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.

胰腺腺癌的特征是胶原蛋白1的广泛沉积，这可能具有深刻的 对细胞行为的影响。我们已经表明，源自胰腺腺癌的细胞在体外反应 通过从非运动上皮细胞转变为高度动力和侵入性来使外源胶原蛋白I转变 间充质细胞。上皮到间充质转变的标志是表达的增加 间充质钙粘着蛋白，N-钙粘着蛋白。基思的实验室一直在研究N-钙黏着蛋白在肿瘤进展中的作用 十多年来，我们令人信服地证明了N-钙粘蛋白的表达 将上皮细胞从良性，非纤维，非侵入性细胞转换为高度镀金和侵入性细胞。从这些研究中，我们假设N-钙粘蛋白促进肿瘤细胞侵袭。我们实验室的临床研究和 其他人已经验证了我们的假设。对于当前的提议特别重要的是Ncadherin 超过50％的浸润性胰腺肿瘤表达。 在这里，长期目标是确定N-钙粘蛋白介导的侵入性和转移的分子基础 在PC中。我们实验室的先前研究表明，BXPC3和Capani中的N-钙粘蛋白敲低 胰腺腺癌细胞可以显着降低原位的肿瘤进展和转移 异种移植模型。但是，肿瘤微环境的各个组成部分的作用并不明确 理解。已经证明了基因工程的小鼠模型忠实地模仿了基因法和 人类对应疾病的生物发展。假设是N-钙粘蛋白在 肿瘤微环境的多个成分对于PC转移至关重要。我们建议测试 通过n-钙粘着蛋白中的替代品的植物肿瘤植入模型来假设。 PC微环境的各个组件中的表达。 除N-钙粘蛋白表达在胰腺腺癌细胞中的关键作用外， 和转移，N-钙粘着蛋白也表达并参与星状细胞的可变性以及 巨噬细胞。胰腺明星细胞和巨噬细胞都已证明可以促进肿瘤发生 胰腺腺癌细胞的侵袭性。因此，我们进一步假设N-辅助蛋白 胰腺星状细胞和巨噬细胞上的表达促进了PC的进展和侵袭。 因此，我们建议测试N-钙粘蛋白表达在星状细胞和巨噬细胞上的相对贡献 通过提出以下特定目的来实现PC的进展和入侵： 目的1：确定N-钙粘蛋白介导的腺癌细胞质细胞间隔的贡献 个人电脑。我们对此目的的工作假设是N-钙粘蛋白介导肿瘤 - 基质相互作用和N-钙粘蛋白 基质细胞上的表达促进其肿瘤募集。 目标2：确定N-钙粘蛋白介导的腺癌细胞巨噬细胞的贡献 迈向PC侵入性。我们对此目标的工作假设是N-钙粘蛋白在巨噬细胞上的表达 促进了他们在肿瘤细胞室中的招募和Acfivafion，并促进了PC的进展。