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

Abstract

Abstract. Clinical familial adenomatous polyposis (FAP) syndrome represents a high risk pre-invasive precursor for colon cancer, and is characterized by germ line mutation in the adenomatous polyposis coli (APC) tumor suppressor gene. Cellular models with relevant genetic and biological characteristics should provide important mechanistic leads for predisposition and preventive intervention. Cloned colon epithelial cell line from the Apc 850 Min /+ mouse represented a model for FAP. Cell cycle progression, cellular apoptosis and anchorage-independent growth represented the biomarkers for carcinogenic risk. The Apc mutant 850Min COL-Cl 1 cells exhibited decreased G 0 /G 1 :S+G 2 /M ratio, increased S+G 2 /M: subG 0 ratio, and increased anchorage-independent colony formation, indicating loss of homeostatic growth control and gain of anchorage-independent growth. Growth of these cells in serum-depleted medium was promoted by mitogenic insulin and epidermal growth factor, and inhibited by antimitogenic transforming growth factor-ß 1 and dexamethasone. Treatment with low dose combinations of synthetic enzyme inhibitor difluoro methylornithine (DFMO), synthetic nonsteroidal anti-inflammatory drug sulindac (SUL), and naturally occurring epigallocatechin gallate (EGCG), and eicosapentaenoic acid (EPA) produced cytostatic growth arrest and inhibited anchorage-independent colony formation. These data identify a novel cell culture model and validate a mechanism-based approach to prioritize combinations of effective chemopreventive compounds for prevention/therapy of colon cancer.

Anti-proliferative effects of Chinese herb Cornus officinalis in a cell culture model for estrogen receptor‑positive clinical breast cancer

“…Anchorage-independent growth represents a specific and sensitive in vitro surrogate end point biomarker for tumorigenic cell lines (11,12,(17)(18)(19)(20). In accord, it is noteworthy that E 2 treatment resulted in an increased number of anchorage-independent colonies, while TAM treatment resulted in decreased colony number.…”

Stem cell models for genetically predisposed colon cancer (Review)

“…For example, organ cultures from histo-pathologically normal colonic crypts treated with the carcinogen dimethyl hydrazine produce hyper-cellular aberrant crypt foci upon transplantation (33). Apc mutant colonic epithelial cells exhibit spontaneous immortalization in vitro and tumorigenic transformation upon in vivo transplantation (18,19,(30)(31)(32).…”

“…Based on the importance of cancer initiating stem cells in colon cancer progression (23)(24)(25), and of published evidence on the parental colonic epithelial cell culture models for the FAP syndrome (31,32), current research has been extended to develop colon cancer stem cell models, and has been summarized in the review.…”

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).…”

“…Min COL model for the FAP syndrome have documented the growth-inhibitory efficacy of several mechanistically distinct pharmacological agents, such as CLX and difluoromethyl ornithine, and naturally occurring agents, such as epigallocatechin gallate, curcumin and eicosapentaenoic acid (7,8). Additionally, selected Chinese nutritional herbs have provided promising leads for their growth-inhibitory mechanisms in the 850…”