Models of carcinogenesis

Volgestein and Kinzler (1993) are the first authors who tried and raised an initial model of carcinogenesis, in colon cancer adenocarcinoma. They argued that the appearance of cancer from normal epithelium requires the epithelial cells to accumulate seven critical lesions in genomic material (loss of heterozygosity, hypermethylation of DNA), tumor-suppressor genes (APC, p53, SMAD4, MMR) and oncogenes (K-RAS).

 Further studies from Gorgoulis et al. [Gorgoulis VG 2005] και Bartkova et al [Bartkova J 2005] elucidated the processes that take place in precancerous lesions that potentially can lead into cancer or remain dormant for a relatively long time. More specifically, aberrant proliferation, that occurs in pre-neoplastic lesions, leads to replicative stress.  Replicative stress either indirectly or directly through DNA double strand breaks, is capable to activate the cell-cycle ATM-Chk2 check-point , which in turn induces cell-cycle arrest, or apoptosis or senescence, thereby obtaining a tumor-suppressor role.

 There are regions in the genome that are sensitive to breaks and DNA recombination, and these are called common fragile sites.  Common fragile sites occur in heterochromatin (i.e., regions that are late-replicated) and therefore are “easy” targets for DNA breaks. Neoplastic and hyperplastic cells, which are characterized by aberrant proliferation e.g. re-replication, or avoid apoptosis, demonstrated sensitivity to common fragile-sites, with the most common site FRA3B. Furthermore, telomere-erosion and hypoxia, leads to additional creation of double strand breaks, activation of cell-cycle checkpoints and genome instability. In conclusion, tumor-suppressor genes, like p53 that normally induce apoptosis or senescence, are deactivated because they escape the process of DNA damage checkpoint (eg.p53 mutations), thus allowing aberrant proliferation and tumor development [Halazonetis TD 2008].

Bartkova J, Horejsi Z, Koed K, Krämer A, Tort F, Zieger K, et al. DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature 2005; 434:864-870

Gorgoulis VG, Vassiliou LV, Karakaidos P, Zacharatos P, Kotsinas A, Liloglou T, et al. Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. Nature  2005; 434(7035):907-13

Halazonetis TD, Gorgoulis VG, Bartek J. An oncogene-induced DNA damage model for cancer development. Science 2008; 319:1352-1355

Vogelstein B and Kinzler KW. The multistep nature of cancer. Trends Genet 1993; 9:138-141

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