Cellular diversity and clinical relevance of stem cells in pancreatic cancer

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），其增强的生长潜力表明其在疾病的发生、维持、复发和进展中发挥重要作用。我们假设，更好地了解CSC将最终改善长期临床结果，并已开始研究CSC在胰腺癌中的作用，胰腺癌是癌症死亡的主要原因。我们发现胰腺癌细胞的致瘤潜能增加，表达乙醛脱氢酶（ALDH），这是一种许多正常干细胞表达的解毒酶。此外，ALDH+细胞表达与上皮-间充质转化一致的基因，并且与大量肿瘤细胞相比更具侵袭性和迁移性。我们还比较了ALDH+细胞与CD 44 + CD 24+细胞，后者也已被其他人鉴定为胰腺CSC，并发现每种表型标志着在很大程度上不重叠的不同细胞群。有趣的是，每个CSC群体都同样能够形成肿瘤，但ALDH+细胞通常更具迁移性和侵袭性。基于这些发现，我们假设个体肿瘤含有不同的CSC群体，这些群体可能具有或不具有特定的功能特性。此外，这些研究结果表明，CSC可能因不同患者的胰腺肿瘤而异，这取决于其特定的基因突变或疾病阶段。由于CSC靶向策略的发展需要精确鉴定，因此必须更好地了解其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，肿瘤微环境中的细胞外信号可能调节CSC的特性，但这也知之甚少。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）检查胰腺CSC的细胞多样性;（3）确定胰腺CSC和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。

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.