Cellular diversity and clinical relevance of stem cells in pancreatic cancer

胰腺癌干细胞的细胞多样性和临床相关性

基本信息

批准号：
8504982
负责人：
WILLIAM H MATSUI
金额：
$ 31.53万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-14 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8504982
关键词：
Address Adenocarcinoma Cell CD44 gene Cancer Etiology Cells Cessation of life Clinical Collagen Type I Desmoplastic Development Disease Disease Progression Drug Metabolic Detoxication Environment Enzymes Epithelial Erinaceidae Extracellular Matrix Focal Adhesion Kinase 1 Gene Mutation Genes Genetic Growth Hereditary Disease Human In Vitro Individual Integrins Laboratories Maintenance Malignant Neoplasms Malignant neoplasm of pancreas Mediating Mesenchymal Newly Diagnosed Normal tissue morphology Outcome Pancreas Pancreatic Adenocarcinoma Pancreatic Ductal Adenocarcinoma Pancreatic carcinoma Patients Phenotype Play Population Property Relapse Reporting Resistance Role Signal Pathway Signal Transduction Staging Stem cells Stromal Cells Therapeutic Validation Work aldehyde dehydrogenases base cancer stem cell chemotherapeutic agent clinically relevant extracellular gemcitabine improved in vivo innovation neoplastic cell notch protein novel outcome forecast pancreatic cancer cells pancreatic neoplasm prevent self-renewal stem cell niche stem cell population success tumor tumor microenvironment tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Cancer stem cells (CSC) have been identified in an increasing number of human malignancies, and their enhanced growth potential has suggested that they play a major role in disease initiation, maintenance, relapse and progression. We hypothesize that better understanding CSCs will ultimately improve long-term clinical outcomes and have begun to study CSC in pancreatic adenocarcinoma, a leading cause of cancer deaths. We have found that pancreatic cancer cells with increased tumorigenic potential express aldehyde dehydrogenase (ALDH), a detoxifying enzyme expressed by many normal stem cells. Moreover, ALDH+ cells express genes consistent with the epithelial-mesenchymal transition and are more invasive and migratory when compared to bulk tumor cells. We have also compared ALDH+ cells with CD44+CD24+ cells that have also been identified by others as pancreatic CSC and found that each phenotype marks distinct cell populations that are largely non- overlapping. Interestingly, each CSC population is equally capable of forming tumors, but ALDH+ cells are often more migratory and invasive. Based on these findings, we hypothesize that individual tumors contain distinct CSC populations that may or may not share specific functional properties. Moreover, these findings suggest that CSCs may vary amongst pancreatic tumors from different patients depending on their specific genetic mutations or stage of disease. Since the development of CSC targeting strategies requires their precise identification, it is imperative that the relationship between their phenotype and functional properties and the factors that influence this relationship are better understood. Moreover, it is likely that extracellular signals within the tumor microenvironment regulate CSC properties, but this is also poorly understood. We propose to address these questions and will: (1) Define the relationship between distinct CSC populations in pancreatic cancer; (2) Examine the cellular diversity of pancreatic CSC; and (3) Determine whether interactions between pancreatic CSCs and the extracellular matrix can serve as novel CSC targeting strategies.

描述（由申请人提供）：在越来越多的人类恶性肿瘤中发现了癌症干细胞（CSC），它们增强的生长潜力表明它们在疾病的发生、维持、复发和进展中发挥着重要作用。我们假设更好地了解 CSC 最终将改善长期临床结果，并已开始研究胰腺癌（癌症死亡的主要原因）中的 CSC。我们发现致瘤潜力增加的胰腺癌细胞表达乙醛脱氢酶（ALDH），这是许多正常干细胞表达的一种解毒酶。此外，ALDH+细胞表达与上皮-间质转化一致的基因，并且与大块肿瘤细胞相比更具侵袭性和迁移性。我们还将 ALDH+ 细胞与 CD44+CD24+ 细胞（也被其他人鉴定为胰腺 CSC）进行了比较，发现每种表型都标记了基本上不重叠的不同细胞群。有趣的是，每个 CSC 群体均具有形成肿瘤的能力，但 ALDH+ 细胞通常更具迁移性和侵袭性。基于这些发现，我们假设单个肿瘤包含不同的 CSC 群体，这些群体可能具有也可能不具有特定的功能特性。此外，这些发现表明，不同患者的胰腺肿瘤中的 CSC 可能会有所不同，具体取决于其特定的基因突变或疾病阶段。由于 CSC 靶向策略的开发需要对其进行精确识别，因此必须更好地了解它们的表型和功能特性之间的关系以及影响这种关系的因素。此外，肿瘤微环境内的细胞外信号很可能调节 CSC 特性，但人们对此也知之甚少。我们建议解决这些问题，并将： (1) 定义胰腺癌中不同 CSC 群体之间的关系； (2)检测胰腺CSC的细胞多样性； (3) 确定胰腺 CSC 与细胞外基质之间的相互作用是否可以作为新的 CSC 靶向策略。