Pancreatic Stem Cells and Cancer

描述(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，胰腺癌对化疗和放射治疗都有抗药性。越来越多的证据表明，许多实体肿瘤特别发生在癌症组织内的干细胞群中。最近从乳腺、脑、结肠和胰腺肿瘤中鉴定了肿瘤起始干细胞，并促进了人们对癌症干细胞起源的兴趣。然而，一个主要的障碍是缺乏明确的标记来识别和分离“纯”癌症干细胞/祖细胞群体。我们已经确定最近报道的新的肠道干细胞标记物DCAMKL-1在正常小鼠胰岛和主要胰腺导管上皮细胞、P48Cre-LSL-KrasG12D胰腺癌小鼠模型组织和人胰腺肿瘤组织中都有表达。这些数据表明，DCAMKL-1可能是正常和癌症胰腺干细胞的一个新的标志物。这一建议的中心假设是：1)干细胞/祖细胞是正常胰腺和胰腺癌中的关键细胞亚群；2)胰腺癌干细胞/祖细胞的鉴定和分离对于开发新的靶向治疗方案以根除肿瘤至关重要。在使用DCAMKL-1用流式细胞仪分离假定的胰腺干/祖细胞后，我们现在可以在体外证明自我更新和球状细胞的形成，以及小鼠同种异体移植物上皮结构的发展。为了验证这些假设，我们提出了以下具体目标：1.从正常成年小鼠胰腺中分离和鉴定正常胰腺干/祖细胞。2.从胰腺肿瘤动物模型中分离和鉴定胰腺癌干细胞的分子特征；3.从人胰腺肿瘤中分离胰腺癌干细胞，并在免疫缺陷小鼠的系列异种移植瘤中概括肿瘤。这些研究代表了一种机械方法来确定正常和胰腺癌干细胞/祖细胞的特征。识别和阐明调控其增殖和分化的独特分子信号和信号通路将有助于开发治疗胰腺癌的新方法。 公共卫生相关性：这些研究将对从正常小鼠胰腺、动物胰腺癌模型和人类胰腺癌中分离的胰腺干/祖细胞的分子特征进行详细的定量评估。总而言之，这些研究应该为干细胞/祖细胞在胰腺癌、胰腺再生以及可能还有糖尿病中的作用提供新的见解。

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.