Cellular diversity and clinical relevance of stem cells in pancreatic cancer

描述(申请人提供)：癌症干细胞(CSC)已在越来越多的人类恶性肿瘤中被发现，其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的CSC，胰腺癌是癌症死亡的主要原因。我们已经发现，具有增强致瘤能力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，与块状肿瘤细胞相比，ALDH+细胞表达与上皮向间充质转化一致的基因，并且具有更强的侵袭性和迁移性。我们还比较了ALDH+细胞和CD44+CD24+细胞，这些细胞也被鉴定为胰腺CSC，发现每种表型都标志着不同的细胞群体，这些细胞群体基本上是不重叠的。有趣的是，每个CSC群体都有同样的能力形成肿瘤，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之间的CSCs可能有所不同，这取决于他们特定的基因突变或疾病阶段。由于CSC靶向策略的发展需要它们的精确识别，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，很可能是肿瘤微环境中的细胞外信号调节CSC的特性，但这一点也鲜为人知。我们建议解决这些问题，并将：(1)确定胰腺癌不同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。

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.