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）：抽象的癌症转移是一个复杂的多步过程，涉及癌细胞与原发性肿瘤的脱离，插入，血液中的生存，渗出和在遥远的器官中建立新的焦点。细胞 - 细胞和细胞基质粘附的变化伴随着从良性肿瘤向侵袭性，恶性癌和随后的转移性肿瘤细胞的转变。钙粘蛋白是在正常组织中以组织特异性表达的细胞粘附分子家族。 E-钙黏着蛋白负责维持上皮的正常组织，并且通常在转移性肿瘤中被下调。相反，在上皮来源的肿瘤中通常观察到N-钙粘蛋白的从头表达。 N-辅助蛋白改变培养乳腺癌细胞的细胞行为，从而使它们更加流动性和侵入性。钙粘着蛋白亚型开关（E-钙粘蛋白至N-钙粘蛋白）是肿瘤进展的标志，但是尚不清楚N-钙粘蛋白如何影响体内肿瘤细胞行为。我们产生了N-钙粘蛋白有条件敲除（CKO）小鼠（常规N-钙粘蛋白KO是胚胎致死的），为在遗传定义的动物模型中提供了一个机会来检查肿瘤进展和转移中N-钙粘蛋白的需求。 N-钙粘蛋白CKO模型与一种新型的胰腺癌致癌模型结合使用，该模型将突变的K-RAS靶向胰腺祖细胞。这种动物模型概括了胰腺内肿瘤（Panin）对胰腺癌患者中观察到的胰腺内肿瘤（Panin）的进展。我们描述了体内证据，表明N-钙粘蛋白的丧失会导致肿瘤发生增加。基于这些初步数据，我们假设N-钙粘蛋白介导的粘附/信号传导的丧失可以通过改变肌动蛋白细胞骨架来减轻细胞接触细胞生长的抑制。以下相互关联的特定目的将提出这一假设：（1）在没有N-钙粘着蛋白的情况下表征Panin向PDA的进展；（2）评估N-钙粘着蛋白损失对细胞骨架调节剂RhoA的影响；（3）确定局灶性粘连在N-钙粘蛋白介导的接触抑制细胞生长中的作用。该探索性R21赠款将决定胰腺癌中从电子钙粘蛋白到N-钙粘着蛋白的转换的后果。了解胰腺癌进展的基础机制可能为新型抗肿瘤疗法的发展提供见解。公共卫生相关性：我们出乎意料的发现，N-钙粘蛋白的丧失会导致K-Rasg12d的Panin发育增加； n-cadflox/flox; PDX1-CRE小鼠提供了一个发现调节肿瘤生长的新型分子机制的切入点。此外，鉴于N-钙粘蛋白拮抗剂ADH-1现在正在IIB期临床试验（http://wwwww.adherex.com）中，因此对体内N-钙粘蛋白功能的更好理解至关重要。了解胰腺癌进展的基础机制可能为新型抗肿瘤疗法的发展提供见解。