Carcinogenesis

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.

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)).

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 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.

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.

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. 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.

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).

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.

A new idea announced in 2011 is an extreme version of multiple mutations, called chromothripsis by its proponents. This idea, affecting only 23% 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.

Depending on their location, cells can be damaged through radiation, chemicals from cigarette smoke, and inflammation from bacterial infection or other viruses. Each cell has a chance of damage. 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.

DEFINITIONS OF EPIGENETICS

MOLECULAR BASIS OF EPIGENETICS

MECHANISMS OF EPIGENETICS

EPIGENETICS IN BACTERIA

MEDICINE AND EPIGENETICS

PSYHOLOGY AND PSYCHIATRY OF EPIGENETICS

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