Abstract 182: Differential response of epithelial cells from colorectal adenomas and adjacent nonneoplastic colonic mucosa to aspirin and atorvastatin in Apc+/Min-FCCC mice.

Abstract

Abstract Although various agents have been identified that are efficacious in inhibiting colorectal adenomas in humans, the precise mechanisms responsible for their antitumor activity remain ill-defined. Significant insight into the use of agents for the prevention and treatment of colorectal cancer can be gained by examining the biological response of nonneoplastic colonic mucosa and colorectal adenomas to drug exposure. The present study compared the gene expression profile of neoplastic and nonneoplastic colonic epithelial cells following short-term administration of aspirin and atorvastatin to a strain of mice that uniquely develop multiple colorectal adenomas (Apc+/Min-FCCC). Tumor-bearing male Apc+/Min-FCCC mice (70 days of age) received either control Teklad 2018SX diet or diet supplemented with aspirin (300 ppm) or atorvastatin (100 ppm) for 7 days. At euthanasia, the colon was examined for gross lesions and matched pairs of colorectal adenomas and adjacent normal mucosa were frozen in OCT for gene expression analyses. Colonic epithelial cells were laser microdissected from pairs of pathologically-confirmed colorectal adenomas and nonneoplastic mucosa (4/treatment group). Amplified RNA was subjected to gene expression profiling using Agilent Mouse Whole Genome 4 X 44K microarrays. Genes differentially expressed in colon tissue from untreated vs. drug-treated mice were identified using LIMMA methodology and filtered (p = 0.01). The number of unique genes differentially expressed in neoplastic epithelial cells exposed to aspirin was 1052, while a much smaller set of genes (N=74) was altered in the nonneoplastic epithelium. Functional enrichment analyses revealed that the pathways modulated in nonneoplastic cells (i.e. protein folding, posttranscriptional regulation, DNA damage response, vascular permeability) were distinct from those altered in adenomas (i.e. cell adhesion, DNA repair, TOR signaling, apoptosis, glucose transport). In contrast, fewer genes were differentially expressed in neoplastic cells (N = 286) than in the adjacent nonneoplastic colonic mucosa (N = 749) following exposure to atorvastatin. The majority of the cellular processes modified in nonneoplastic cells by atorvastatin (i.e. DNA damage, cell death, immune function, cilium assembly) differed from those affected in neoplastic cells (i.e. lipid metabolism, apoptosis, cell cycle control, DNA repair). These data suggest that the mechanisms responsible for the protection conferred to nonneoplastic cells by aspirin or atorvastatin vary from those that lead to inhibition of tumor growth. Further mining of these expression data when combined with endoscopic monitoring of individual lesions during drug exposure should significantly enhance our understanding of the cellular processes responsible for their activity. (Supported by NIH N01 CN43309) Citation Format: Lisa Vanderveer, Suresh Paramasivam, Kara Williams, Harry Cooper, Karthik Devarajan, Suraj Peri, Yan Zhou, Laura Henik, Wen-Chi Chang, Ronald Lubet, Margie Clapper. Differential response of epithelial cells from colorectal adenomas and adjacent nonneoplastic colonic mucosa to aspirin and atorvastatin in Apc+/Min-FCCC mice. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 182. doi:10.1158/1538-7445.AM2013-182