Pancreatic Stem Cells and Cancer

描述（由申请人提供）：胰腺癌是美国第四大癌症死亡原因，预后极差，中位生存期为3个月。此外，胰腺癌对化疗和放疗都有耐药性。越来越多的证据表明，许多实体瘤特异性地发生在肿瘤组织内的干细胞群中。从乳腺、脑、结肠和胰腺肿瘤中鉴定肿瘤起始干细胞最近得到了描述，并加速了对癌症干细胞起源的兴趣。然而，一个主要的障碍是缺乏确定的标记物来识别和分离“纯”的癌症干细胞/祖细胞群体。我们已经确定，最近报道的新型肠道干细胞标志物DCAMKL-1在正常小鼠胰岛和主要胰腺导管上皮细胞、P48Cre-LSL-KRASG12D胰腺癌小鼠模型和人类胰腺肿瘤组织中表达。这些数据表明DCAMKL-1可能是正常和癌症胰腺干细胞的新标志物。本研究的中心假设是：1)干细胞/祖细胞是正常胰腺和胰腺癌中一个关键的细胞亚群；2)胰腺癌干细胞/祖细胞的鉴定和分离对开发新的靶向治疗模式至关重要。在使用DCAMKL-1的FACS分离假定的胰腺干/祖细胞后，我们现在可以在体外证明自我更新和球体形成以及小鼠等移植物中上皮结构的发育。为了验证这些假设，我们提出以下具体目标：1。从正常成年小鼠胰腺中分离正常胰腺干/祖细胞并对其进行鉴定。2. 目的：分离胰腺肿瘤动物模型胰腺癌干细胞并确定其分子特征。目的：从人胰腺肿瘤中分离胰腺癌干细胞，并在免疫缺陷小鼠中连续异种移植肿瘤。这些研究代表了一种机制方法来定义正常和胰腺癌干细胞/祖细胞的特征。鉴定和阐明调节其增殖和分化的独特分子特征和信号通路将有助于开发治疗胰腺癌的新方法。

DESCRIPTION (provided by applicant): Pancreatic cancer is the fourth leading cause of cancer death in the U.S. and has an extremely poor prognosis, with a median survival of 3 months. Moreover, pancreatic cancer is resistant to both chemotherapy and radiotherapy. Increasing evidence suggests that many solid tumors arise specifically in the stem cell population located within cancer tissues. Identification of tumor initiating stem cells from breast, brain, colonic and pancreatic tumors has recently been described, and has accelerated interest in the stem cell origin of cancer. A major obstacle however, has been the lack of definitive markers to identify and isolate "pure" populations of cancer stem/progenitor cells. We have determined that the recently reported novel intestinal stem cell marker DCAMKL-1 is expressed in normal mouse pancreatic islet and main pancreatic ductal epithelial cells, and in tissues from the P48Cre-LSL-KRASG12D pancreatic cancer mouse model and in human pancreatic tumors. These data suggest that DCAMKL-1 may be a novel marker of normal and cancer pancreatic stem cells. The central hypotheses of this proposal are 1) stem/progenitor cells are a key subpopulation of cells within the normal pancreas and in pancreatic cancers, and 2) identification and isolation of pancreatic cancer stem/progenitor cells is critical to the development of novel targeted therapeutic paradigms for tumor eradication. Following isolation of putative pancreatic stem/progenitor cells by FACS using DCAMKL-1, we can now demonstrate self-renewal and spheroid formation in vitro and development of epithelial structures in mouse isografts. To test these hypotheses we propose the following specific aims: 1. To isolate and characterize normal pancreatic stem/progenitor cells from the normal adult mouse pancreas. 2. To isolate and determine the molecular features of pancreatic cancer stem cells derived from animal model of pancreatic neoplasia and 3. To isolate pancreatic cancer stem cells from human pancreatic tumors and recapitulate the tumors in serial xenografts in immunodeficient mice. These studies represent a mechanistic approach to defining the characteristic features of normal and pancreatic cancer stem/progenitor cells. Identification and elucidation of the unique molecular signatures and signaling pathways that regulate their proliferation and differentiation should aid in the development of novel therapeutic approaches for treating pancreatic cancer. PUBLIC HEALTH RELEVANCE: These studies will provide a detailed quantitative assessment of the molecular features of pancreatic stem/progenitors isolated from the normal mouse pancreas, neoplastic model of pancreatic cancer in animals and in human pancreatic cancer. Collectively these studies should provide new insights into the roles of stem/progenitor cells in pancreatic cancer, pancreatic regeneration, and perhaps diabetes.