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: 7935258
• 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/7935258
• 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（由申请人提供）：在胰腺癌发展模型中，胰管经历了一系列渐进的建筑，细胞学和遗传学变化，这些变化是由胰腺上皮内肿瘤（PANIN）定义的。由于体外和体内模型有限，Panin的评估一直在挑战。小鼠Panin模型通过靶向内源性表达的K-Ras突变等位基因的最早发展，最早的人类遗传异常概括了人类Panin，并提供了研究其机制的必要工具。最近，我们的实验室是第一个确定趋化因子受体CXCR4在Panin生长和增殖中的潜在作用的实验室。使用小鼠和人类Panin组织，我们观察到在组织学正常胰管中没有CXCR4表达，但Panin病变中CXCR4的表达增加。我们还注意到，CXCR4受体的激活通过其特异性配体CXCL12导致了Panin细胞增殖增强（Gut，2008）。失调的K-RAS信号传导将胰管转化为Panin病变，但看来这些依赖K-RAS的变化可能会被激活的CXCR4进一步驱动。 小鼠Panin模型的建立和使用是研究人类Panin的必要且独特的临床前工具。它将允许我们探索和修改CXCR4信号通路及其介体。我们假设CXCR4信号是Panin增殖和进展所必需的。由于尚未定义导致Panin和胰腺癌增殖增强的离散CXCR4信号传导，因此我们的目标是在这方面定义CXCR4信号转导，并评估体内特定CXCR4信号介体的靶向靶向，以防止Panin的初始发展或预防其进展，以防止其进展，从而对其进行转化和转移性癌症。我们提出以下目的：1）目标I：表征与增强增殖相关的CXCR4信号传导，并确定最佳目标以拮抗CXCR4增强增殖。 2）AIM II：确定下游CXCR4信号是否由K-RAS调节。 3）AIM III：确定CXCR4的治疗靶向是否可以防止或消除Panin在体内鼠Panin模型中的胰腺癌进展。 公共卫生相关性：胰腺癌是与癌症相关死亡的主要原因。生存率差是治愈手术后经常复发和对化学放疗疗法的耐药性。显然需要更好地了解胰腺癌的发病机理，以改善临床结果。我们提出的研究的结果可以应用于预防和/或治疗人类胰腺疾病的结果。