Stem Cells and Gastric Cancer

描述（由申请人提供）：许多（如果不是大多数）恶性肿瘤与组织损伤和/或慢性炎症有关，然而炎症诱导癌症的机制直到最近仍未明确。癌细胞的许多特性，如无限的生长潜力、避免细胞凋亡的能力和侵袭/转移的潜力，都是骨髓源性干细胞（BMDC）固有的特性。我的实验室已经证明，幽门螺杆菌感染（一种已知的胃癌致癌物）的BMDC在胃中，沿着化生-发育不良-癌的序列植入并分化，从而形成胃癌的细胞基础。利用体内和体外结合的方法，我们的实验室已经确定了胃干细胞是骨髓来源的细胞。基于我们的发现，我们提出了一种新的上皮癌模型。这个新的RO1提案将使用我们描述良好的胃癌小鼠模型严格测试这种新的癌症形成范式。在第一个特定目标中，我们将利用体外和体内实验的结合来表征粘附间充质干细胞（MSC）群体中负责归巢和移植的细胞。在第二个特定目标中，我们将描述CXCR-4/SDF1相互作用在MSC动员中的作用，并测试受体表达的稳定性。在第三个具体目标中，我们将使用基于cre-lox的方法来确定融合在这些事件中可能发挥的作用。这些研究将结合原代MSC培养的体外研究以及慢病毒修饰MSC群体的体内骨髓移植模型，并将为我们实验室的长期目标奠定基础，即确定BMDC在炎症诱导的上皮癌中的作用，并确定癌症预防和治疗的新方法。我们已经确定了骨髓干细胞在癌症形成中的作用。这笔拨款将从机制上解决这些细胞如何导致癌症，并可能揭示治疗上皮癌的新方法。

DESCRIPTION (provided by applicant): Many, if not most malignancies are associated with tissue injury and/or chronic inflammation, however the mechanisms responsible for inflammation induced cancer has until recently remained undefined. Many of the properties of cancer cells such as unlimited growth potential, ability to avoid apoptosis and invasion/metastasis potential are properties that are inherent to bone marrow derived stem cells (BMDC). My laboratory has shown that with Helicobacter infection (a known gastric carcinogen) BMDC home to the stomach, engraft and differentiate along a metaplasia-dysplasia-carcinoma sequence thus forming the cellular basis of gastric cancer. Using a combined in vivo and in vitro approach, our laboratory has identified the gastric stem cell as a bone marrow derived cell. Based on our findings, we propose a new model of epithelial cancer. This new RO1 proposal will stringently test this new paradigm of cancer formation using our well described gastric cancer mouse model. In the first specific aim, we will characterize the cell within the adherent mesenchymal stem cell (MSC) population responsible for homing and engraftment using a combination of in vitro and in vivo experiments. In the second specific aim, we will characterize a role for CXCR-4/SDF1 interaction in mobilization of MSC, and test the stability of receptor expression. In the third specific aim we will use a cre-lox based approach to determine what role fusion may play in these events. These studies will employ a combination of in vitro studies on primary MSC cultures as well as in vivo bone marrow transplantation models of lentiviral modified MSC populations and will lay the ground work for our long term objectives of our laboratory, which is to define the role of BMDC in inflammation induced epithelial cancers and to identify novel approaches to cancer prevention and treatment. We have identified a role for bone marrow stem cells in cancer formation. This grant will mechanistically address how these cells cause cancer, and may shed light on new approaches to treat epithelial cancers.