Prevention of early-onset familial/hereditary colon cancer: New models and mechanistic biomarkers (Review)

Abstract

Abstract. Human colon cancer is a multi-factorial, multi-step disease wherein genetic and dietary factors represent important regulators of initiation, promotion and progression. While the etiology of sporadic colon cancer remains largely unidentified, familial adenomatous polyposis (FAP) and hereditary non-polyposis colon cancer (HNPCC) represent predisposing genetic syndromes for early-onset familial/hereditary colon cancer. These syndromes are characterized by germ-line mutations in the adenomatous polyposis coli (APC) and/or DNA mismatch repair genes, respectively. Currently available preclinical animal models for human FAP and HNPCC syndromes, expressing clinically relevant germ-line mutations, exhibit adenomas in the small intestine rather than in the colorectum. These models are, therefore, subject to extrapolation for direct clinical translatability of the data for colon carcinogenesis and chemoprevention. Experimental models expressing clinically relevant genetic defects (APC and/or DNA mismatch repair gene mutations) in an appropriate target site (colon) may represent novel approaches that reduce extrapolation of the data for their clinical relevance. This report provides an overview on carcinogenesis and chemoprevention in preclinical models of FAP and HNPCC syndromes, and summarizes recent data on i) development of new cell culture models for FAP and HNPCC syndromes; and ii) validation of developed models for rapid, mechanism-based screening of new pharmacological or naturally occurring chemopreventive agents.

Novel cell culture model for prevention of carcinogenic risk in familial adenomatous polyposis syndrome

“…The status of these quantitative biomarkers was determined following previously published methods (14)(15)(16). The data were expressed as the mean of five time points during the exponential growth phase of 120 h, and as the number of viable cells at day 5 post-seeding of 1.0x10 5 cells, respectively.…”

“…published data generated by different combinations on other cell culture models (14,15,23). In a recent study a novel miRNA based mechanism for positive regulation of APC has been proposed from the data generated from colon carcinoma cell lines as well as from limited patient samples (37).…”

“…Cell culture models from appropriate target organ site expressing clinically relevant genetic defects and exhibiting quantifiable risk for carcinogenesis promise to provide a rapid alternative approach that complements the traditional longterm in vivo animal studies (13)(14)(15)(16). Such cell culture studies should facilitate identification of critical molecular mechanisms for carcinogenic risk as well as for validating and prioritizing efficacious preventive intervention in long-term animal studies.…”

“…Our previous studies have documented development and validation of cell culture models for genetically predisposed early onset colon cancer (13)(14)(15). Experiments designed in the present study were focused on developing a cell culture model from the well established Apc Min /+ mouse, to characterize the model for carcinogenic risk and to validate the developed model as a mechanism-based screen for the efficacy of low dose combinations of mechanistically distinct chemopreventive agents.…”

Anti‑inflammatory drug resistance selects putative cancer stem cells in a cellular model for genetically predisposed colon cancer

“…These preclinical cell culture models exhibit spontaneous immortalization as evidenced by telomerase re-expression, loss of homeostatic growth control as evidenced by hyper-proliferation, aberrant cell cycle progression and downregulated cellular apoptosis, and persistent cancer risk as evidenced by anchorage-independent (AI) growth in vitro and development of tumors in vivo. These colonic epithelial cell culture models for the FAP syndrome have also been utilized as novel experimental approaches to examine the efficacy of selecting mechanistically distinct chemo-preventive agents (5)(6)(7)(8)(9)(10).…”