Cancer-associated myofibroblasts are distinct from normal fibroblasts and appear to contribute directly to the progression of many cancers, but the reason for these differences has not been clarified. Gastric cancer is the 2nd leading cause of cancer mortality worldwide, and has been strongly linked to infection with Helicobacter pylori, a pathogen that induces chronic gastritis. Work from our laboratory employing a murine model of Helicobacter-dependent gastric cancer has revealed that circulating bone marrow-derived stem cells (BMDCs) are recruited to the stomach by chronic inflammation, and then undergo progression to metaplasia, dysplasia and cancer. We have postulated that this abnormal progression is due to an """"""""alterred niche"""""""" and in a variety of mouse models there is an early and marked increase in activated myofibroblasts. Work from our laboratory has shown that activated myofibroblasts in the inflamed stomach can be bone marrow-derived, and that mesenchymal stem cells (MSCs) can give rise to both myofibroblasts and gasric epithelial progenitors. It is our hypothesis that the unique properties of cancer-associated myofibroblasts is due in part to their origin from bone marrow-derived mesenchymal stem cells. In order to investigate this novel hypothesis regarding tumor stroma, we are proposing four specific aims. (1) In the first aim, we will utilize trangenic reporter gene mice (alpha-SMA-RFP and collagen-EGFP/luciferase) to characterize the changes in stroma that occur during chronic Helicobacter infection, and explore the nature of bone marrow -derived myofibroblasts. These studies will include both microarrays and imaging (bioluminescence, optical and MRI). (2) In the second aim, we will characterize human gastric myofibroblasts from both normal and neoplastic tissues and examine their gene expression/proteome and study their interactions with normal and neoplastic epithelial cells, (3) We will then test the hypothesis that BMDCs (primarily MSCs) can give rise to both myofibroblasts and dysplastic epithelial cells, and that chronic inflammation and TGF-beta signaling are critical to these lineage decisions. (4) Finally, we will examine the role of a key chemokine (SDF-1) in the recruitment of BMDCs and progression to gastric cancer. Overall, these studies will clarify the role of inflammation-dependent stem cell recruitment in the development of the abnormal stromal environment that characterizes the earliest stages of gastric carcinogenesis.
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