Colorectal carcinogenesis

Hagiwara, A. et al., Pronounced inhibition by a natural anthocyanin, purple com color, of 2-amino-l-methyl-6-phenylimidazo[4,5-b]pyridine (PhlP)-associated colorectal carcinogenesis in male F344 rats pretreated with 1,2-dimethylhydrazine. Cancer Lett., 171, 17, 2001. 

The model of multi-stage human colorectal carcinogenesis, based on accumulating genetic and epigenetic hits , leading to sequential loss of... 

Evidence that Bile Acids Play a Role in Colorectal Carcinogenesis... 

There are three main sources of evidence for pro-tumorigenic activity of bile acids in the lower gastro-intestinal tract (activity in rodent CRC models, human observational data and mechanistic studies using CRC cells in vitro), which together create a strong case for a role for colorectal mucosal bile acid exposure during human colorectal carcinogenesis. 

Several strands of indirect evidence from human observational studies help put the in vivo rodent data into the context of human colorectal carcinogenesis. 

In contrast to the effects of secondary bile acids like DCA, UDCA, which is found at a high concentration in bear bile but only in trace amounts in humans, has anti-neoplastic activity in vitro and in vivo. UDCA has significant chemopreventative activity in rodent models of sporadic and colitis-colorectal carcinogenesis induced by chemical carcinogens. 

Anti-neoplastic activity of UDCA was demonstrated first in the context of ulcerative colitis-associated colorectal carcinogenesis. Subsequently, encouraging (but not definitive) results have been obtained in clinical trials of UDCA for prevention of sporadic colorectal adenoma recurrence, which should prompt further evaluation of UDCA for polyp prevention, particularly given its excellent safety profile compared with other candidate chemoprevention agents such as the nonsteroidal anti-inflammatory drugs. 

D. P. Hurlstone and S. S. Cross, Role of aberrant crypt foci detected using high-magnification-chromoscopic colonoscopy in human colorectal carcinogenesis, J. Gastroenterol. Hepatol, 2005, 20, 173. 

Williams AC, Collard TJ, Paraskeva C (1999) An acidic environment leads to p53 dependent induction of apoptosis in human adenoma and carcinoma cell lines implications for clonal selection during colorectal carcinogenesis. Oncogene 18 3199-3204... 

Fig. 3. Working hypothesis for the potential role of COX-2 in colorectal carcinogenesis (ref. 51).

CA017 Mori, H., K. Kawabata, K. Matsunaga, et al. Chemopreventive effects of cof-fee bean, and rice constituents on colorectal carcinogenesis. Biofactors 2000 12(1-4) 101-105. 

Figure 24.26. Genetic model for colorectal carcinogenesis. (Adapted fromFearon, E. R., and Vogelstein B. A genetic model for colorectal tumorigenesis. Cell 61, 759-767,1990.)...

The potential of a natural anthocyanin with purple corn color (PCC) has been tested against colorectal carcinogenesis, using male F344/DuCrj rats that were initially treated with 1,2-dimethylhydrazine (DMH). 2-Amino-l-melhyl-6-phenylimidazo [4,5-fc] pyridine (PhIP) exerted promoting effects on... 

Barsoum GH, Thompson J, Neoptolemos JP, et al. 1992. Dietary calcium does not reduce experimental colorectal carcinogenesis after small bowel resection despite reducing cellular proliferation. Gut 33 1515-1520. 

A recent study by Mort et al. [71 ] showed that the NER genes XPD, XPF, XPG, and ERCCl, and the BER gene XRCCl are not important genetic determinants in colorectal carcinogenesis, while a modest association between colorectal cancer and a polymorphism in the recombination repair gene XRCC3 gene was found. 

Additional intervention trials of various micronutrients, including selenium and folic acid, and other chemopreventive agents have been completed or are ongoing. - Because of their different mechanisms of action and sites of influence on the process of colorectal carcinogenesis, certain populations of individuals may benefit most from selected agents. 

Younes M, Lechago LV, Lechago J. Overexpression of the human erythrocyte glucose transporter occurs as a late event in human colorectal carcinogenesis and is associated with an increased incidence of lymph node metastases. Clin Cancer Res. 1996 2 1151-1154. 

Pool-Zobel, B., Veeriah, S., and Bohmer, F. D. (2005) Modulation of xenobiotic metabohsing enzymes by anticarcinogens—focus on glutathione S-transferases and their role as targets of dietary chemoprevention in colorectal carcinogenesis. Mutat. Res. 591, 74-92. 

Cancers with a high frequency of CpG transitions include colorectal cancer (45%), adenocarcinoma of the esophagus (48%) and stomach (34%), tumors of the brain (35%) and uterus (35%), and some hematopoietic malignancies (e.g., Burkitt s lymphoma (32%) (Fig. 3B). In colorectal carcinogenesis, p53 mutation is typically a relatively late event that correlates with the acquisition of an invasive potential (Fearon and Vogelstein, 1990). Acquisition of a CpG mutation in this context may be a consequence of deregulated cell proliferation, DNA instability, or altered nitric oxide metabolism. In the development of adenocarcinoma of the esophagus, however, mutations are often detectable in the preneoplastic lesion, Barrett s mucosa (Montesano et al., 1996). In the latter case, it has been speculated that... 

Fig. 3 The two phases of variant colorectal carcinogenesis. The dots symbolize the numerous mutations accumulated because of the RER mutator phenotype. The arrows symbolize the three assumptions of the model (1) The first step is acquisition of the RER mutator phenotype. Cells with MMR deficiency have no growth advantage. (2) Cells with an RER mutator phenotype may undergo malignant transformation through a several-step process that is purely mutation driven initially. (3) The mutation load rapidly causes the elimination of nontransformed cells with an RER mutator phenotype. Apoptosis or senescence restrict their life span to a limited number of replications.

Use of nonsteroidal anti-iirflammatory drugs has been found to inhibit colorectal carcinogenesis, presumably by apoptosis of the neoplastic cells via mechaiusms both dependent and independent of cyclooxygenase. In randomized trials showed that dmgs such as indomethacin, aspirin, etc. cause regression of colorectal tumors. ... 

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