Published online before print April 1, 2004, doi: 10.1161/01.RES.0000126925.66005.39
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© 2004 American Heart Association, Inc.
Molecular Medicine |
Essential Role of PDGFR
-p70S6K Signaling in Mesenchymal Cells During Therapeutic and Tumor Angiogenesis In Vivo
Role of PDGFR
During Angiogenesis
From the Division of Pathophysiological and Experimental Pathology, Department of Pathology (N.T., Y.Y., Y.S., M.O., M.T., S.O., K.K., K.S.), Department of Surgery and Science (N.T., Y.S., M.T., K.K., Y.M.), and Department of Disaster and Emergency Medicine (M. Hashizume), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; DNAVEC Research Inc (M. Hasegawa), Tsukuba, Ibaraki, Japan.
Correspondence to Yoshikazu Yonemitsu, MD, PhD, Division of Pathophysiological and Experimental Pathology, Department of Pathology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. E-mail yonemitu{at}pathol1.med.kyushu-u.ac.jp
Discovery of the common and ubiquitous molecular targets for the disruption of angiogenesis, that are independent of the characteristics of malignant tumors, is desired to develop the more effective antitumor drugs. In this study, we propose that the platelet-derived growth factor receptor- (PDGFR)-p70S6K signal transduction pathway in mesenchymal cells, which is required for functional angiogenesis induced by fibroblast growth factor-2, is the potent candidate. Using murine limb ischemia as a tumor-free assay system, we demonstrated that p70S6K inhibitor rapamycin (RAPA) targets mesenchymal cells to shut down the sustained expression of vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF), via silencing of the PDGFR-p70S6K pathway. Irrespective of the varied expression profiles of angiogenic factors in each tumor tested, RAPA constantly led the tumors to dormancy and severe ischemia in the time course, even associated with upregulated expression of VEGF from tumors. Because RAPA showed only a minimal effect to hypoxia-related expression of VEGF in culture, these results suggest that RAPA targets the host-vasculature rather than tumor itself in vivo. Thus, our current study indicates that the PDGFR-p70S6K pathway is an essential regulator for FGF-2–mediated therapeutic neovascularization, as well as for the host-derived vasculature but not tumors during tumor angiogenesis, via controlling continuity of expression of multiple angiogenic growth factors.
Key Words: tumor • angiogenesis • mesenchymal cells • PDGF-AA • p70S6K
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