|
|
|
|||
Education:
Hebrew University of Jerusalem,
Jerusalem, Israel, B.S., 1978. Hebrew University Medical School, Jerusalem,
Israel, M.S., 1981. Hebrew University Medical School, Jerusalem, Israel, Ph.D.,
1986.
Postdoctoral Training:
Guest Researcher, National
Institute of Dental Research, NIH, Bethesda, MD, 11/1986-10/1987.Visiting Associate,
National Institute of Dental Research, NIH, Bethesda, MD, 11/1987-3/1990
Professional and Faculty Appointments:
Guest Researcher, Laboratory
of Pathology, NCI, NIH, Bethesda, MD, 4/1990-3/1991; Staff Scientist, Molecular
Oncology Inc., Gaithersburg, MD, 4/1991-9/1992; Associate Professor of Pathology,
Wayne State University School of Medicine, 10/1992-4/2000; Professor of Pathology,
Wayne State University School of Medicine, 4/2000-present.
Research Interests:
Matrix metalloproteinases,
tumor biology, metastasis, breast cancer, tumor-stroma interactions.
The research of our group focusses in understanding the molecular mechanisms
involved in tumor cell invasion and metastasis. It has been shown that tumor
cells utilize proteases capable of degrading extracellular matrix components.
An important group of enzymes associated with tumor cell invasion are the matrix
metalloproteinases (MMPs). MMPs are specfically inhibited by a family of inhibitors,
the tissue inhibitors of metalloproteinases (TIMPs). Two MMPs studied in my
lab are MMP-9 and MMP-2 because their known association with metastasis formation.
To study the role of MMPs and TIMPs in malignancy, we utilize a comprehensive
approach involving molecular biology, structure-function studies, tumor biology
and biochemical techniques. We use recombinant enzymes and inhibitors to characterize
their biochemical and biophysical properties and to define the mechanism of
activation and inhibition. We are particularly interested in understanding how
MMP-9 and MMP-2 associate with the cell surface since this is the area in motile
cells that is in contact with the extracellular matrix. We have also studied
the expression of MMPs and TIMP-2 in human tumors including breast and bladder
cancers and found that expression of MMP-9 , MMP-2 and TIMP-2 is the result
of a complicated interaction between the tumor cells and the surrounding stroma.
Our long term goal is to understand how MMPs contribute to the metastatic cascade.
Eventually, this information will help to develop new approaches to inhibit
the actvity of MMPs in malignant processes.
Selected
Publications
1. Fridman, R., Giaconne, G., Kanemoto, T., Martin, G.R., Gazdar, A.
F., and Mulshine, J. Reconstituted basement membrane (Matrigel) and laminin
can enhance the tumorigenicity and the drug resistance of small cell lung carcinoma
cell lines. Proc. Natl. Acad. Sci. USA 87:6698-6702, 1990. [Medline]
2. Fridman, R., Fuerst, T.R., Bird, R.E., Hoyhtya, M., Oelkuct, M., Kraus,
S., Komarek, D., Liotta, L.A., Berman, M.L., and Stetler-Stevenson, W.G. Domain
structure of human 72 kDa gelatinase/type IV collagenase: characterization of
proteolytic activity and identification of TIMP-2 binding regions. J. Biol.
Chem. 267:15398-15405, 1992. [Medline]
3. Fridman, R., Bird, R., Hoyhtya, M., Oelkuct, M., Komarek, D., Liang,
C-M., Berman, M.L., Liona, L.A., Stetler-Stevenson, W. G., and Fuerst, T.R.
Expression of human recombinant 72 kDa gelatinase/type IV collagenase and TIMP-2:
characterization of complex and free enzyme. Biochem. J. 289:411-416, 1993.
[Medline]
4. Hoyhtya, M., Fridman, R., Komarek, D., Porter-Jordan, K., Stetler-Stevenson,
W.G., Liotta, L.A., and Liang, C-M. Immunohistochemical localization of matrix
metalloproteinas 2 and its specific inhibitor TIMP-2 in neoplastic tissues with
monoclonal antibodies. Int. J. Cancer 56:500-505, 1994. [Medline]
5. Fridman, R. The role of the extracellular matrix in tumor growth.
Advances in Molecular and Cell Biology 6:253-269, 1993.
6. Visscher, D., Hoyhtya, M., Ottosen, S.K., Liang, C-M., Sarkar, F.H., Crissman,
J.D. and Fridman R. Enhanced expression of tissue inhibitor of metalloproteinase-2
(TIMP-2) in the stroma of breast carcinomas correlates with tumor recurrence.
Int. J. Cancer, 59, 339-344, 1994. [Medline]
7. Roher, A.E., Kasunic, T.C., Woods, A.S., Cotter, R.J., Ball, M.J., and Fridman, R. Proteolysis of Aß peptide from Alzheimer disease brain by gelatinase A. Biochem. Biophys. Res. Comm., 205, 1755-176, 1994. [Medline]
8. Fridman, R., Toth, M., Peña D, and Mobashery, S. Progelatinase B activation by gelatinase A. Cancer Res., 55, 2548-2555, 1995. [Medline]
9. Grignon, D.J., Sakr, W., Toth, M., Ravery, M., Angulo, J., Shamsa, F., Pontes, J.E., Crissman J.C., and Fridman, R. High levels of tissue inhibitor of metalloproteinases-2 (TIMP-2) expression are associated with poor outcome in invasive bladder cancer. Cancer Res., 56, 1654 1659, 1996. [Medline]
10. Gervasi, D., Raz, A., Dehem, M., Yang, M., Kurkinen, M., and Fridman, R. Carbohydrate mediated regulation of matrix metalloproteinase-2 activation in normal human fibroblasts and fibrosarcoma cells. Bioch.Biophys. Res. Comm., 228, 530-538, 1996. [Medline]
11. Massova, I., Fridman, R., and Mobashery, S. Structural insights into the catalytic domains of human matrix metalloprotease-2 and human matrix metalloprotease-9: Implications for substrate specificities J. Mol. Model. 3, 17-30, 1997.
12. Toth, M., Gervasi, D.C., and Fridman, R. (1997) Phorbol ester-induced cell surface association of matrix metalloproteinase-9 in human MCF10A breast epithelial cells, Cancer Res., 57, 3159-3167. [Medline]
13. Olson, M., Gervasi, D.C., Mobashery, and Fridman, R. (1997) Kinetics analysis of the binding of human matrix metalloproteinase-2 and -9 tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 J. Biol. Chem., 272, 29975-29983. [Medline]
14. Menashi, S., Dehem, M., Souliac, I., Legrand, Y. and Fridman, R. (1998) Density-dependent regulation of cell surface association of matrix metalloproteinase-2 (MMP-2) in metastatic MDA-MB-231 breast carcinoma cells. Int. J. Cancer, 75, 259-265. [Medline]
15. Olson, M., Toth, M., Gervasi, D.C., Sado, Y, Ninomiya, Y., and Fridman, R. (1998) High affinity binding of latent matrix metalloproteinase-9 to the alpha2 (IV) chain of collagen IV. J. Biol. Chem., 273, 10672-10681. [Medline]
16. Massova, I., Kotra, L.P., Fridman, R. and Mobashery, S. (1998) Matrix Metalloproteinases: Structures, Substrate Specificities, Evolution and Diversification. FASEB J., 12, 1075-1095.
17. Bianco, F.J., Grignon, D.J., Pontes, J.E., Crissman, J.D., Fridman, R. and Wood, D.P. (1998) Gelatinase B (MMP-9) overexpression in bladder washing specimens predicts pathological stage and grade in bladder cancer patients. Clin. Cancer Res., 4, 3011-3016.
18. Toth, M., Sado, Y, Ninomiya, Y., and Fridman, R. (1998). Biosynthesis of a2(IV) and a1(IV) chains of collagen IV and interactions with matrix metalloproteinase-9. J. Cell. Physiol., 180, 131-139.
19. Upadhyay J., Shekarriz B., Nemeth J.A., Dong, Z., Cummings, G.D., Fridman, R., Sakr, W., Grignon, D.J., and Cher, M.L. (1999) MT1-MMP and MMP-2 immunolocalization in human prostate: change in cellular localization associated with high-grade prostatic intraepithelial neoplasia. Clinical Cancer Res., 12, 4105-4110.
20. Li, G., Fridman, R., and Kim, H-R C. (1999). TIMP-1 inhibits apoptosis of human breast epithelial cells. Cancer Res., 59, 6267-6275.
21. Olson, M.W., Bernardo, M.M., Pietila, M., Gervasi, D.C., Kotra, L.P., Massova, I., Mobashery, S., and Fridman, R. (2000). Characterization of the monomeric and dimeric forms of latent and active matrix metalloproteinase-9. Differential rates for activation by stromelysin 1. J. Biol. Chem., 275, 2661-2668.
22. Hernandez-Barrantes, S., Toth, M., Bernardo, M.M., Yurkova, M., Gervasi, D.C., Raz, Y., Sang, Q-X. A., and Fridman, R. (2000). Stabilization of active (57 kDa) membrane type 1-matrix metalloproteinase (MT1-MMP) by tissue inhibitor of metalloproteinase (TIMP)-2 regulates pro-MMP-2 activation. J. Biol. Chem., 275, 12080-12089.
23. Brown, S., Bernardo, M. M., Li, Z-H., Kotra, L.P., Tanaka, S., Fridman, R., and Mobashery, S. (2000). Potent and selective mechanism-based inhibition of gelatinases. J. Am. Chem. Soc., 122, 6799-6800.
24. Toth, M., Gervasi, D.C., Bernardo, M.M., Soloway, P.D., Wang, Z., Bigg, H.F., Overall, C.M., DeClerck, Y.A., Tschesche, H., Cher, M., Brown, S., Mobashery, S., and Fridman, R. (2000). TIMP-2 acts synergistically with synthetic MMP inhibitors but not with TIMP-4 to enhance the MT1-MMP-dependent activation of pro-MMP-2. J. Biol. Chem., 275, 41415-41423.
25. Puyraimond, A, Fridman, R., Lemesle, M., Arbeille, B., and Menashi, S.(2001). MMP-2 colocalizes with caveolae on endothelial cell surface. Exp. Cell Res., 262, 28-36.
26. Hernandez-Barrantes, S., Shimura, Y., Soloway, P.D., Sang, Q-X.A., and Fridman, R. (2001). Differential roles of TIMP-4 and TIMP-2 in pro-MMP-2 activation by MT1-MMP. Bioch. Biophys. Res. Comm., 281, 126-130.
27. Kotra, L.P., Cross, J.B., Shimura, Y., Fridman, R., Schlegel, H.B., and Mobashery, S. (2001). Insight into the complex process of activation of matrix metalloproteinases. J. Am. Chem. Soc.,123, 3108 -3113.
28. Kleifeld, O., Kotra, L.P., Gervasi, D.C., Brown, S., Bernardo, M.M., Fridman, R. Mobashery, S. and Sagi, I. (2001). X-Ray absorption studies of human matrix metalloproteinase-2 (MMP-2) bound to a highly selective mechanism-based inhibitor: comparison to the latent and active forms of the enzyme. J. Biol. Chem., 276: 17125-17131.
29. Dong, Z., Nemeth, J.A., Cher, M.L., Palmer, K.C., Bright, R.C. and Fridman, R. (2001). Differential regulation of MMP-9 and TIMP-1 and TIMP-2 expression in co-cultures of prostate cancer and stromal cells. Int. J. Cancer, in press.
email: rfridman@med.wayne.edu
office: (313) 577-1218
lab: (313) 577-1174
fax: (313) 577-818