VIP RECEPTOR SECOND MESSENGERS IN PANCREATIC CANCER

导管胰腺腺癌是五大肿瘤之一

Ductal pancreatic adenocarcinoma is one of the five largest cancer killers in adults. The failure of current therapeutic strategies in patients with this malignancy suggests that a better understanding of the integrative pathophysiology of neoplastic pancreatic duct cells will be required to develop effective novel strategies. Based on the importance of certain G protein-coupled receptors to duct cell physiology, we feel that their second messengers may play key growth modulatory roles. PRELIMINARY STUDIES in our laboratory support the UNIFYING HYPOTHESIS that VIP-1 receptors are commonly expressed in human ductal pancreatic adenocarcinomas and couple to opposing pathways with the potential to both stimulate and arrest tumor growth. Specifically, our data suggest that VIP-1 receptors couple to both cAMP-independent growth stimulatory and cAMP-dependent growth inhibitory pathways in neoplastic pancreatic duct cells. With regard to the later, cAMP inhibits tyrosine kinase receptor (TKR)-induction of mitogen-activated protein kinases, TKR-stimulated G1 yields S phase transition, and subsequent progression of neoplastcic pancreatic duct cells through G2/M. Based on the potential importance of these findings, we will further test this UNIFYING HYPOTHESIS through studies (1) comparing the effects of VIP and forskolin ( a direct activator of adenylyl cyclases ) on in vitro growth of a variety of VIP-1 receptor-bearing human tumor- derived cell lines with well-defined molecular profiles , (2) confirming the identity of growth stimulatory and growth inhibitory pathways activated by VIP-1 receptors in these cells, and (3) defining the mechanisms through which cAMP inhibits G1 yields S phase transititon and subsequent progression of these cells through G2/M. VIP's modest overall effect on in vitro growth of VIP-1 receptor-bearing human tumor- derived cells, presumably reflecting concomitant activation of growth stimulatory and growth inhibitory pathways, suggests that generic VIP receptor antagonists will not provide us with a magic bullet . Rather, in order to achieve our GOAL - to eventually turn this widely expressed adenylyl cyclase-coupled receptor to our advantage in combination therapeutic strategies-we must first discern the specific growth regulatory roles of its G protein-coupled second messengers in human ductal pancreatic cancers.