Stromal Myofibroblasts in Gastric Carcinogenesis

Columbia University Health Sciences, New York NY

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Abstract

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