Role of N-Cadherin in Pancreatic Tumor Microenvironment

N-钙粘蛋白在胰腺肿瘤微环境中的作用

• 批准号: 8555506
• 负责人: KEITH R JOHNSON
• 金额: $ 17.24万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-26 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8555506
• 关键词: Adenocarcinoma; Adenocarcinoma Cell; Benign; Biological; Cadherins; Cell Communication; Cells; Clinical Research; Collagen; Deposition; Disease; Distant; Environment; Epithelial Cells; Evolution; Genetic; Genetically Engineered Mouse; Goals; Growth; Human; In Vitro; Individual; Knock-out; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Mesenchymal; Modeling; Molecular; N-Cadherin; Neoplasm Metastasis; Organ; Pancreas; Pancreatic Adenocarcinoma; Relative (related person); Role; Signal Transduction; Staging; Stromal Cells; Stromal Neoplasm; Testing; Tissues; Tumor Cell Invasion; Up-Regulation; Work; Xenograft Model; base; cancer invasiveness; cell behavior; cell motility; epithelial to mesenchymal transition; implantation; macrophage; mouse model; neoplastic cell; pancreatic neoplasm; stellate cell; tumor; tumor progression; tumorigenesis

Pancreafic adenocarcinomas are characterized by extensive deposition of collagen 1, which can have profound effects on cell behavior. We have shown that cells derived from pancreatic adenocarcinomas respond In vitro to exogenous collagen I by transforming from a non-motile epithelial cell to a highly motile and invasive mesenchymal cell. A hallmark of epithelial to mesenchymal transition is an increase in expression of the mesenchymal cadherin, N-cadherin. Keith's lab has been studying the role of N-cadherin in tumor progression for more than a decade, and we have convincingly demonstrated that upregulafion of N-cadherin expression converts epithelial cells from benign, non-mofile, non-invasive cells to highly mofile and invasive cells. From these studies, we hypothesized that N-cadherin promotes tumor cell invasion. Clinical studies from our lab and others have validated our hypothesis. Of particular significance to the current proposal is the fact that Ncadherin is expressed by more than 50% of invasive pancreatic tumors. Here, long-temn goal is to determine the molecular basis of N-cadherin-mediated invasiveness and metastasis in PC. Previous studies from our lab have demonstrated that N-cadherin knockdown in BxPC3 and Capani pancreatic adenocarcinoma cells can significantly decrease tumor progression and metastasis in orthotopic xenograft models. However, the role of individual components of the tumor microenvironment is not cleariy understood. Genetically engineered mouse models have been shown to faithfully mimic the genefic and biological evolufion of their human counterpart diseases. The hypothesis is that N-cadherin expression In multiple components of tumor microenvironment is critical for PC metastasis. We propose to test the hypothesis by generafing and ufilizing syngeneic tumor implantafion models with alterafions in N-cadherin expression in individual components of PC microenvironment. In addition to the critical role of N-cadherin expression in pancreafic adenocarcinoma cells in promoting cancer and metastasis, N-cadherin is also expressed and involved in the mofility of stellate cells as well as macrophages. Both, pancreafic stellate cells and macrophages have been shown to facilitate tumorigenesis and invasiveness of pancreatic adenocarcinoma cells. Thus, we further hypothesize that N-cadherin expression on pancreatic stellate cells and macrophages facilitates PC progression and invasion. Hence, we propose to test the relative contribufion of N-cadherin expression on stellate cells and macrophages toward PC progression and invasion by proposing the following specific aims: Aim 1: To determine the contribufion of N-cadherin-mediated adenocarcinoma cell-stromal cell interacfions in PC. Our working hypothesis of this aim is that N-cadherin mediates tumor-stromal interactions and N-cadherin expression on stromal cells facilitates their tumor recruitment. Aim 2: To determine the contribufion of N-cadherin-mediated adenocarcinoma cell-macrophage interacfions toward PC invasiveness. Our working hypothesis of this aim is that N-cadherin expression on macrophages facilitates their recruitment and acfivafion in the tumor cell compartments and facilitates PC progression.

胰腺腺癌的特征在于胶原蛋白1的广泛沉积，其可具有深刻的病理改变。 对细胞行为的影响我们已经证明，胰腺癌细胞在体外 外源性I型胶原蛋白，从非运动性上皮细胞转化为高度运动性和侵袭性的 间充质细胞上皮细胞向间质细胞转化的标志是上皮细胞的表达增加， 间充质钙粘蛋白，N-钙粘蛋白。基思的实验室一直在研究N-钙粘蛋白在肿瘤进展中的作用 十多年来，我们已经令人信服地证明了N-钙粘蛋白表达的上调 将上皮细胞从良性、非移动、非侵入性细胞转化为高度移动和侵入性细胞。从这些研究中，我们假设N-钙粘蛋白促进肿瘤细胞的侵袭。我们实验室的临床研究， 其他人证实了我们的假设。对目前的建议特别重要的是，Ncadherin 在50%以上的侵袭性胰腺肿瘤中表达。 本研究的长期目标是确定N-钙粘蛋白介导的侵袭和转移的分子基础 在PC上。我们实验室以前的研究表明，BxPC 3和Capani中的N-钙粘蛋白敲低 胰腺癌细胞可以显着减少肿瘤的进展和转移， 异种移植模型。然而，肿瘤微环境的单个组分的作用尚不清楚， 明白基因工程小鼠模型已被证明忠实地模仿基因和 人类疾病的生物进化。假设N-钙粘蛋白的表达在 肿瘤微环境的多种成分对PC转移至关重要。我们建议测试 通过N-钙粘蛋白改变建立和应用同基因肿瘤模型的假说 在PC微环境的单个组件中表达。 除了N-钙粘蛋白在胰腺癌细胞中的表达在促进癌症发生中的关键作用外， 和转移，N-钙粘蛋白也表达，并参与星状细胞的运动， 巨噬细胞胰腺星状细胞和巨噬细胞都能促进肿瘤的发生 和胰腺癌细胞的侵袭性。因此，我们进一步假设N-钙粘蛋白 胰腺星状细胞和巨噬细胞上的表达促进PC进展和侵袭。 因此，我们建议检测星形细胞和巨噬细胞上N-钙粘蛋白表达的相对贡献， 通过提出以下具体目标，对PC进展和侵袭进行研究： 目的1：探讨N-钙粘蛋白介导的腺癌细胞-间质细胞相互作用在肿瘤发生发展中的作用。 PC.我们的工作假设是，N-钙粘蛋白介导的肿瘤间质的相互作用和N-钙粘蛋白 在基质细胞上的表达促进它们的肿瘤募集。 目的2：探讨N-钙粘蛋白介导的腺癌细胞-巨噬细胞相互作用 对PC的入侵。我们的工作假设是，巨噬细胞上的N-钙粘蛋白表达 促进它们在肿瘤细胞区室中的募集和活化，并促进PC进展。