Stem Cells and Gastric Cancer

许多（如果不是大多数）恶性肿瘤与组织损伤和/或慢性炎症相关，然而， 炎症诱发癌症的机制直到最近仍不清楚。许多 癌细胞的特性，例如无限的生长潜力/避免凋亡和侵袭的能力/ 转移潜能是骨髓衍生干细胞（BMDC）固有的特性。我 实验室已经表明，随着螺杆菌感染（一种已知的胃致癌物）BMDC回家， 移植并沿着化生-异型增生-癌序列分化，从而形成 胃癌的细胞基础使用体内和体外相结合的方法，我们的实验室已经确定了 胃干细胞作为骨髓来源的细胞。根据我们的研究结果，我们提出了一个新的模型， 这项新的RO 1提案将严格测试这种新的癌症形成模式， 良好描述的胃癌小鼠模型。在第一个具体目标中，我们将描述细胞内的 贴壁间充质干细胞（MSC）群体负责归巢和植入， 体外和体内实验的组合。在第二个具体目标中，我们将描述一个角色， CXCR-4/SDF 1在动员MSC中的相互作用，并检测受体表达的稳定性。第三 具体目标我们将使用基于cre-lox的方法来确定聚变在这些事件中可能扮演的角色。 这些研究将采用原代MSC培养物的体外研究和体内骨研究相结合的方法。 慢病毒修饰的MSC群体的骨髓移植模型，并将为我们的研究奠定基础。 我们实验室的长期目标是确定BMDC在炎症诱导的上皮细胞中的作用， 癌症，并确定新的方法来预防和治疗癌症。 我们已经确定了骨髓干细胞在癌症形成中的作用。这项补助金将机械地 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。

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 withinthe' 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.