Title

Dissecting molecular pathways involved in the multistage progression of colon cancer using a murine model

Date of Completion

January 2003

Keywords

Biology, Molecular|Health Sciences, Pharmacology|Health Sciences, Immunology|Health Sciences, Oncology

Degree

Ph.D.

Abstract

Evasion from the immune surveillance system is an important aspect during the process of tumorigenesis. It allows a transformed cell to survive immune attack and undergo clonal expansion. In the present study, we have identified a novel mechanism by which colon tumor cells became resistant to inflammatory cytokines induced apoptosis. ^ Cytosolic phospholipase A2 (cPLA2) is an essential enzyme that hydrolyze membrane phospholipids to generate arachidonic acids, which can be used by cyclooxygenase (COX) to synthesis prostaglandins (PG). The role of COX-2, the inducible form of COX, and PGE2, the major PG product in the intestine, in tumorigenesis has been well characterized; however the role of cPLA2 is not yet clear. ^ In the present study, we found that cPLA2 level is barely detectable in mouse colon tumors induced by organotropic carcinogen azoxymethane (AOM), despite the fact that COX-2 is significantly upregulated with concomitant overproduction of PGE2. This phenomenon is also found to be present in 76% of human colorectal adenocarcinomas and the preneoplastic lesions. Dysregulation of cPLA2 and COX-2 expression will lead to reduced arachidonic acid production, but enhanced utilization, thus decreasing the amount of intracellular arachidonic acid levels. Since AA has been proposed to be an important mediator of immune response-induced apoptosis, we hypothesize that imbalance of cPLA2 and COX-2 expression will promote tumor cell survival against cell death signals via reduction of AA. This hypothesis is confirmed by the resistance to tumor necrosis factor α (TNF-α) induced apoptosis observed in colon tumor cells in which cPLA2 enzymatic activity or expression is inhibited. ^ Using mouse AOM-model for human colon cancer, we also found Pref-1, a gene previously known to be involved in adipogenesis, is specifically induced in the colon of AOM-sensitive inbred mouse strain, but not in the resistant strain. In addition, pref-1 is found to be present in a subset of human colon cancers. In vitro functional study demonstrated that pref-1 can inhibit butyrate induced growth arrest and differentiation, indicating that it may promote tumorigenesis in the mouse and human colon. ^