Introduction to cancer

Oxford American handbook of oncology. Second Edition. Oxford University Press (2015)

Multistep carcinogenesis

The development of cancer is a multistep process characterized by accumulation of a number of genetic alterations. This process can be referred  to as “oncogenesis.” Genetic alterations can take the form of mutations (changes in the sequence of the DNA code), deletions (loss of sections of DNA), amplifications (multiple copies of the same DNA section), or epigenetic changes (altering the methylation status of DNA, resulting in activation or repression of genes in the region).

In the aggregate, multiple changes in the DNA of cancer cells alter normal cellular physiology so as to allow limitless proliferation, independence from external growth-promoting or growth-inhibiting influences, avoidance of programmed cell death (apoptosis), and recruitment of blood vessels (angiogenesis). Mutations in DNA repair genes appear to be a necessary feature of most cancers.

For cancer to spread beyond the site of origin, additional changes including loss of cellular polarity, decreased intracellular adhesion, and migratory or invasive characteristics are often required.

Most normal human cells can be transformed into tumor-forming cells by the introduction of four changes: the activation of telomerase (an enzyme that protects the ends of replicating chromosomes), the viral protein large T (which inhibits p53 and Rb proteins), the viral protein small t (which inactivates the signaling protein PP 2A), and the expression of an activated Ras oncogene. Although this represents a minimal number of genetic changes required for human cells to acquire tumor-like characteristics, the development of a cancer in a person is likely to require additional changes.

Recent work suggests that colon cancers have, on average, nine mutations in cancer-related genes. Thus, although the genetic basis of cancer has been established, an understanding of the oncogenic process is far from complete.


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