Embryonic Signaling Pathways in Pancreatic Cancer

描述(申请人提供)：本研究的目标是研究两个胚胎信号通路Hedgehog和Wnt在胰腺癌形成和生长过程中的作用。胰腺癌是一种破坏性疾病，由于发现较晚、侵袭性强以及转化细胞的早期转移，预后较差。建议的研究旨在测试Hedgehog和Wnt信号的异位激活是否可以激活肿瘤的形成，以及抑制这些信号通路是否会导致肿瘤消退。 我们假设，解除这两种途径中的任何一种都足以诱导胰腺组织的肿瘤发生，并且它们的持续活动是肿瘤存活所必需的。我们的一般方法是使用细胞培养试验和转基因小鼠实验相结合的方法来解除对正常和转化的胰腺细胞中这两个途径的活动水平的调节。 第一个特定的目的是确定失控的Hedgehog信号是否是胰腺癌形成过程中最早的事件之一。我们建议建立细胞培养和体内模型系统来研究胰腺癌的形成。 第二个具体目的是确定抑制Wnt信号是否足以阻止胰腺癌细胞的增殖和导致细胞凋亡。我们还将测试Wnt信号在培养的胰腺管细胞中的异位激活，以及在体内成熟的胰腺组织中是否诱导腺癌的形成。 第三个具体目标是确定Hedgehog和Wnt信号通路是否相互调节彼此的活动，以及胰腺癌细胞的生长和生存是否依赖于它们的合作功能。 综上所述，我们将探索胚胎信号通路的失控是否与胰腺癌的发展和生存有关。我们预计，这些研究将提高我们对这种癌症的分子病因的理解。在最好的情况下，他们将帮助设计治疗患有这种疾病的人类患者的新策略。

DESCRIPTION (provided by applicant): The goal of the proposed study is to investigate the role of two embryonic signaling pathways, Hedgehog and Wnt, during the formation and growth of pancreatic adenocarcinoma. Pancreatic adenocarcinoma constitutes a devastating disease that is marked by a poor prognosis due to late detection, aggressive nature, and early metastasis of transformed cells. The proposed studies are designed to test whether ectopic activation of Hedgehog and Wnt signaling can activate tumor formation and if inhibition of these pathways induces tumor regression. We hypothesize that deregulation of either pathway is sufficient to induce tumorigenesis in pancreatic tissue and that their continued activities are required for tumor survival. Our general approach is to use a combination of cell culture assays and transgenic mouse experiments to deregulate the activity levels of both pathways in normal and transformed pancreatic cells. The first specific aim is to determine if uncontrolled Hedgehog signaling is one of the earliest events during formation of pancreatic adenocarcinoma. We propose to establish cell culture and in vivo model systems to study the formation of pancreatic cancer. The second specific aim is to determine if inhibition of Wnt signaling is sufficient to block proliferation and cause apoptosis in pancreatic adenocarcinoma cells. We will also test if ectopic activation of Wnt signaling in cultured pancreatic duct cells, as well as in mature pancreatic tissue in vivo, induces adenocarcinoma formation. The third specific aim is to determine if the Hedgehog and Wnt signaling pathways regulate each other's activities and whether growth and survival of pancreatic cancer cells depends on their cooperative functions. In summary, we will explore if deregulation of embryonic signaling pathways is implicated in the development and survival of pancreatic adenocarcinoma. We anticipate that these studies will improve our understanding of the molecular causes of this cancer. In the best case, they will help to design new strategies for treatment of human patients suffering from this disease.