VIP RECEPTOR SECOND MESSENGERS IN PANCREATIC CANCER

胰腺导管腺癌是五大恶性肿瘤之一， 成人杀手 目前治疗策略的失败， 这种恶性肿瘤的患者表明，更好地了解 肿瘤性胰管细胞的综合病理生理学将 需要制定有效的新战略。 基于 某些G蛋白偶联受体对导管细胞重要性 从生理学上讲，我们认为它们的第二信使可能在它们的生长发育中起着关键作用， 调节作用我们实验室的初步研究支持 推翻VIP-1受体通常在人类中表达的假设 胰腺导管腺癌和偶联到相反的途径， 刺激和抑制肿瘤生长的潜力。具体地说， 我们的数据表明VIP-1受体与cAMP非依赖性 生长刺激和cAMP依赖性生长抑制途径 胰腺导管肿瘤细胞。至于后者，cAMP 抑制酪氨酸激酶受体（TKR）诱导的丝裂原活化 蛋白激酶，TKR刺激的G1产生S相变，和 胰腺导管肿瘤细胞的后续进展 G2/M。基于这些发现的潜在重要性，我们将 通过研究进一步验证这一假设（1）比较 VIP和Forskolin（腺苷酸环化酶的直接激活剂）的作用 ）对多种携带VIP-1受体的人肿瘤的体外生长的影响， 具有明确分子特征的衍生细胞系，（2） 确认生长刺激和生长抑制的同一性 在这些细胞中由VIP-1受体激活的通路，以及（3）定义 cAMP抑制G1期产生S期转变的机制 以及这些细胞通过G2/M的后续进展。 VIP的谦虚 对携带VIP-1受体的人肿瘤的体外生长的总体影响- 衍生细胞，可能反映了伴随的生长激活 刺激和生长抑制途径，这表明， 受体拮抗剂不会给我们提供灵丹妙药。 相反， 为了实现我们的目标-最终把这个广泛表达的 腺苷酸环化酶偶联受体，以我们的优势， 治疗策略-我们必须首先辨别 其G蛋白偶联第二信使在人类中的调节作用 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.