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

CXCL12/CXCR4 信号传导 - 胰腺上皮内瘤变的新靶点

• 批准号: 7788760
• 负责人: JOSEPH KIM
• 金额: $ 19.17万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-18 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7788760
• 关键词: AMD3100; Alleles; Animals; CXCL12 gene; CXCR4 Receptors; CXCR4 Signaling Pathway; CXCR4 gene; Cancer Etiology; Cancer Model; Cell Line; Cell Proliferation; Cells; Cessation of life; Chemoprevention; Clinical; Clinical Research; Clinical Trials; Co-Immunoprecipitations; Curative Surgery; Data; Development; Disease; Duct (organ) structure; Evaluation; Genes; Goals; Growth; Histologic; Human; Human Genetics; In Vitro; Investigation; Laboratories; Lesion; Ligands; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Mediator of activation protein; Metastatic Neoplasm to the Liver; Modeling; Mus; Mutation; Outcome; Pancreas; Pancreatic Diseases; Pancreatic Intraepithelial Neoplasia; Pancreatic duct; Pathogenesis; Pathway interactions; Phosphorylation; Prevention; Proto-Oncogene Proteins c-akt; Recurrence; Research; Resistance; Role; Series; Signal Transduction; Testing; Therapeutic; Therapeutic Agents; Time; Tipifarnib; Tissues; Transfection; Translations; Work; cancer therapy; chemokine receptor; drug testing; gain of function; improved; in vivo; in vivo Model; inhibitor/antagonist; innovation; model development; mutant; new therapeutic target; novel; novel therapeutics; outcome forecast; pre-clinical; prevent; public health relevance; ras Proteins; research study; response; small molecule; therapeutic target; tool

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.

描述（由申请方提供）：在胰腺癌发展模型中，胰腺导管经历了一系列渐进的结构、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，PanIN的评价一直具有挑战性。最近开发的小鼠PanIN模型，通过有针对性的内源性表达的K-ras突变等位基因，最早认识到的人类遗传异常，概括人类PanIN，并提供了一个必要的工具来研究其机制。最近，我们的实验室是第一个确定趋化因子受体CXCR 4在PanIN的生长和增殖中的潜在作用。使用小鼠和人PanIN组织，我们观察到在组织学正常的胰管中CXCR 4表达缺失，但在PanIN病变中CXCR 4表达增加。我们还注意到，CXCR 4受体通过其特异性配体CXCL 12的活化导致PanIN细胞增殖增强（Gut，2008）。失调的K-Ras信号转导将胰管转化为PanIN病变，但似乎这些K-Ras依赖性变化可能进一步由活化的CXCR 4驱动。 小鼠PanIN模型的建立和使用是研究人PanIN的必要且唯一可用的临床前工具。它将使我们能够探索和修改CXCR 4信号通路及其介质。我们假设CXCR 4信号传导是PanIN增殖和进展所必需的。由于导致PanIN和胰腺癌增殖增强的离散CXCR 4信号传导尚未确定，我们的目标是在这方面定义CXCR 4信号转导，并评估特异性CXCR 4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进展为侵袭性和转移性胰腺癌。我们提出以下目标：1）目标一：表征与增强的增殖相关的CXCR 4信号传导，并确定拮抗CXCR 4增强的增殖的最佳靶点。2)目的II：确定下游CXCR 4信号传导是否受K-Ras调节。3)目标三：在体内鼠PanIN模型中确定CXCR 4的治疗靶向是否阻止或消除PanIN进展为胰腺癌。 公共卫生相关性：胰腺癌是癌症相关死亡的主要原因。根治性手术后的频繁复发和对放化疗的抵抗导致生存率低。更好地了解胰腺癌的发病机制显然是需要改善临床结果。我们提出的研究结果可以应用于预防和/或治疗人类胰腺疾病。