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

描述(申请人提供)：在胰腺癌发展的模型中，胰腺导管经历了一系列渐进性的结构、细胞学和遗传学变化，这些变化由胰腺上皮内瘤变(Panin)的程度定义。由于体外和体内模型有限，对Panin的评价一直具有挑战性。最近通过靶向内源性表达K-ras突变等位基因的小鼠Panin模型的发展，概括了人类Panin的最早发现的遗传变异，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了趋化因子受体CXCR4在Panin的生长和增殖中的潜在作用。利用小鼠和人的Panin组织，我们观察到CXCR4在组织学上正常的胰管中不表达，但在Panin病变中表达增加。我们还注意到，CXCR4受体被其特定的配体CXCL12激活，导致Panin细胞的增殖增强(Gut，2008)。异常调节的K-RAS信号将胰腺导管转化为PanIN病变，但似乎这些K-RAS依赖的变化可能由激活的CXCR4进一步驱动。小鼠Panin模型的建立和使用是研究人类Panin的必要和唯一可用的临床前工具。它将使我们能够探索和修改CXCR4信号通路及其介体。我们推测CXCR4信号对Panin的增殖和进展是必需的。由于导致Panin增强和胰腺癌增殖的离散CXCR4信号尚未确定，我们的目标是确定这方面的CXCR4信号转导，并评估特定CXCR4信号介质的体内治疗靶向性，以防止Panin的初始发展或其向侵袭性和转移性胰腺癌的进展。我们提出了以下目标：1)目的I：研究CXCR4信号与细胞增殖增强的关系，并寻找最佳靶点以对抗CXCR4促进的细胞增殖。2)目的II：确定CXCR4下游信号是否受K-RAS调控。3)目的III：在体内的小鼠胰腺癌模型中，确定CXCR4的治疗靶向是否阻止或消除Panin向胰腺癌的进展。 公共卫生相关性：胰腺癌是癌症相关死亡的主要原因。由于根治性手术后经常复发以及对放化疗的抵抗，导致存活率低。为了改善临床结果，显然需要更好地了解胰腺癌的发病机制。我们提出的研究结果可以应用于人类胰腺疾病的预防和/或治疗。

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.