Courtney W. Houchen, M.D.

DEPARTMENT OF Internal Medicine
Keywords: apoptosis, colorectal cancer, epithelial cell proliferation, prostaglandins

Colorectal cancer, the second-leading cause of cancer death in the western world, arises through the acquisition of multiple, independent genetic mutations and subsequent clonal expansion of mutated crypt epithelial stem cells. Programmed cell death, or apoptosis, is an effective method of removal of these genetically damaged epithelial cells. The continuous and rapid renewal of the gastrointestinal epithelium under both normal conditions and during injury repair makes the gut an attractive model system to study regulation of the balance between proliferation and apoptosis in the carcinoma sequence.

Human adenocarcinomas contain high levels of prostaglandins (PGs). PGs have broad physiologic and pathophysiologic effects. They regulate a wide variety of cellular processes in nearly all mammalian tissues. PGs, such as PGE2, are critical mediators of epithelial integrity in the gastrointestinal tract and play a major role in the regulation of apoptosis, cell differentiation and oncogenesis in many tissues. We have shown that PGE2 synthesized by cyclooxygenase-1 (COX-1) is an important regulator of crypt epithelial stem cell survival and crypt epithelial apoptosis in response to radiation injury in the intestine. However, the mechanism by which PGE2 regulates intestinal epithelial stem cell fate during normal turnover or during wound repair remains unknown. The biological activities of PGE2 are mediated through its interaction with plasma membrane G protein-coupled receptors termed EP receptors. There are currently four EP receptor subtypes, EP1, EP2, EP3 and EP4, which differ in their ligand-binding specificities and in their downstream signal transduction pathways. We have shown that EP2 receptor mRNA and protein are expressed throughout the gastrointestinal tract in mice and receptor levels are increased following radiation injury. Using EP2 receptor-null mice, we have generated data that demonstrates that endogenous PGE2 signaling through the EP2 receptor regulates crypt epithelial apoptosis and stem cell survival. Our strategy for examining the functional role of EP receptors is to completely characterize the expression of the EP receptors following intestinal and colonic injury, and to investigate their role in the regulation of epithelial proliferation and apoptosis. These studies should contribute to our understanding of the role of prostaglandin signaling in gastrointestinal cancers.