Head, Tumor Biology Research Unit
Department of Oncology
Hadassah University Hospital
Jerusalem, Israel
E-mail: vlodavsk@cc.huji.ac.il
Education
1968 B.Sc. Biology Hebrew University, Jerusalem, Israel
1970 M.Sc. Biochemistry Hebrew University, Jerusalem, Israel
1975 Ph.D. Cancer Research, Weizmann Institute, Rehovot, Israel
1976-79 Post doc. Growth factors & ECM University of California, Los Angeles & San Francisco
Positions and Honors
Professional Experience
1974-1976: Associate Researcher, Dept. of Genetics, Weizmann institute of Science, Rehovot, Israel
1978-1979: Associate Research Biochemist, cancer Research Institute, UCSF.
1979-1981: Lecturer, Experimental Oncology, Hebrew University- Hadassah Medical School, Jerusalem.
1981-1984: Senior Lecturer, Experimental Oncology; Hebrew University- Hadassah Medical School, Jerusalem.
1985-1986: Visiting Professor, Department of Surgical Research, Harvard Medical School, Boston, MA.
1985-1990: Associate Professor, Department of Oncology, Hadassah-Hebrew University Hospital, Jerusalem, Israel.
1990-present: Professor, Department of Oncology, Hadassah-Hebrew University Hospital, Jerusalem, Israel.
Tumor Biology Research Unit, Hadassah-Hebrew University Medical Center.
2002-present: Professor, Cancer & Vascular Biology Research Center, Rappaport Faculty of Medicine & The Rappaport Institute, Technion, Haifa.
Honors
1975: Mifal Hapais prize for a distinguished Ph.D. Thesis.
1980: Judith Segal Prize for studies of Breast Cancer.
1997: Elkeles Prize - Distinguished scientist in Medicine.
2002: Teva Prize - Distinction in Cancer Research.
2005: The Henry Taub Prize for Excellence in Research
2006: The Landau Prize in Medicine
2007: ICRF Professorship Award
Selected peer-reviewed publications (in chronological order from a total of 315)
1. Vlodavsky, I., Friedmann, Y., Elkin, M., Aingorn, H., Atzmon, A., Ishai-Michaeli, R., Bitan, M., Pappo, O., Peretz, T., Michal, I., Spector, L., and Pecker, I. Mammalian heparanase: gene cloning, expression and function in tumor progression and metastasis. Nature Medicine, 5: 793-802, 1999.
2. Vlodavsky, I., and Friedmann, Y. Molecular properties and involvement of heparanase in cancer metastasis and angiogenesis. J. Clin. Invest. 108: 341-347, 2001.
3. Elkin, M., Ishai-Michaeli, R., Friedmann, Y., Papo, O., Pecker, I., and Vlodavsky, I. Heparanase as mediator of angiogenesis: mode of action. FASEB J. 15: 1661-1663, 2001.
4. Goldshmidt, O., Zcharia, E., Aingorn, H., Guatta-Rangini, Z., Atzmon, R., Michal, I. Pecker, I., Mitrani, E., and Vlodavsky, I. Expression pattern and secretion of human and chicken heparanase are determined by their signal peptide sequence. J. Biol. Chem. 276: 29178-29187, 2001.
5. Goldshmidt, O., Zcharia, E., Abramovitch, R., Metzger, S., Guatta-Rangini, Z., Aingorn, H., Friedmann, Y., Mitrani, E., and Vlodavsky, I. Cell surface expression and secretion of heparanase markedly promote tumor angiogenesis and metastasis. Proc. Natl. Acad. Sci. USA. 99: 10031-10036, 2002.
6. Goldshmidt, O., Zcharia, E., Cohen, M., Aingorn, H., Nadav, L., Cohen, I., Katz, B-Z. Geiger, B., and Vlodavsky, I. Heparanase mediates cell adhesion independent of its enzymatic activity. FASEB J. 17: 1015-1025, 2003.
7. Shteper, P.J., Zcharia, E., Ashhab, Y., Peretz, T., Vlodavsky , I., and Ben-Yehuda, D. Role of promoter methylation in regulation of the mammalian heparanase gene. Oncogene, 22: 7737-7749, 2003.
8. Elkin, M., Zcharia, E., Orgel, A., Cohen, I., Zehava Guatta-Rangini, Z., Peretz, T., Vlodavsky, I., and Kleinman, H. Regulation of heparanase gene expression by estrogen in breast cancer. Cancer Res. 63: 8821-8826, 2003.
9. Zcharia, E., Metzger, S., Chajek-Shaul, T., Aingorn, H., Weinstein, T., Li, J-P., Lindahl, U., Elkin, M., and Vlodavsky, I. Transgenic expression of mammalian heparanase uncovers physiological functions of heparan sulfate in tissue morphogenesis, vascularization and feeding behavior. Faseb J. 18: 252-263, 2004.
10. Zetser, A., Levy-Adam, F., Kaplan, V., Gingis, S., Bashenko, Y., Schubert, S., Flugelman, M., Vlodavsky, I., and Ilan N. Processing and activation of latent heparanase occurs in lysosomes. J. Cell Sci. 117: 2249-2258, 2004.
11. Gingis-Velitski, S., Zetser, A., Flugelman, M., Israel Vlodavsky, I., and Ilan, N. Heparanase induces endothelial cell migration via protein kinase B/Akt activation. J. Biol. Chem. 279:23536-41, 2004.
12. Edovitsky, E., Elkin, M., Zcharia, E., Peretz, T., and Vlodavsky, I. Heparanase gene silencing averts tumor invasiveness, angiogenesis and metastatic spread. J. Nat. Cancer Inst. 96: 1219-1230, 2004.
13. Gingis-Velitski, S., Zetser, A., Kaplan, V., Levy-Adam, F., Bashenko, Y., Flugelman, M.Y., Vlodavsky, I., and Ilan. N. Heparanase uptake is mediated by cell membrane heparan sulfate proteoglycans. J. Biol. Chem. 279: 44084-44092, 2004.
14. Naggi, A., Casu, B., Perez, M., Torri, G., Cassinelli, G., Penco, S., Pisano, C., Giannini, G., Ishai-Michaeli, R., and Vlodavsky, I. Modulation of the heparanase-inhibiting activity of heparin through selective desulfation, graded N-acetylation, and glycol-splitting. J Biol. Chem. 280 :12103-12113, 2005.
15. Abboud-Jarrous, G., Aingorn, A., Rangini-Guetta, Z., Atzmon, R., Elgavish, S., Peretz, T., and Vlodavsky, I. Heparanase processing: Site-directed mutagenesis, proteolytic cleavage and activation J. Biol. Chem., 280: 13568-13575, 2005.
16. Zcharia, E., Zilka, R., Yaar, A., Yacoby, O., Metzger, S., Naggi, A., Casu, B., Ilan, N., Vlodavsky, I., and Abramovitch, R. Heparanase accelerates wound angiogenesis and wound healing in mouse and rat models. Faseb J. 19: 211-221, 2005.
17. Zcharia, E., Philip, D., Edovitsky, E., Aingorn, H., Metzger, S., Kleinman, H., Vlodavsky, I., and Kleinman, K. Heparanase regulates murine hair growth. Am. J. Pathol. 166: 999-1008, 2005.
18. Li, J-P., Escobar, M.L., Gong, F., Zhang, X., Zcharia, E., Kisilevsky, R., Vlodavsky, I., and Lindahl, U. Over-expression of human heparanase renders mice resistant to inflammation-associated amyloidosis. PNAS U S A. 102:6473-6477, 2005.
19. Levy-Adam, F., Abboud-Jarrous, G., Guerrini, M., Beccoti, D., Vlodavsky, I., and Ilan, N. Identification and characterization of heparin/heparan sulfate binding domains of the endoglycosidase heparanase. J. Biol. Chem., 280: 20457-66, 2005.
20. Nasser, N.J., Nevo, E., Shafat, I., Ilan, I., Vlodavsky, I., and Avivi, A. Adaptive evolution of heparanase in hypoxia-tolerant Spalax: gene cloning and identification of a novel splice variant. Proc. Natl. Acad. Sci. U S A. 42: 1516-15166, 2005.
21. Cohen, I., Pappo, O., Elkin, M., San, T., Bar-Shavit, R., Hazan, R., Peretz, T., Vlodavsky, I., and Abramovitch, R. Heparanase promotes growth, angiogenesis and survival of primary breast tumors. Int. J. Cancer, 118:1609-1617, 2006.
22. Zetser, A., Bashenko, Y., Edovitsky, E., Levy-Adam, F., Vlodavsky, I. and Ilan, I. Heparanase induces VEGF expression: Correlation with p38 phosphorylation levels and Src activation. Cancer Res. 66, 2006.
23. Shafat, I., Zcharia, Z., Nisman, B., Nadir, Y., Nakhoul, F., Vlodavsky, I., and Ilan, N. An ELISA method for the detection and quantification of human heparanase. Biochem. Biophys. Res. Comm. 341: 958-963, 2006.
24. Baraz, B., Haupt, Y., Elkin, M., Peretz, T., and Vlodavsky, I. Tumor suppressor p53 regulates heparanase geneexpression. Oncogene, 25:3939-4, 2006.
25. Edovitsky, E., Lerner, E., Zcharia, E., Vlodavsky, V., and Elkin, M. Role of endothelial heparanase in delayed-type hypersensitivity. Blood, 107: 3609-3616, 2006.
26. Shafat, I., Vlodavsky, I., and Ilan, N. Characterization of mechanisms involved in secretion of active heparanase. J. Biol. Chem. 281:23804-11, 2006.
27. Ilan, N., Elkin, M., and Vlodavsky, I. Regulation, function and clinical significance of heparanase in cancer metastasis and angiogenesis, The International Journal of Biochemistry & Cell Biology, 38: 2018-39, 2006.
28. Vlodavsky I, Abboud-Jarrous G, Elkin M, Naggi A, Casu B, Sasisekharan R, and Ilan N. The impact of heparanese and heparin on cancer metastasis and angiogenesis. Pathophysiol. Haemost Thromb. 35:116-27, 2006.
29. Sommerfeldt., N, Beckhove, P., Ge, Y., Schutz, F., Choi, C., Bucur, M., Domschke, C., Sohn, C., Schneeweis, A., Rom, J., Pollmann, D., Leucht, D., Vlodavsky. I., and Schirrmacher, V. Heparanase: a new metastasis-associated antigen recognized in breast cancer patients by spontaneously induced memory T lymphocytes. Cancer Res. 66:7716-23, 2006.
30. Nadir, Y., Brenner, B., Zetser, A., Ilan, N., Shafat, I., Zcharia, E., Goldshmidt, O., and Vlodavsky, I. Heparanase induces tissue factor expression in primary endothelial and cancer-derived cells, independent of its enzymatic activity. J. Thromb. Haemostasis, 4:2443-51, 2006.
31. Ben-Izhak, O., Kaplan-Cohen, V., Ilan , N., Gan , S., Vlodavsky, I., and Nagler, R. Heparanase Expression in Malignant Salivary Gland Tumors Inversely Correlates with Long-Term Survival. Neoplasia, 8: 879-84, 2006.
32. Waterman, M., Ilan, N., Eliakim, R., Groisman, G., Vlodavsky, I., and Ben-Izhak, O. Heparanase upregulation by colonic epithelium of inflammatory bowel disease. Modern Pathol. 19: 878-888, 2006.
33. Doweck, I., Kaplan-Cohen, V., Naroditsky, I., Sabo, E., Ilan, N., and Vlodavsky, I. Heparanase localization and expression by head and neck cancer: correlation with tumor progression and patient's survival. Neoplasia. 8: 1055-1061, 2006.
34. van den Hoven, M.J., Rops, AL., Bakker, M.A., Aten, J., Rutjes, N., Roestenberg, P., Goldschmeding, R., Zcharia, E., Vlodavsky, I., van der Vlag, J., and Berden, J.H. Increased expression of heparanase in overt diabetic nephropathy. Kidney Int. 70:2100-2108, 2006.
35. Vlodavsky I, Abboud-Jarrous G, Elkin M, Naggi A, Casu B, Sasisekharan R, and Ilan N. The impact of heparanese and heparin on cancer metastasis and angiogenesis. Pathophysiol Haemost Thromb. 35:116-27, 2006.
36. Nasser, N.J., Avivi, A., Shushy, M., Vlodavsky, I., and Nevo, E. Cloning, expression and characterization of an alternatively spliced variant of human heparanase. Biochem. Biophys. Res. Comm. 354: 33-38, 2007.
37. Yang, Y., Macleod, V., Miao H.Q., Theus, A., Zhan, F., Shaughnessy, J.D. Jr., Sawyer, J., Li, J.P., Zcharia, E., Vlodavsky, I., and Sanderson, R.D. Heparanase enhances syndecan-1 shedding: A novel mechanism for stimulation of tumor growth and metastasis. J. Biol. Chem. 282:13326-33, 2007.
38. Cohen, I., Maly, B., Simon, I., Meirovitz, A., Pikarsky, E., Zcharia, E., Peretz, T., Vlodavsky I., and Elkin, M. Tamoxifen induces heparanase expression in estrogen receptor-positive breast cancer: basic aspects and clinical implications. Clin. Cancer Res. 13: 4069-4077, 2007.
39. Hostettler, N., Naggi, N., Torri, G., Vlodavsky, I., Casu, B., and Borsig L. Selectin-mediated and heparanase-dependent antimetastatic activities of non-anticoagulant heparins. Faseb. J. 21:3562-3572, 2007.
40. Yang, Y., MacLeod, V., Dai, Y., Khotskaya-Sample, Y., Shriver, Z., Venkataraman, G., Sasisekharan, R., Naggi, A., Torri, G., Casu, B., Vlodavsky, I., Suva, L.J., Epstein, J., Yaccoby, S., Shaughnessy, J.D., Barlogie, B., and R.D. Sanderson, R.D. The syndecan-1 heparan sulfate proteoglycan is a viable target for myeloma therapy. Blood, 110: 2041-2048, 2007.
41. Svetlana Gingis-Velitski, S., Bashenko, Y., Ishai-Michaeli, R., Vlodavsky, I., and Ilan, N. Anti-heparanase antibody enhances heparanase enzymatic activity and facilitates wound healing. Faseb. J. 21:3986-3993, 2007.
42. Ostrovsky, O., Korostishevsky, M., Levite, I., Leiba, M., Galski, H., Vlodavsky, I., and Nagler A. Association of Heparanase Gene (HPSE) Single Nucleotide Polymorphisms with Hematological Malignancies. Leukemia, 21:2296-303, 2007.
43. Ben-Zaken O, Gingis-Velitski S, Vlodavsky I, Ilan N. Heparanase induces Akt phosphorylation via a lipid raft receptor. Biochem Biophys Res Commun. 361: 829-834, 2007.
44. Shafat, I., Ben Barak, A., Postovsky, S., Elhasid, R., Ilan, N., Vlodavsky, I., and Weyl Ben Arush, M. Heparanase levels are elevated in the plasma of pediatric cancer patients and correlate with response to anticancer treatment. Neoplasia, 9: 909-916, 2007.
45. Ben-Zaken, O., Shafat, I., Gingis-Velitski, S., Bangio, H., Kelson, I.K., Alergand, T., Amor, Y., Maya, R.B., Vlodavsky, I, and Ilan, N. Low and high affinity receptors mediate cellular uptake of heparanase. Int. J. Biochem. Cell. Biol. 40:530-42, 2007.
46. Patel, V.N., Knox, S.M., Likar, K.M., Lathrop, C.A., Hossain, R., Eftekhari, S., Whitelock, J.M,, Elkin, M., Vlodavsky, I., and Hoffman, M.P. Heparanase cleavage of perlecan heparan sulfate modulates FGF10 activity during ex vivo submandibular gland branching morphogenesis. Development. 110:2732-9, 2007.
47. Nagler, R., Ben-Izhak, O., Cohen-Kaplan, V., Shafat, I., Vlodavsky, I., Akrish, S., and Ilan, N. Heparanase up-regulation in tongue cancer: tissue and saliva analysis. Cancer, 110:2732-2739, 2007.
48. Escobar Galvis, M.L., Jia, J., Zhang, X., Jastrebova, N., Spillmann, D., Gottfridsson, E., van Kuppevelt, T.H., Zcharia, E., Vlodavsky, I., Lindahl, U,, and Li, J.P. Transgenic or tumor-induced expression of heparanase upregulates sulfation of heparan sulfate. Nat. Chem. Biol. 3:773-778. 2007.
49. Vlodavsky, I., Ilan, N., Naggi, A., and Casu., B. Heparanase: Structure, Biological Functions, and Inhibition by Heparin-Derived Mimetics of Heparan Sulfate. Curr. Pharm. Des. 13: 2057-2073, 2007.
50. Ilan, N., Fux, L., Elkin, M., and Vlodavsky, I. Molecular and cellular aspects of hparanase. In: Tumor Angiogenesis, Ed. Marmé and Fusenig. Springer-Verlag. Chapter 14, pp. 247-272, 2007.
51. Lerner, I., Baraz, L., Pikarsky, E., Meirovitz, A., Edovitsky, E., Peretz, P., Vlodavsky, I., and Elkin, M. Function of heparanase in prostate tumorigenesis: potential for therapy. Clin. Cancer Res. 14: 668-676, 2008.
52. Nadir, Y., Brenner, B., Gingis-Velitski, S., Levy-Adam, F., Ilan, N., Zcharia, E., Nadir, E., Vlodavsky, I. Heparanase induces tissue factor pathway inhibitor expression and extracellular accumulation in endothelial and tumor cells. Thromb Haemost. 99:133-141, 2008.
53. Shafat, I., Pode, D., Peretz, T., Ilan, N., Vlodavsky, I., and Nisman, B. Clinical significance of urine heparanase in bladder cancer progression. Neoplasia, 10: 125-130, 2008.
54. Spiegel A, Zcharia E, Vagima Y, Itkin T, Kalinkovich A, Dar A, Kollet O, Netzer N, Golan K, Shafat I, Ilan N, Nagler A, Vlodavsky I, Lapidot T. Heparanase regulates retention and proliferation of primitive Sca-1+/c-Kit+/Lin- cells via modulation of the bone marrow microenvironment. Blood. 111:4934-43, 2008.
55. Cohen, E., Doweck, I., Naroditsky, I., Ben-Izhak, O., Kramer, R., Best, L.A., Vlodavsky, I., and Ilan, N. Heparanase is over-expressed in lung cancer and inversely correlates with patient's survival. Cancer, 113:1004-1011, 2008.
56. Vlodavsky I, Elkin M, Abboud-Jarrous G, Levi-Adam F, Fuks L, Shafat I, Ilan N. Heparanase: one molecule with multiple functions in cancer progression.
57. Levy-Adam F., Feld S., Vlodavsky I. and Ilan N. Heparanase facilitates cell adhesion and spreading by binding and activating cell surface heparan sulfate. PLoS ONE, 2008;3:e2319.
58. Cohen-Kaplan, V., Naroditsky, I., Zetser, A., Ilan, N., Vlodavsky, I., and Doweck, I. Heparanase induces VEGF C and facilitates tumor lymphangiogenesis. Int. J. Cancer. 123: 2566-2573, 2008.
59. Nadir, Y., Vlodavsky, I., and Brenner, B. Heparanase, tissue factor, and cancer. Semin. Thromb. Hemost. 34:187-194, 2008.
60. Cohen-Kaplan, V., Doweck, I., Naroditsky, I., Vlodavsky, I., and Ilan, N. Heparanase augments EGF-receptor phosphorylation: correlation with head & neck tumor progression. Cancer Res. 68:10077-85, 2008.
61. Abboud-Jarrous, G., Guatta-Rangini, Z., Atzmon, R., Peretz, T., Palermo, C., Gadea, B.B., Joyce, J.A., and Vlodavsky, I. Cathepsin L is responsible for processing and activation of proheparanase through multiple cleavages of a linker segment. J. Biol. Chem. 283:18167-76, 2008.
62. Casu, B., Vlodavsky, I.,and Sanderson, R.D. Non-anticoagulant heparins and inhibition of cancer. Pathophysiol. Haemost. Thromb. 36:195-203, 2008.
63. Nasser, N.J., Avivi, A., Shafat, I., Edovitsky, E., Zcharia, E., Ilan, N., Vlodavsky, I., and Nevo E. Alternatively spliced Spalax heparanase inhibits extracellular matrix degradation, tumor growth, and metastasis. Proc Natl Acad Sci U S A. 106: 2253-2258, 2009.
64. Fux, L., Feibish, N., Cohen-Kaplan, V., Gingis-Velitski, S., Feld, S., Geffen, C., Vlodavsky, I., and Ilan, N. 2009. Structure-function approach identifies a C-terminal domain that mediates heparanase signaling. Cancer Res. 69: 1758-1767, 2009.
65. Zcharia, E., Jia, J., Zhang, X., Lindahl, U., Peretz, T., Vlodavsky I, and Li J. P. Newly generated heparanase knock-out mice unravel co-regulation of heparanase and matrix metalloproteinases. PLoS ONE, 4(4): e5181, 2009.
65. Fux, L., Ilan, N., Sanderson, R., and Vlodavsky, I. Heparanase: Busy at the cell surface. TiBS, Aug. 2009.
Textual CV
Israel Vlodavsky was born (Aug. 1944) in Haifa, Israel. He received his B.Sc and M.Sc. degrees from the Hebrew University of Jerusalem and his Ph.D. from the Wiezmann Institute. Following a postdoctoral training in UCLA and UCSF, he received an academic position in the Sharett Oncology Institute of the Hadassah-Hebrew University Medical Center and established there the Tumor Biology Research Unit.
He then served as a visiting prof. in Harvard and the Memorial Sloan-Kettring Cancer Center. From 2002 till present, he is heading (joint agreement with Hadassah) the Cancer & Vascular Biology Research Center of the Rappaport Faculty of Medicine at the Technion.
Vlodavsky's long-term research in the area of cancer metastasis led to the cloning of a human gene encoding an enzyme (heparanase) that degrades an abundant polysaccharide constituent (heparan sulfate) of the vessel wall and extracellular matrix. Clearly, the research team headed by Vlodavsky is the pioneering and world leading group in this area of research. Enhanced heparanase expression was found to be causally associated with the metastatic potential of cancer cells, tumor angiogenesis and reduced postoperative survival of cancer patients. These observations indicate heparanase as a promising target for a rational design of inhibitory compounds and antibodies that improve early detection and treatment of cancer patients.
In fact, the research team headed by Vlodavsky has already developed heparanase-inhibiting compounds and strategies. One of these compounds is highly effective in experimental models of myeloma and will enter a clinical trial in 2009. Dr. Vlodavsky has supervised 24 students to a Ph.D. degree. The results of his long term research were published in more than 350 scientific papers and presented (plenary lectures) in >130 international conferences.
Vlodavsky is regarded as a pioneer in the area of cell interaction with the extracellualr matrix and the significance of the tumor microenvironment in cancer progression. In recognition of his scientific achievements, Israel was awarded prestigious awards (e.g., Elkeles, Teva, Taub, Landau) and his research is supported by the National Institutes of Health (NIH). Dr. Vlodavsky is a research Professor of the Israel Cancer Research Fund (ICRF), and a member of international and national scientific committees and granting agencies.
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