The Role of N-cadherin in Tumor Progresion

N-钙粘蛋白在肿瘤进展中的作用

基本信息

批准号：
7749951
负责人：
GLENN Lawrence RADICE
金额：
$ 20.39万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-01-01 至 2010-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7749951
关键词：
Actins Adhesions Affect Alleles Animal Model Animals Antineoplastic Agents Behavior Benign Binding Blood Circulation Breast Cancer Cell Cadherins Cancer Etiology Cardiac Myocytes Cell Adhesion Cell Adhesion Molecules Cell Proliferation Cell surface Cell-Matrix Junction Cells Cessation of life Clinical Trials Complex Contact Inhibition Cytoskeleton Data Development Diagnosis Disease Distant Dominant-Negative Mutation Ductal Ductal Epithelial Cell E-Cadherin Embryo Endothelial Cells Epithelial Epithelium Event Extravasation Family Focal Adhesion Kinase 1 Focal Adhesions Genes Goals Grant Human Incidence Integrins K-ras Oncogene Knock-out Knockout Mice Lesion Malignant - descriptor Malignant Neoplasms Malignant neoplasm of pancreas Mediating Modeling Molecular Mus Mutation N-Cadherin Neoplasm Metastasis Normal tissue morphology Organ Pancreas Pancreatic Adenocarcinoma Pancreatic Ductal Adenocarcinoma Pancreatic Intraepithelial Neoplasia Patients Phase Point Mutation Primary Neoplasm Process Protein p53 Regulation Role Signal Transduction Stem cells Survival Rate Symptoms System Tissues Transgenes Tumor Suppressor Genes United States Up-Regulation abstracting adhesion receptor base cancer cell carcinogenesis cell behavior cell growth human disease in vivo insight mortality mouse model mutant neoplastic cell novel public health relevance tumor tumor growth tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Abstract Cancer metastasis is a complex multistep process, involving the detachment of cancer cells from the primary tumor, intravasation, survival in the bloodstream, extravasation, and establishment of new foci in distant organs. Changes in cell-cell and cell-matrix adhesion accompany the transition from benign tumors to invasive, malignant cancer and the subsequent metastatic dissemination of tumor cells. Cadherins are a family of cell adhesion molecules expressed in a tissue specific manner in normal tissues. E-cadherin is responsible for maintaining the normal organization of the epithelia and is often downregulated in metastatic tumors. In contrast, de novo expression of N-cadherin is often observed in tumors of epithelial origin. N-cadherin alters the cellular behavior of breast cancer cells in culture rendering them more motile and invasive. Cadherin subtype switching (E-cadherin to N- cadherin) is a hallmark of tumor progression, yet it is poorly understood how N-cadherin affects tumor cell behavior in vivo. We generated an N-cadherin conditional knockout (CKO) mouse (conventional N-cadherin KO is embryonic lethal), providing an opportunity to examine the requirement for N- cadherin in tumor progression and metastasis in a genetically defined animal model. The N-cadherin CKO model was combined with a novel pancreatic ductal carcinogenesis model that targets mutant K-ras to pancreatic progenitor cells. This animal model recapitulates the progression of pancreatic intraepithelial neoplasia (PanIN) to pancreatic ductal adenocarcinoma (PDA) observed in human patients with pancreatic cancer. We describe in vivo evidence that loss of N-cadherin results in increased tumorigenesis. Based on these preliminary data, we hypothesize that loss of N-cadherin- mediated adhesion/signaling relieves cell contact inhibition of cell growth by altering the actin cytoskeleton. This hypothesis will be pursued by the following interrelated Specific Aims: (1) To characterize the progression of PanIN to PDA in the absence of N-cadherin; (2) To evaluate the effects of loss of N-cadherin on the cytoskeletal regulator, RhoA; (3) To determine the role of focal adhesions in the regulation of N-cadherin-mediated contact inhibition of cell growth. This exploratory R21 grant will determine the consequences of genetically blocking the switch from E-cadherin to N- cadherin in pancreatic cancer. Understanding the molecular mechanisms underlying the progression of pancreatic cancer may provide insight for the development of novel antineoplastic therapies. PUBLIC HEALTH RELEVANCE: Our unexpected finding that loss of N-cadherin leads to increased PanIN development in K-rasG12D; N-cadflox/flox; Pdx1-Cre mice provides an entry point to uncover novel molecular mechanisms regulating tumor growth. Furthermore, a better understanding of N-cadherin function in vivo is imperative given that the N-cadherin antagonist, ADH-1, is now in Phase IIb clinical trial (http://www.adherex.com). Understanding the molecular mechanisms underlying the progression of pancreatic cancer may provide insight for the development of novel antineoplastic therapies.

描述（由申请人提供）：摘要癌症转移是一个复杂的多步骤过程，涉及癌细胞从原发肿瘤脱离、内渗、在血流中存活、外渗以及在远处器官中建立新病灶。细胞-细胞和细胞-基质粘附的变化伴随着从良性肿瘤到侵袭性恶性癌症的转变以及随后的肿瘤细胞的转移性传播。钙粘蛋白是在正常组织中以组织特异性方式表达的细胞粘附分子家族。 E-钙粘蛋白负责维持上皮细胞的正常组织，并且在转移性肿瘤中经常下调。相反，N-钙粘蛋白的从头表达经常在上皮来源的肿瘤中观察到。 N-钙粘蛋白改变培养中乳腺癌细胞的细胞行为，使它们更具活动性和侵袭性。钙粘蛋白亚型转换（E-钙粘蛋白至 N-钙粘蛋白）是肿瘤进展的标志，但人们对 N-钙粘蛋白如何影响体内肿瘤细胞行为知之甚少。我们培育了一只 N-钙粘蛋白条件性敲除 (CKO) 小鼠（传统的 N-钙粘蛋白 KO 是胚胎致死的），为在基因定义的动物模型中检查肿瘤进展和转移中 N-钙粘蛋白的需求提供了机会。 N-钙粘蛋白 CKO 模型与一种新型胰腺导管癌发生模型相结合，该模型将突变型 K-ras 靶向胰腺祖细胞。该动物模型概括了在人类胰腺癌患者中观察到的胰腺上皮内瘤变 (PanIN) 到胰腺导管腺癌 (PDA) 的进展。我们描述了 N-钙粘蛋白缺失会导致肿瘤发生增加的体内证据。基于这些初步数据，我们假设 N-钙粘蛋白介导的粘附/信号传导的丧失通过改变肌动蛋白细胞骨架来减轻细胞接触对细胞生长的抑制。这一假设将通过以下相互关联的具体目标来实现： (1) 表征在 N-钙粘蛋白缺失的情况下 PanIN 向 PDA 的进展； (2) 评估N-钙粘蛋白缺失对细胞骨架调节因子RhoA的影响； (3)确定粘着斑在调节N-钙粘蛋白介导的细胞生长接触抑制中的作用。这项探索性的 R21 资助将确定从基因上阻断胰腺癌中从 E-钙粘蛋白到 N-钙粘蛋白的转变的后果。了解胰腺癌进展的分子机制可能为新型抗肿瘤疗法的开发提供见解。公共健康相关性：我们意外地发现 N-钙粘蛋白的缺失会导致 K-rasG12D 中 PanIN 的发育增加； N-cadflox/flox； Pdx1-Cre 小鼠为揭示调节肿瘤生长的新分子机制提供了一个切入点。此外，鉴于 N-钙粘蛋白拮抗剂 ADH-1 目前正处于 IIb 期临床试验中，更好地了解 N-钙粘蛋白的体内功能势在必行 (http://www.adherex.com)。了解胰腺癌进展的分子机制可能为新型抗肿瘤疗法的开发提供见解。