Biomedical Engineering Reference
In-Depth Information
2.5. Single Pathway Versus Multiple Pathways of
Carcinogenesis
In some type of cancers such as retinoblastoma, cancer tumor is derived by
a single pathway
9;34;55
. In many other cancers, however, the same cancer
may arise from dierent carcinogenic pathways. This include skin cancers,
liver cancers and mammary gland in animals, the melanoma development
in skin cancer in human beings, breast cancer, colon cancer, liver cancer
and lung cancer in human beings.
To serve as an example, consider the colon cancer of human beings. For
this cancer, genetic studies have indicated that there are two major avenues
by means of which colon cancer is developed (see [29, 31, 35, 39, 47, 53, 10,
18, 22, 45, 65]): The Chromosomal Instability (CIN) and the Micro-Satellite
Instability (MSI). The CIN pathway involves loss or mutation of the sup-
pressor genes- the APC gene in chromosome 5q, the Smad4/DCC gene in
chromosome 18q and the p53 gene in chromosome 17p. This pathway ac-
counts for about 75-80% of all colon cancers and has been referred to as the
LOH (Loss Of Heterozygosity) pathway because it is often characterized by
aneuploidy /or loss of chromosome segments (chromosomal instability); it
has also been referred to as the APC-cateninT cfmyc pathway
because it involves - catenin, T cf (T-cell factor) and the myc oncogene;
see Remark 3. The MSI pathway involves microsatellite mis-match re-
pair genes (MMR gene), hMLH1, hMSH2, hPMS1, hPMS2, hMSH6 and
hMSH3. (Mostly hMLH1 and hMSH2.) This pathway accounts for about
10-15% of all colon cancers and appears mostly in the right colon. It has
been referred to as the MSI (Micro-Satellite Instability ) pathway or the
mutator phenotype pathway because it is often characterized by the loss or
mutations in the mis-match repair genes creating a mutator phenotype to
signicantly increase the mutations rate of many critical genes.
Remark 3: In the APC-cateninT cfmyc pathway, the APC
gene forms a complex with -catenin and GSK3 (Glycogen Synthase
Kinases 3-) to degrade the catenin protein. When both copies of APC
gene is lost or mutated, the -catenin protein then accumulates to form
a complex with T cf to promote cell proliferation, usually via the elevated
level of the myc gene and /or cyclin D1.
3. Some Stochastic Models of Carcinogenesis
Based on the above biological mechanisms of carcinogenesis, we now pro-
pose some general stochastic models of carcinogenesis.
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