VIP RECEPTOR SECOND MESSENGERS IN PANCREATIC CANCER

摘要导管型胰腺癌是我国五大癌症之一。 成年人中的杀手。当前治疗策略的失败 患有这种恶性肿瘤的患者建议更好地理解 肿瘤胰腺管细胞的综合病理生理学将 被要求制定有效的新战略。基于 某些G蛋白偶联受体对导管细胞的重要性 生理上，我们认为它们的第二信使可能起着关键的生长作用 起到调节作用。我们实验室的初步研究支持 统一了VIP-1受体在人类中普遍表达的假设 导管型胰腺癌与相反途径的偶联 刺激和抑制肿瘤生长的潜力。具体来说， 我们的数据表明，VIP-1受体与两种cAMP非依赖性受体偶联 生长刺激和cAMP依赖的生长抑制通路 肿瘤性胰管细胞。关于后者，坎普 抑制酪氨酸激酶受体(TKR)诱导丝裂原活化 蛋白激酶，TKR刺激的G1产生S相变，以及 肿瘤胰腺管细胞的后续进展 基于这些发现的潜在重要性，我们将 通过研究进一步检验这一统一假说(1)比较 血管活性肠肽和腺苷环化酶直接激活剂Forsklin的作用 )对多种携带VIP-1受体的人肿瘤细胞的体外生长的影响。 分子谱清晰的衍生细胞系，(2) 确认生长促进与生长抑制的同一性 这些细胞中由VIP-1受体激活的通路，以及(3)定义 CAMP抑制G1期细胞产生S相变的机制 以及随后这些细胞通过G2/M期VIP的适度进展 对携带VIP-1受体的人肿瘤体外生长的整体影响 衍生细胞，推测反映伴随的生长激活 刺激和生长抑制通路，提示普通VIP 受体拮抗剂不会为我们提供灵丹妙药。更确切地说， 为了实现我们的目标--最终把这个广为表达的 腺酰环化酶偶联受体在组合中的优势 治疗策略-我们必须首先辨别具体的生长 其G蛋白偶联第二信使对人体的调节作用 胰腺导管癌。

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.