUROSCI.1924-15.2015. PMID 26631474.
- Hajishengallis G, Chavakis T (January 2013). "Endogenous modulators of inflammatory cell recruitment". Trends in Immunology. 34 (1): 1–6. doi:10.1016/j.it.2012.08.003. PMC . PMID 22951309.
- Nelson AM, Katseff AS, Ratliff TS, Garza LA (February 2016). "Interleukin 6 and STAT3 regulate p63 isoform expression in keratinocytes during regeneration". Experimental Dermatology. 25 (2): 155–7. doi:10.1111/exd.12896. PMID 26566817.
- Vidal PM, Lemmens E, Dooley D, Hendrix S (February 2013). "The role of "anti-inflammatory" cytokines in axon regeneration". Cytokine & Growth Factor Reviews. 24 (1): 1–12. doi:10.1016/j.cytogfr.2012.08.008. PMID 22985997.
- Hsueh YY, Chang YJ, Huang CW, Handayani F, Chiang YL, Fan SC, Ho CJ, Kuo YM, Yang SH, Chen YL, Lin SC, Huang CC, Wu CC (October 2015). "Synergy of endothelial and neural progenitor cells from adipose-derived stem cells to preserve neurovascular structures in rat hypoxic-ischemic brain injury". Scientific Reports. 5: 14985. doi:10.1038/srep14985. PMC . PMID 26447335.
- Yaniv M (September 2014). "Chromatin remodeling: from transcription to cancer". Cancer Genetics. 207 (9): 352–7. doi:10.1016/j.cancergen.2014.03.006. PMID 24825771.
- Zhang X, He N, Gu D, Wickliffe J, Salazar J, Boldogh I, Xie J (October 2015). "Genetic Evidence for XPC-KRAS Interactions During Lung Cancer Development". Journal of Genetics and Genomics = Yi Chuan Xue Bao. 42 (10): 589–96. doi:10.1016/j.jgg.2015.09.006. PMID 26554912.
- Dubois-Pot-Schneider H, Fekir K, Coulouarn C, Glaise D, Aninat C, Jarnouen K, Le Guével R, Kubo T, Ishida S, Morel F, Corlu A (December 2014). "Inflammatory cytokines promote the retrodifferentiation of tumor-derived hepatocyte-like cells to progenitor cells". Hepatology. 60 (6): 2077–90. doi:10.1002/hep.27353. PMID 25098666.
- Finkin S, Yuan D, Stein I, Taniguchi K, Weber A, Unger K, et al. (December 2015). "Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma". Nature Immunology. 16 (12): 1235–44. doi:10.1038/ni.3290. PMID 26502405.
- Vlahopoulos SA, Cen O, Hengen N, Agan J, Moschovi M, Critselis E, Adamaki M, Bacopoulou F, Copland JA, Boldogh I, Karin M, Chrousos GP (August 2015). "Dynamic aberrant NF-κB spurs tumorigenesis: a new model encompassing the microenvironment". Cytokine & Growth Factor Reviews. 26 (4): 389–403. doi:10.1016/j.cytogfr.2015.06.001. PMC . PMID 26119834.
- Grivennikov SI, Karin M (February 2010). "Dangerous liaisons: STAT3 and NF-kappaB collaboration and crosstalk in cancer". Cytokine & Growth Factor Reviews. 21 (1): 11–9. doi:10.1016/j.cytogfr.2009.11.005. PMC . PMID 20018552.
- Rieger S, Zhao H, Martin P, Abe K, Lisse TS (January 2015). "The role of nuclear hormone receptors in cutaneous wound repair". Cell Biochemistry and Function. 33 (1): 1–13. doi:10.1002/cbf.3086. PMC . PMID 25529612.
- Lu X, Yarbrough WG (February 2015). "Negative regulation of RelA phosphorylation: emerging players and their roles in cancer". Cytokine & Growth Factor Reviews. 26 (1): 7–13. doi:10.1016/j.cytogfr.2014.09.003. PMID 25438737.
- Sionov RV, Fridlender ZG, Granot Z (December 2015). "The Multifaceted Roles Neutrophils Play in the Tumor Microenvironment". Cancer Microenvironment. 8 (3): 125–58. doi:10.1007/s12307-014-0147-5. PMC . PMID 24895166.
- Venturi, Sebastiano (2011). "Evolutionary Significance of Iodine". Current Chemical Biology-. 5 (3): 155–162. doi:10.2174/187231311796765012. ISSN 1872-3136.
- Venturi S (2014). "Iodine, PUFAs and Iodolipids in Health and Disease: An Evolutionary Perspective". Human Evolution. 29 (1–3): 185–205. ISSN 0393-9375.
- Walsh CJ, Luer CA, Bodine AB, Smith CA, Cox HL, Noyes DR, Maura G (December 2006). "Elasmobranch immune cells as a source of novel tumor cell inhibitors: Implications for public health". Integrative and Comparative Biology. 46 (6): 1072–1081. doi:10.1093/icb/icl041. PMC . PMID 19343108.
- Vogelstein B, Kinzler KW (August 2004). "Cancer genes and the pathways they control". Nature Medicine. 10 (8): 789–99. doi:10.1038/nm1087. PMID 15286780.
- Brand KA, Hermfisse U (April 1997). "Aerobic glycolysis by proliferating cells: a protective strategy against reactive oxygen species". FASEB Journal. 11 (5): 388–95. PMID 9141507.
- Bos JL (September 1989). "ras oncogenes in human cancer: a review". Cancer Research. 49 (17): 4682–9. PMID 2547513.
- Chang EH, Furth ME, Scolnick EM, Lowy DR (June 1982). "Tumorigenic transformation of mammalian cells induced by a normal human gene homologous to the oncogene of Harvey murine sarcoma virus". Nature. 297 (5866): 479–83. doi:10.1038/297479a0. PMID 6283358.
- Vlahopoulos SA, Logotheti S, Mikas D, Giarika A, Gorgoulis V, Zoumpourlis V (April 2008). "The role of ATF-2 in oncogenesis". BioEssays. 30 (4): 314–27. doi:10.1002/bies.20734. PMID 18348191.
- Matoba S, Kang JG, Patino WD, Wragg A, Boehm M, Gavrilova O, Hurley PJ, Bunz F, Hwang PM (June 2006). "p53 regulates mitochondrial respiration". Science. 312 (5780): 1650–3. doi:10.1126/science.1126863. PMID 16728594.
- Knudson AG (April 1971). "Mutation and cancer: statistical study of retinoblastoma". Proceedings of the National Academy of Sciences of the United States of America. 68 (4): 820–3. doi:10.1073/pnas.68.4.820. PMC . PMID 5279523.
- Fodde R, Smits R (October 2002). "Cancer biology. A matter of dosage". Science. 298 (5594): 761–3. doi:10.1126/science.1077707. PMID 12399571.
- Stephens PJ, Greenman CD, Fu B, Yang F, Bignell GR, Mudie LJ, et al. (January 2011). "Massive genomic rearrangement acquired in a single catastrophic event during cancer development". Cell. 144 (1): 27–40. doi:10.1016/j.cell.2010.11.055. PMC . PMID 21215367. Lay summary – The New York Times (10 January 2011).
- Carrillo-Infante C, Abbadessa G, Bagella L, Giordano A (June 2007). "Viral infections as a cause of cancer (review)". International Journal of Oncology. 30 (6): 1521–8. doi:10.3892/ijo.30.6.1521. PMID 17487374.
- Safdar A (2011-06-01). Management of Infections in Cancer Patients. Springer. pp. 478–. ISBN 978-1-60761-643-6. Retrieved 17 August 2011.
- Samaras V, Rafailidis PI, Mourtzoukou EG, Peppas G, Falagas ME (June 2010). "Chronic bacterial and parasitic infections and cancer: a review". Journal of Infection in Developing Countries. 4 (5): 267–81. doi:10.3855/jidc.819. PMID 20539059.
- Daniel FI, Cherubini K, Yurgel LS, de Figueiredo MA, Salum FG (February 2011). "The role of epigenetic transcription repression and DNA methyltransferases in cancer". Cancer. 117 (4): 677–87. doi:10.1002/cncr.25482. PMID 20945317. Review.
- Kanwal R, Gupta S (April 2012). "Epigenetic modifications in cancer". Clinical Genetics. 81 (4): 303–11. doi:10.1111/j.1399-0004.2011.01809.x. PMC . PMID 22082348.
- Pattani KM, Soudry E, Glazer CA, Ochs MF, Wang H, Schussel J, Sun W, Hennessey P, Mydlarz W, Loyo M, Demokan S, Smith IM, Califano JA (2012). Tao Q, ed. "MAGEB2 is activated by promoter demethylation in head and neck squamous cell carcinoma". PLoS One. 7 (9): e45534. doi:10.1371/journal.pone.0045534. PMC . PMID 23029077.
- Sampath D, Liu C, Vasan K, Sulda M, Puduvalli VK, Wierda WG, Keating MJ (February 2012). "Histone deacetylases mediate the silencing of miR-15a, miR-16, and miR-29b in chronic lymphocytic leukemia". Blood. 119 (5): 1162–72. doi:10.1182/blood-2011-05-351510. PMC . PMID 22096249.
- Hitchler MJ, Oberley LW, Domann FE (December 2008). "Epigenetic silencing of SOD2 by histone modifications in human breast cancer cells". Free Radical Biology & Medicine. 45 (11): 1573–80. doi:10.1016/j.freeradbiomed.2008.09.005. PMC . PMID 18845242.
- Baldassarre G, Battista S, Belletti B, Thakur S, Pentimalli F, Trapasso F, Fedele M, Pierantoni G, Croce CM, Fusco A (April 2003). "Negative regulation of BRCA1 gene expression by HMGA1 proteins accounts for the reduced BRCA1 protein levels in sporadic breast carcinoma". Molecular and Cellular Biology. 23 (7): 2225–38. doi:10.1128/MCB.23.7.2225-2238.2003. PMC . PMID 12640109.
- Dalerba P, Cho RW, Clarke MF (2007). "Cancer stem cells: models and concepts". Annual Review of Medicine. 58: 267–84. doi:10.1146/annurev.med.58.062105.204854. PMID 17002552.
- Zhang W, Hanks AN, Boucher K, Florell SR, Allen SM, Alexander A, Brash DE, Grossman D (January 2005). "UVB-induced apoptosis drives clonal expansion during skin tumor development". Carcinogenesis. 26 (1): 249–57. doi:10.1093/carcin/bgh300. PMC . PMID 15498793.
- Tokar EJ, Benbrahim-Tallaa L, Waalkes MP (2011). "Chepter 14. Metal Ions in Human Cancer Development". In Astrid Sigel, Helmut Sigel and Roland K. O. Sigel. Metal ions in toxicology: effects, interactions, interdependencies. Metal Ions in Life Sciences. 8. RSC Publishing. pp. 375–401. doi:10.1039/9781849732116-00375.
- Dixon K, Kopras E (December 2004). "Genetic alterations and DNA repair in human carcinogenesis". Seminars in Cancer Biology. 14 (6): 441–8. doi:10.1016/j.semcancer.2004.06.007. PMID 15489137.
- Kleinsmith LJ (2006). Principles of cancer biology. San Francisco: Pearson Benjamin Cummings. ISBN 978-0-8053-4003-7.
- Sarasin A (November 2003). "An overview of the mechanisms of mutagenesis and carcinogenesis". Mutation Research. 544 (2–3): 99–106. doi:10.1016/j.mrrev.2003.06.024. PMID 14644312.
- Schottenfeld D, Beebe-Dimmer JL (2005). "Advances in cancer epidemiology: understanding causal mechanisms and the evidence for implementing interventions". Annual Review of Public Health. 26: 37–60. doi:10.1146/annurev.publhealth.26.021304.144402. PMID 15760280.
- Tannock I, Hill R, Bristow R, Harrington L (2005). The basic science of oncology (4th ed.). New York: McGraw-Hill. ISBN 978-0-07-138774-3.
- Wicha MS, Liu S, Dontu G (February 2006). "Cancer stem cells: an old idea--a paradigm shift". Cancer Research. 66 (4): 1883–90; discussion 1895–6. doi:10.1158/0008-5472.CAN-05-3153. PMID 16488983.