The origin for many neoplasms is obscure. However, there are several
theories of origin:
Chemicals: including those that are man-made (such as aniline dyes and bladder cancer), drugs (cigarette smoke and lung cancer), and natural compounds (aflatoxins and liver cancer) which are carcinogenic.
Oncogenic viruses: such as human papillomavirus (HPV) implicated in most
squamous cell carcinomas of cervix and anogenital squamous papillomas,
Epstein-Barr virus (EBV) implicated in African Burkitt's lymphoma, and hepatitis
B virus (HBV) implicated in development of hepatocellular carcinomas.
Radiation: including ultraviolet light that induces pyrimidine dimers in DNA and promotes skin cancers. Ionizing radiation (such as gamma radiation) induces mutations in DNA and promotes malignancies such as leukemia, thyroid, lung, colon, and breast cancers.
There are two steps: initiation and promotion
An initiating carcinogenic agent irreversibly damages cell DNA (it is
mutagenic) to start the process. Examples of carcinogenic initiators include:
alkylating agents like cyclophosphamide, polycyclic aromatic hydrocarbons like
epoxides found in smoked foods, aromatic amines or azo dyes used in food
coloring, aflatoxins in moldy peanuts, nitrosamines in pickled foods.
A promoting agent (which may be the same as the carcinogen) then acts
(reversibly) to cause proliferation of a neoplastic cell clone, but there
appears to be a "dose-threshold" concentration of promoter below which
neoplasia will not occur. Examples of promoters include: hormones such as
estrogen, drugs such as diethylstilbesterol, and chemicals such as cyclamates
used as sweeteners.
Chromosomes which have absent or defective anti-oncogenes that control
growth (retinoblastoma results from defective chromosome 13)
Obscure defects: racial predilections (American women have breast cancer
more often than Japanese women; Japanese men have stomach cancer far more often
than American men).
Age: older persons have a greater propensity to develop neoplasms from lack of effective control mechanisms.
All of the above are probably mediated by the cause, whatever it is,
producing a mutation in, or damage to, cell DNA
There can be mutations involving tumor suppressor genes (such as p53), which then fail to exert a controlling influence upon growth activation. The majority of human neoplasms probably arise via this mechanism.
In some cases these mutations are probably mediated by proto-oncogenes (genes which control cellular growth) that undergo mutation to oncogenes which give rise to neoplasia. Proto-oncogenes can be activated by point mutations, translocations, and by gene amplification.
An example of this is chronic myelogenous leukemia (CML) which is a neoplastic proliferation of white blood cells. All cases of CML have the "Philadelphia chromosome" which is a translocation between chromosomes 9 and 22. This translocation juxtaposes the proto-oncogene ABL with the breakpoint cluster region (BCR) on chromosome 22. The chimeric ABL-BCR gene leads to production of a mutant protein with enhanced tyrosine kinase activity. This protein may play a role in regulation of cell growth in CML.
About 15 to 20% of human cancers have been linked to oncogenic activity. The ras oncogene is the transforming gene found most frequently in human cancers.
Oncogenic viruses may bring oncogenes with them, so-called viral oncogenes (typical of RNA containing "retroviruses" such as human T-lymphotropic
DNA repair mechanisms may be affected. There are DNA excision repair genes that can be mutated, introducing genomic instability and a greater likelihood that mutations in other genes will occur to drive oncogenesis. Examples include:
DNA mismatch repair genes: defective nucleotide "spell checker" introducing "microsatellite instability" of tandem repeat sequences in DNA. Seen in hereditary non-polyposis colon cancer (HNPCC)
Nucleotide excision repair genes: defective function in xeroderma pigmentosa, allowing DNA damage from pyrimidine dimer formation induced by ultraviolet light
Growth factors such as epidermal growth factor (EGF), platelet-derived
growth factor (PDGF) and colony-stimulating factor-1 (CSF-1) assist oncogene
activity. Transforming growth factor (TGF-alpha) also promotes tumor growth.