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. ? ? ?
