CXCL12/CXCR4 Signaling - A Novel Target for Pancreatic Intraepithelial Neoplasia

描述（由申请人提供）：在胰腺癌的发展模型中，胰管经历一系列渐进式的结构、细胞学和遗传变化，这些变化由胰腺上皮内瘤变（PanIN）的程度决定。由于体外和体内模型有限，对PanIN的评估一直具有挑战性。最近通过靶向内源性表达K-ras突变等位基因（最早被发现的人类遗传异常）建立小鼠PanIN模型，概括了人类PanIN，并为研究其机制提供了必要的工具。最近，我们的实验室首次发现趋化因子受体CXCR4在PanIN生长和增殖中的潜在作用。在小鼠和人的PanIN组织中，我们观察到组织学正常的胰管中没有CXCR4的表达，但在PanIN病变中CXCR4的表达增加。我们还注意到CXCR4受体通过其特异性配体CXCL12激活，导致PanIN细胞增殖增强（Gut, 2008）。失调的K-Ras信号将胰管转变为PanIN病变，但这些K-Ras依赖性的变化似乎也可能由激活的CXCR4进一步驱动。小鼠PanIN模型的建立和使用是研究人类PanIN的必要和独特的临床前工具。它将允许我们探索和修改CXCR4信号通路及其介质。我们假设CXCR4信号是PanIN增殖和进展所必需的。由于离散的CXCR4信号传导导致PanIN增强和胰腺癌增殖尚未被定义，我们的目标是在这方面定义CXCR4信号转导，并评估特异性CXCR4信号传导介质的体内治疗靶向，以防止PanIN的初始发展或防止其发展为侵袭性和转移性胰腺癌。我们提出以下目标：1)目标1：表征与增殖增强相关的CXCR4信号，并确定拮抗CXCR4增强增殖的最佳靶点。2)目的二：确定下游CXCR4信号是否受K-Ras调控。3)目的三：在体内小鼠PanIN模型中，确定靶向治疗CXCR4是否能阻止或消除PanIN向胰腺癌的进展。

DESCRIPTION (provided by applicant): In the model for the development of pancreatic cancer, the pancreatic ducts undergo a progressive series of architectural, cytologic, and genetic changes that are defined by degrees of pancreatic intraepithelial neoplasia (PanIN). The evaluation of PanIN has been challenging due to limited in vitro and in vivo models. The recent development of a mouse PanIN model through targeted endogenous expression of a K-ras mutant allele, the earliest recognized human genetic aberrancy, recapitulates human PanIN and provides a necessary tool to study its mechanisms. Recently, our laboratory was the first to identify a potential role for chemokine receptor CXCR4 in the growth and proliferation of PanIN. Using mouse and human PanIN tissues, we observed absence of CXCR4 expression in histologically normal pancreatic ducts, but increased CXCR4 expression in PanIN lesions. We also noted that activation of the CXCR4 receptor, by its specific ligand CXCL12, resulted in enhanced PanIN cell proliferation (Gut, 2008). Dysregulated K-Ras signaling transforms pancreatic ducts into PanIN lesions, but it also appears that these K-Ras dependent changes may be further driven by activated CXCR4. The establishment and use of a mouse PanIN model is a necessary and uniquely available preclinical tool for the investigation of human PanIN. It will allow us to explore and modify CXCR4 signaling pathways and its mediators. We hypothesize that CXCR4 signaling is requisite for PanIN proliferation and progression. Since discrete CXCR4 signaling leading to enhanced PanIN and pancreatic cancer proliferation has not been defined, our objectives are to define CXCR4 signal transduction in this regard and to assess in vivo therapeutic targeting of specific CXCR4 signaling mediators to prevent the initial development of PanIN or prevent its progression to invasive and metastatic pancreatic cancer. We propose the following Aims: 1) Aim I: Characterize CXCR4 signaling associated with enhanced proliferation and identify optimal targets to antagonize CXCR4-enhanced proliferation. 2) Aim II: Determine whether downstream CXCR4 signaling is regulated by K-Ras. 3) Aim III: Determine whether therapeutic targeting of CXCR4 prevents or abrogates progression of PanIN into pancreatic cancer in an in vivo murine PanIN model. PUBLIC HEALTH RELEVANCE: Pancreatic cancer is a major cause of cancer-related deaths. Poor survival results from frequent recurrence after curative surgery and resistance to chemoradiation therapies. A better understanding of the pathogenesis of pancreatic cancer is clearly needed to improve clinical outcomes. The results of our proposed research studies can be applied to the prevention and/or treatment of human pancreatic disease.