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2004 Scientific Report

involving visiting

involving visiting scientists Ilan Tsarfaty (of the University of Tel Aviv) and Galia Tsarfaty (of Sheba Medical Center) and our colleagues Brian Ross and Alnawaz Rehemtulla (University of Michigan)—is supported by an NIH center grant. We use fluorescence-based strategies and noninvasive functional imaging technology (confocal laser microscopy, ultrasound, and MRI) to evaluate interactions between Met and HGF/SF as they occur in vitro and in vivo. With fluorescent Met derivatives, we can visualize spatial and temporal aspects of Met-HGF/SF interactions and signaling in transfected cells. Using timelapse confocal microscopy, we visualize the distribution of Met and its association with other proteins in the plasma membrane. When Met- GFP constructs are used as transgenes, mice develop subcutaneous tumors. The development and progression of these tumors can be studied by intravital confocal microscopy (microscopy of sedated live animals) starting at the single cell level. Also, using contrast ultrasound and MRI, we have shown that exposing Met-expressing tumor xenografts in host mice to intravenously administered HGF/SF results in profound changes in the hemodynamic parameters and the blood oxygen levels near the tumor. The pattern of response in normal Met-expressing tissues such as liver and kidney is significantly different from that in tumors, most likely reflecting the abnormal tumor vasculature. Thus, we are studying the role of Met- HGF/SF signaling at the biological, biochemical, and molecular levels in vitro. We use animal models of human cancer to address the relationships between Met-HGF/SF signaling, tumor development, and malignant progression. We are also developing strategies for molecular imaging, as well as therapies that inhibit Met-HGF/SF function or expression in in vivo animal models. External Collaborators David Wenkert, Michigan State University, East Lansing Milton Gross, Department of Veterans Affairs Healthcare System, Ann Arbor, Michigan Nadia Harbeck and Ernest Lengyel, Technische Universität, Munich, Germany Richard Jove, H. Lee Moffitt Cancer and Research Institute, Tampa, Florida Beatrice Knudsen, Fred Hutchinson Cancer Research Center, Seattle, Washington Brian Ross and Alnawaz Rehemtulla, University of Michigan, Ann Arbor Laura Schmidt and Bert Zbar, National Cancer Institute, Bethesda, Maryland Yuehai Shen, Michigan State University, East Lansing Olga Volpert, Northwestern University, Evanston, Illinois David Waters, Gerald P. Murphy Cancer Foundation, West Lafayette, Indiana Robert Wondergem, East Tennessee State University, Johnson City Recent Publications Lee, C.C., A.J. Putnam, C.K. Miranti, M. Gustafson, L.M. Wang, G.F. Vande Woude, and C.F. Gao. In press. Overexpression of sprouty-2 inhibits HGF/SF-mediated cell growth, invasion, migration, and cytokinesis. Oncogene. Fan, Jianqing, Paul Tam, George Vande Woude, and Yi Ren. 2004. Normalization and analysis of cDNA microarrays using within-array replications applied to neuroblastoma cell response to a cytokine. Proceedings of the National Academy of Sciences U.S.A. 101(5): 1135–1140. Birchmeier, Carmen, Walter Birchmeier, Ermanno Gherardi, and George F. Vande Woude. 2003. Met, metastasis, motility, and more. Nature Reviews Molecular Cell Biology 4(12): 915–925. Frankel, Arthur E., Han-Mo Koo, Stephan H. Leppla, Nicholas S. Duesbery, and George F. Vande Woude. 2003. Novel protein-targeted therapy of metastatic melanoma. Current Pharmaceutical Design 9(25): 2060–2066. 50

Hammond, Dean E., Stephanie Carter, John McCullough, Sylvie Urbé, George Vande Woude, and Michael J. Clague. 2003. Endosomal dynamics of Met determine signaling output. Molecular Biology of the Cell 14(4): 1346–1354. Hay, Rick V., Brian Cao, R. Scot Skinner, Ling-Mei Wang, Yanli Su, James H. Resau, Beatrice S. Knudsen, Margaret F. Gustafson, Han-Mo Koo, George F. Vande Woude, and Milton D. Gross. 2003. Radioimmunoscintigraphy of human Met-expressing tumor xenografts using Met3, a new monoclonal antibody. Clinical Cancer Research 9(10): 3839S–3844S. You, Xueke, Hsiao-Man Yu, Leona Cohen-Gould, Brian Cao, Marc Symons, George F. Vande Woude, and Beatrice S. Knudsen. 2003. Regulation of migration of primary prostate epithelial cells by secreted factors from prostate stromal cells. Experimental Cell Research 288(2): 246–256. Zhang, Yu-Wen, Yanli Su, Olga V. Volpert, and George F. Vande Woude. 2003. Hepatocyte growth factor/scatter factor mediates angiogenesis through positive VEGF and negative thrombospondin- 1 regulation. Proceedings of the National Academy of Sciences U.S.A. 100(22): 12718–12723. Zhang, Yu-Wen, and George F. Vande Woude. 2003. HGF/SF-met signaling in the control of branching morphogenesis and invasion. Journal of Cellular Biochemistry 88(2): 408–417. Frankel, Arthur E., Bayard L. Powell, Nicholas S. Duesbery, George F. Vande Woude, and Stephan H. Leppla. 2002. Anthrax fusion protein therapy of cancer. Current Protein and Peptide Science 3(4): 399–407. Hay, Rick, Brian Cao, Ilan Tsarfaty, Galia Tsarfaty, James Resau, and George Vande Woude. 2002. Grappling with metastatic risk: bringing molecular imaging of Met expression toward clinical use. Journal of Cellular Biochemistry S39: 184–193. Knudsen, Beatrice S., Glenn A. Gmyrek, Jennifer Inra, Douglas S. Scherr, E. Darracott Vaughan, David M. Nanus, Michael W. Kattan, William L. Gerald, and George F. Vande Woude. 2002. High expression of the Met receptor in prostate cancer metastasis to bone. Urology 60(6): 1113–1117. Shinomiya, Nariyoshi, and George F. Vande Woude. 2003. Suppression of Met expression: a possible cancer treatment. Commentary on “Reduced c-Met expression by an adenovirus expressing a c-Met ribozyme inhibits tumorigenic growth and lymph node metastases of PC3-LN4 prostate tumor cells in an orthotopic nude mouse model” (Kim et al.). Clinical Cancer Research 14: 5161–5170. Fan, Jianqing, Paul Tam, George F. Vande Woude, and Yi Ren. 2004. Normalization and significant analysis of cDNA micro-arrays using within-array replications applied to neuroblastoma cell response to MIF. Proceedings of the National Academy of Sciences U.S.A. 101: 1135–1140. Back row, standing: Zhang, G. Tsarfaty, Su, Gustafson, Laser, Shinomiya, I. Tsarfaty, Gao; middle row, seated: Xie, Vande Woude, Moshkovitz; front row: Graveel, Bruch, Kaufman 51

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