Michael Cher, M.D.
Proteases and Metastasis
M.D., Washington University, 1986

The main objective in our laboratory is to study the biology of prostate cancer bone metastasis. In particular, we are interested in how the bone microenvironment is conducive to the establishment and progression of metastases. We are particularly interested in the role of proteases in this process, and we use a variety of in vitro and in vivo models to model the bone environment and metastatic growth.

Selected Publications

Cher ML, Biliran HR, Jr., Bhagat S, Meng Y, Che M, Lockett J, Abrams J, Fridman R, Zachareas M, Sheng S. Maspin expression inhibits osteolysis, tumor growth, and angiogenesis in a model of prostate cancer bone metastasis. Proc Natl Acad Sci U S A. Jun 24; 100(13):7847-7852, 2003.

Nemeth JA, Cher ML, Zhou Z, Mullins C, Bhagat S, Trikha M. Inhibition of alpha(v)beta3 integrin reduces angiogenesis, bone turnover, and tumor cell proliferation in experimental prostate cancer bone metastases. Clin Exp Metastasis 20(5):413-420, 2003.

Nie D, Nemeth J, Qiao Y, Zacharek A, Li L, Hanna K, Tang K, Hillman GG, Cher ML, Grignon DJ, Honn KV. Increased metastatic potential in human prostate carcinoma cells by overexpression of arachidonate 12-lipoxygenase. Clin Exp Metastasis. 20(7):657-663, 2003.

Li Y, Che M, Bhagat S, Ellis KL, Kucuk O, Doerge DR, Abrams J, Cher ML, Sarkar FH. Regulation of gene expression and inhibition of experimental prostate cancer bone metastasis by dietary genistein. Neoplasia. Jul-Aug; 6(4):354-363, 2004.

Ustach CV, Taube ME, Hurst NJ, Jr., Bhagat S, Bonfil RD, Cher ML, Schuger L, Kim HR. A potential oncogenic activity of platelet-derived growth factor d in prostate cancer progression. Cancer Res. Mar 1; 64(5):1722-1729, 2004.

Dong Z, Bonfil RD, Chinni S, Deng X, Trindade Filho JC, Bernardo M, Vaishampayan U, Che M, Sloane BF, Sheng S, Fridman R, Cher ML. Matrix metalloproteinase activity and osteoclasts in experimental prostate cancer bone metastasis tissue. Am J Pathol. Apr; 166(4):1173-1186, 2005.

Podgorski I, Linebaugh BE, Sameni M, Jedeszko C, Bhagat S, Cher ML, Sloane BF. Bone microenvironment modulates expression and activity of cathepsin B in prostate cancer. Neoplasia. Mar; 7(3):207-223, 2005.

Sloane BF, Yan S, Podgorski I, Linebaugh BE, Cher ML, Mai J, Cavallo-Medved D, Sameni M, Dosescu J, Moin K. Cathepsin B and tumor proteolysis: contribution of the tumor microenvironment. Semin Cancer Biol. Apr; 15(2):149-157, 2005.

Bonfil RD, Sabbota A, Nabha S, Bernardo MM, Dong Z, Meng H, Yamamoto H Chinni SR, Lim IT, Chang M, Filetti LC, Mobashery S, Cher ML, Fridman R.  Inhibition of human prostate cancer growth, osteolysis and angiogenesis in a bone metastasis model by a novel mechanism-based selective gelatinase inhibitor.  Int J Cancer 118:2721-26, 2006.

Chinni SR, Sivalogan S, Dong Z, Filho JC, Deng X, Bonfil RD, Cher ML.  CXCL12/CXCR4 signaling activates Akt-1 and MMP-9 expression in prostate cancer cells: The role of bone microenvironment-associated CXCL12.  Prostate 66:32-48, 2006.

Li Y, Kucuk O, Hussain M, Abrams J, Cher ML, Sarkar FH.  Anti-tumor and anti-metastatic activities of docetaxel are enhanced by genistein through regulation of OPG/RANK/RANKLigand/MMP-9 signaling in prostate cancer.  Cancer Research 66: 4816-25, 2006.

Yin S, Lockett J, Meng Y, Biliran H Jr, Blouse GE, Li X, Reddy N, Zhao Z, Lin X, Anagli J, Cher ML, Sheng S.  Maspin retards cell detachment via a novel interaction with the urokinase-type plasminogen activator/urokinase-type plasminogen activator receptor system.  Cancer Res Apr 15;66(8):4173-81, 2006.

Deng X, Bhagat S, Dong Z, Mullins C, Chinni SR, Cher ML.  Tissue inhibitor of metalloproteinase-3 induces apoptosis in prostate cancer cells and confers increased sensitivity to paclitaxel.  Eur J Cancer 42(18):3267-73, 2006.

Nabha SM, Bonfil RD, Yamamoto HA, Belizi A, Wiesner C, Dong Z, Cher ML.   Host matrix metalloproteinase-9 contributes to tumor vascularization without affecting tumor growth in a model of prostate cancer bone metastasis.  Clin Exp Metastasis 23: 335–344, 2006.

Yamamoto H, Bonfil RD, Wiesner C, Nabha S, Dong Z, Meng H, Saliganan A, Sabbota A, Chinni SR, Cher ML.  Quantitative Assessment of Small Intraosseous Prostate Cancer Burden in SCID Mice by Fluorescence Imaging.  Prostate 67:107-14, 2007.

Bonfil RD, Dong Z, Trindade Filho JC, Osenkowski P, Nabha S, Yamamoto H, Sabbota A, Chinni SR, Zhao H, Vessella R, Fridman R, Cher ML.  Membrane Type-1 Matrix Metalloproteinase (MT1-MMP) Promotes Tumor Growth and Bone Degradation in Prostate Cancer Bone Metastasis.  American Journal of Pathology;170:2100-2111, 2007.

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Rafael Fridman, Ph.D.
Proteases and Tumor Metastasis
Ph.D., Hebrew University, Jerusalem, 1986

Our research focuses in understanding the molecular mechanisms involved in tumor cell invasion and metastasis. To invade tissue barriers, metastatic tumor cells utilize proteases capable of degrading extracellular matrix components. An important group of enzymes associated with tumor invasion and metastasis are the matrix metalloproteinases (MMPs). To study the role and function of MMPs in malignancy, we utilize a comprehensive approach involving molecular biology, cell biology and biochemical techniques. We have characterized the biochemical properties of several members of the MMP family and their mechanism of activation and inhibition in tumor cells. One important group of MMPs is the membrane-anchored MMPs, known as MT-MMPs, which by their surface localization they are major mediators of pericellular proteolysis. We have shown that the activity of MTMMPs on the cell surface is regulated by specific interactions of the enzymes with TIMPs, specific protein MMP inhibitors. As membrane-anchored proteases, the MT-MMPs are regulated by a complex process of turnover involving shedding of the enzyme ectodomain, which regulate surface and extracellular activity. Structure-function relationship studies using mutant enzymes are addressing how processing of MT-MMPs alter the ability of cells to control pericellular proteolysis and invasive behavior. We have also various active collaborations aimed at developing specific MMP inhibitors and at investigating the role of MMPs in various models of human cancer.

Selected Publications

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. 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, 2000.

Bernardo, M.M., Brown, S., Li, Z-H., Fridman, R., and Mobashery S. Design, synthesis and characterization of potent, slow binding inhibitors that are selective for gelatinases. J Biol Chem, 277: 11201-11207, 2002.

Toth, M., Hernandez-Barrantes, S., Osenkowski, P., Bernardo, M.M., Gervasi, D.C., Shimura, Y., Meroueh, O., Kotra, L.P., Galvez, B.G., Arroyo, A.G., Mobashery, S., and Fridman, R. Complex pattern of membrane type 1-matrix metalloproteinase shedding regulation by autocatalytic cell surface inactivation of active enzyme. J Biol Chem, 277: 26340-26350, 2002.

Hernandez-Barrantes, S., Bernardo, M.M., and Fridman, R. Regulation of membrane type-matrix metalloproteinases. Semin Cancer Biol 12: 131-138, 2002.Fridman, R., Toth, M., Chvyrkova, I., Meroueh, S.O., and Mobashery, S.Cell Surface association of MMP-9. Cancer Metastasis Rev 22: 153-166, 2003.

Bernardo, M.M., and Fridman, R. TIMP-2 regulates MMP-2 activity in the extracellular environment after pro-MMP-2 activation by MT1-MMP. Biochem. J, 374, 739-745, 2003.

Zhao, H., Bernardo, M.M., Osenkowski, P., Pei, D., Nagase, H., Kashiwagi, M., Soloway, P.D., DeClerck, Y.A., and Fridman R. Differential inhibition of MT3-MMP and MT1-MMP by TIMP-2 and TIMP-3 regulates pro-MMP-2 activation.  J Biol  Chem, 279: 8592-8601, 2004.

Osenkowski, P., Toth, M. and Fridman, R. Processing, shedding and internalization of membrane type 1-matrix metalloproteinase (MT1-MMP).  J Cell Physiol, 200: 2-10, 2004.

Toth, M, Osenkowski, P., Hesek, D., Brown, S., Merohue, S., Sakr, W, Mobashery, S., and Fridman, R. Cleavage at the stem region releases an active ectodomain of the membrane type 1-matrix metalloproteinase.  Biochem. J., 387, 497-506, 2005.

Kruger, A., Arlt, M., Gerg, M., Bernardo, M., Kopitz, C., Chang, M., Mobashery, S. and Fridman, R.  Antimetastatic activity of a novel mechanism-based gelatinase inhibitor.  Cancer Res., 65, 3523-3526, 2005.

Osenkowski, P., Meroueh, S.O., Pavel, D, Mobashery, S. and Fridman, R.  A highly flexible and proteolytically sensitive hinge domain facilitates the autocatalytic processing of MT1-MMP.  J. Biol. Chem., 280, 26160-26168, 2005.

Bonfil, R.D., Sabbota, R., Nabha, S., Dong, Z., Meng, H., Yamamoto, H., Chinni, S.R., Bernardo, M.M., Lim, I.T., Chang, M., Filetti, L.C., Mobashery, S., Cher, M.L., and Fridman, R.  Inhibition of human prostate cancer growth, osteolysis and angiogenesis in a bone metastasis model by a novel mechanism-based selective gelatinase inhibitor.  Int. Journal of Cancer, 118, 2721-2726, 2006. 

Sun Q., Weber, C.R., Sohail, A., Bernardo, M.M., Toth, M., Zhao, H., Turner, J.R., and Fridman, R.  MT6-MMP is highly expressed in human colon cancer, promotes tumor growth and exhibits unique biochemical properties.  J. Biol. Chem., 282, 21998-22010, 2007.

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Kenneth V. Honn, Ph.D.
Proteases and Metastasis
Ph.D., Wayne State University, 1977

Dr Honn's laboratory research is focused on two major areas as they relate to tumor progression and metastasis. The first area involves the examination of the role played by Bioactive Lipids in processes such as cancer cell motility and invasion, regulation of the cell cycle and apoptosis, angiogenesis and cell signaling. The regulation of enzymes responsible for bioactive lipid synthesis, such as lipoxygenases, cyclooxygenases and thromboxane synthesis is being examined at the genetic and cellular level. In addition translational research on these enzymes is attempting to link their expression in patient tissues with disease progression and response to chemo and radiation therapy. A drug development program has identified a candidate lipoxygenase inhibitor, which is being readied for clinical trial. The second area of research focuses on adhesion receptors, in particular integrins, and their role in metastasis. This research has identified novel truncated forms of integrin receptors, which may have antagonistic function relative to the parent integrin. This research is also conducted at the basic and translational level. Dr Honn's laboratory research employs a multidisciplinary approach utilizing molecular, biochemical and cell biology methodologies.

Selected Publications

Nie, D., Tang, K., Diglio, C., and Honn, K. V.. Eicosanoid regulation of angiogenesis: role of endothelial arachidonate 12-lipoxygenase. Blood, 95, 2304-11, 2000.

Szekeres, C. K., Tang, K., Trikha, M., and Honn, K. V.. Eicosanoid activation of extracellular signal-regulated kinase1/2 in human epidermoid carcinoma cells. J. Biol. Chem., 275, 38831-41, 2000.

Pidgeon, G. P., Mustapha, K., Meram, A., and Honn, K. V.. Mechanisms controlling cell cycle arrest and induction of apoptosis following 12-lipoxygenase inhibition in prostate cancer cells. Cancer Res. 62(9):2721-7, 2002.

Pidgeon, G.P., Tang, K., Cai, Y., Piasentin, E., and Honn, K.V.. Over-expression of Platelet-type 12 Lipoxygenase Promotes Tumor Cell Survival by alpha(v)beta(3) and alpha(v)beta(5) integrin expression. Cancer Res. 63(14):4258-4267, 2003.

Kandouz, M., Nie, D., Pidgeon, G. P., Krishnamoorthy, S., Maddipati, K., and Honn, K.V.. Platelet-type 12-Lipoxygenase Activates NF-?B in Prostate Cancer Cells. Prostaglandins and Other Lipid Mediators 71:189-204, 2003.

Nie, D., Nemeth, J. Qiao, Y., Zacharek, A., Li, L., Hanna, K., Tang, K., Hillman, G.G., Cher, M., Grignon, D.J., and Honn, K.V.. Increased metastatic potential in human prostate carcinoma cells by overexpression of arachidonate 12-lipoxygenase. Clinical and Experimental Metastasis 20:657-663, 2003.

Nie, D., Che, M., Zacharek, A., Qiao, Y., Li, L., Li, X., Lamberti ,M., Tang, K., Cai, Y., Guo, Y., Grignon, D., Honn, K.V. Differential expression of thromboxane synthase in prostate carcinoma: role in tumor cell motility. Am J Pathol. 164(2): 429-39, 2004.

Raso E., Dome B., Somlai B., Zacharek A,. Hagmann W., Honn K,V., Timar J. Molecular identification, localization and function of platelet-type 12-lipoxygenase in human melanoma progression, under experimental and clinical conditions. Melanoma Res. 14(4):245-50, 2004.

Dome B., Raso E., Dobos J., Meszaros L., Varga N., Puskas L.G., Feher L.Z., Lorincz T., Ladanyi A., Trikha M., Honn K.V., Timar J. 2005 Parallel expression of alphaIIbbeta3 and alphavbeta3 integrins in human melanoma cells upregulates bFGF expression and promotes their angiogenic phenotype. Int J Cancer 116(1):27-35, 2005.

Nie D, Krishnamoorthy S, Jin R, Tang K, Chen Y, Qiao Y, Zacharek A, Guo Y, Milanini J, Page G,  Honn KV.   Mechanisms Regulating Tumor Angiogenesis by 12-Lipoxygenase in Prostate Cancer Cells.  Journal Biological Chemistry 281(27):18601-18609, 2006.

Krishnamoorthy, S. and Honn, K.V.  Inflammation and disease progression. Cancer Metastasis Reviews. 25(3):481-491, 2006.

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Avraham Raz, Ph.D.
Proteases and Metastasis
Ph.D., Institute of Science, Israel, 1978

The propensity of cancer cells to spread from the primary tumor to distant organs where they can grow and produce metastases is a problem of consideration importance in cancer research, because metastasis is the major cause of death by cancer. The process of metastasis is very complex and its outcome is undoubtedly influenced by many properties of the tumor cells and by many different host factors. It is probable that factors controlling metastasis vary among different tumor and even among different target organs in the same host. Despite such variability, however, common denominator processes (minor and major) for metastasis must exist. Based on this reasoning, I have established various experimental systems in order to determine common processes shared by metastasizing cells irrespective of their histology and species of origin. One such fundamental property is cell adhesiveness and migration which plays a role in normal morphogenisis and homeostasis as well as in the pathogenesis of various diseases including the behavior of malignant cells. Thus, far, I have concentrated on tumorcells heterogeneity and on elucidating the cellular and molecular mechanisms by which and nonmetastatic tumor cells adhere to each other and to extracellular substrates, and migrate throughout the body. We have closed and characterized the genes responsible for these functions in metastatic cells. Anitmetastatic drugs developed in the lab are in the clinical trials and antibodies against metastatic-related genes that we developed are for tumor diagnosis.

Selected Publications

Dobashi, Y., Watanabe, H., Matsubara, M., Yanagawa, T., Raz, A., Shimamiya, T. And Ooi, A.   Autocrine motility factor/glucose-6-phosphate isomerase, a possible predictor of metastasis in bone and soft tissue tumors.  Journal of Pathology 208:44-53, 2006.

Fukumori, T., Oka, N., Takenaka, Y., Nangia-Makker, Pl, Elsamman, E., Kasai, T., Shono, M., Kanayama, H-O., Ellerhorst, J., Lotan, R. and Raz, A.  Galectin-3 regulates mitochondrial stability and anti-apoptotic function in response to anti-cancer drugs in prostate cancer.  Cancer Research 66:3114-3119, 2006.

Tanaka, N.,  Haga, A., Naba, N., Shiraiwa, K., Kusakabe, Y., Hashimoto, K., Funasaka, T., Nagase, H., Raz, A., Nakamura, K.T.   Structures of mouse autocrine motility factor in complex with carbohydrate phosphate inhibitors provide insight into structure-activity relationship of the inhibitors.  J. Mol. Biol. 356:312-324, 2006.

Haga, A., Tanaka, N., Funasaka, T., Hiashmoto, K., Nakumura, K.T., Waanabe, H., Raz,      A., and Nagase, H.   The autocrine  motility factor (AMF) and AMF-receptor  combination  needs sugar chain recognition ability and interaction using the c-terminal region of AMF.  J. Mol. Biol.  358:741-753, 2006.

Jiang, W.G., Raz, A., Douglas-Jones, A., and Mansel, R.E.   Expression of autocrine motility factor receptor, AMFR, in human breast cancer. Journal Histochemistry Cytochemistry 54:231-241, 2006.

Lagana, A., Goetz, J.G., Cheung, P., Raz, A., Dennis, J.W. and Nabi, I.R. Galectin binding to Mgat5-modified N-glycans regulates fibronectin matrix remodeling in  tumor cells. Molecular and Cell Biology 26:3181-3193, 2006.

Shen, K.C., Miller, F., Tait, L., Santner, S.J., Pauley, R., Raz, A., Tainsky, M., Brooks,   S.C., Wang, Y.A.  Isolation and characterization of a breast progenitor epithelial  cell line with robust DNA damage responses.  Breast Cancer Res. Treat. 98:357-364, 2006.

Nakahara, S., Oka, N., Hogan, V., Inohara, H., and Raz, A.  Characterization of the Nuclear Translocation Sequence of Galectin-3. Cancer Research 66:9995-10006, 2006.

Haga, A., Komazaki, S., Funasaka, T., Hashimoto, K., Yokoyama, Y., Watanabe, H.,    Raz, A., and Nagase, H.  AMF/G6PI induces differentiation of leukemic cells via  an unknown receptor that differs from gp78, Leuk Lymphoma 47:2234-2243, 2006.

Nakkara, S., Bogan, V., Inohara, H. and Raz, A.  Importins-mediated nuclear translocation of galectin-3, Journal of Biological Chemistry, 281:39649-39659, 2006..

Nakahara, S., Oka, N., Wang, Y., Hogan, V., Inohara, H., and Raz, A. Characterization of the nuclear import pathways of galectin-3.  Cancer Research, 66:9995-10006, 2006.

Prieto, V.G., Mourad-Zeidan, A.A., Melnikova, V., Johnson, M.M., Lopez, A., Diwan, A.H., Lazar, A.J., shen, S.s., Zhang, P.S., Reed, J.A., Gershenwald, J.E., Raz, A., and    Bar-Eli, M. Galectin-3 expression is associated with tumor progression and pattern of sun exposure in melanoma.  Clin. Cancer Res.  12:6709-6715, 2006.

Shen, K., Wang, Y., Brooks, S.C., Raz, A., Wang, Y.A.  (2006)  ATM is activated by mitotic stress and suppresses centrosome amplification in primary but not in tumor cells.  Journal of Cell Biochemistry 99:1267-1274, 2006.

Funasaka, T., Hu, H., Yanagawa, T., Hogan, V., and Raz, A. Down-regulation of phosphoglucose isomerase/autocrine motility factor results in mesenchymal-to-epithelial transition of human lung fibrosarcoma cells.  Cancer Research 67: 4236-4243, 2007.

Nangia-Makker, P., Tait, L., Shekhar, M.P., Palomino, E., Hogan, V., Piechocki, M.P., Funasaka, T., and Raz A.  Inhibition of breast tumor growth and angiogenesis by a medicinal herb: Ocimum gratissimum.  Int. J. Cancer 121:884-94, 2007.

Mazurek, N., Sun, Y.J., Liu, K.F., Gilcrease, M.Z., Schober, W., Nangia-Makker, P., Raz, A. and Bresalier, R.  J. Biol Chem ;282:21337-21348, 2007.

Yanagawa, T., Funasaka, T., Tsutsumi, S., Watanabe, H. and Raz, A.  Regulation of Phosphoglucose Isomerase/Autocrine Motility Factor Activities by the Poly (ADP-ribose) Polymerase Familly-14.   Cancer res. 67:8682-8689, 2007.

Nangia-Makker P, Raz T, Tait L, Hogan V, Fridman R,  Raz A Galectin-3 cleavage: A novel surrogate marker for matrix metalloproteinase activity in growing breast cancers. Cancer Res. 67:11760-11768, 2007.

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Bonnie F. Sloane, Ph.D.
Proteases and Metastasis
Ph.D., Rutgers University, 1976

Dr. Sloane's laboratory has had a longstanding interest in the roles of proteases in development and progression of cancer, with an emphasis on breast, colon and prostate cancers. Her research group has established a role for lysosomal proteases, primarily the cysteine protease cathepsin B, and the endogenous inhibitors of cysteine cathepsins (the cystatins and stefins) in malignant progression. They were the first to demonstrate molecular mechanisms for the increased expression of cathepsin B in human tumors and to identify binding partners responsible for alterations in localization of cathepsin B in tumors, e.g., its association with caveolae on the cell surface through binding to S100A10 in a heterotetrameric complex with annexin II. Her group has been a leader in the implementation of cellular imaging in the protease field. They established new assays to follow proteolysis by live cells as they form three-dimensional structures in matrices and migrate through the matrices. This has included imaging of cell-cell interactions and how these contribute to proteolysis, including the finding that stromal fibroblasts and inflammatory macrophages enhance proteolysis of type IV collagen ~15-fold in cocultures with breast or colon carcinoma cells. Their studies have revealed interactions among cysteine, serine and matrix metalloproteases in pericellular degradation of the basement membrane protein type IV collagen as well as an intracellular component to this degradation, the latter via lysosomal cysteine cathepsins. Recent efforts by her group through multi-disciplinary and multi-institutional collaborations are directed toward defining proteolytic pathways in tumors, rather than focusing on a single protease or a single class of proteases, and delineating mechanisms by which the tumor microenvironment impacts proteolysis with the ultimate aim of identifying targets for novel therapeutic strategies.

Selected Publications

Cavallo-Medved, D., Mai, J., Dosescu, J., Sameni, M. and Sloane, B.F.: Caveolin-1 mediates expression and localization of cathepsin B, pro-urokinase plasminogen activator and their cell surface receptors in human colorectal carcinoma cells. J. Cell Sci. 118: 1493-1503, 2005.

Podgorski, I., Linebaugh, B.E., Sameni, M., Jedeszko, C., Bhagat, S., Cher, M.L. and Sloane, B.F.: Bone microenvironment modulates expression and activity of cathepsin B in prostate cancer. Neoplasia 7: 207-223, 2005.

Blum, G., Mullins, S.R., Keren, K., Fonovic, M., Jedeszko, C., Rice, M.J., Sloane, B.F. and Bogyo, M.: Dynamic imaging of protease activity with fluorescently quenched activity-based probes. Nature Chem. Biol. 1: 203-209, 2005.

Acuff, H.B., Sinnamon, M., Fingleton, B., Boone, B., Levy, S.E., Chen, X., Pozzi, A., Carbone, D.P., Schwartz, D.R., Moin, K., Sloane, B.F. and Matrisian, L.M. Analysis of host- and tumor-derived proteinases using a custom dual species microarray reveals a protective role for stromal matrix metalloproteinase-12 in non-small cell lung cancer. Cancer Res. 66: 7968-7975, 2006.

Mohamed, M.M. and Sloane, B.F.: Cysteine cathepsins: multifunctional enzymes in cancer. Nature Rev. Cancer 6: 764-775, 2006.

Sloane, B.F., Gillies, R.J., Mohla, S., Sogn, J.A., Menkens, A.E. and Sullivan, D.C.: I2 imaging: cancer biology and the tumor microenvironment. Cancer Res. 66: 11097-11099, 2006.

Sloane, B.F., Sameni, M., Podgorski, I., Cavallo-Medved, D. and Moin, K.: Functional imaging of tumor proteolysis. Annu. Rev. Pharmacol. Toxicol. 46: 301-315, 2006.

Schwartz, D.R., Moin, K., Yao, B., Matrisian, L.M., Coussens, L.M., Bugge, T.H., Fingleton, B., Acuff, H.B., Sinnamon, M., Nassar, H., Platts, A., Krawetz, S.A., Linebaugh, B.E. and Sloane, B.F.  Hu/Mu ProtIn oligonucleotide microarray: dual species array for profiling protease and protease inhibitor gene expression in tumors and their microenvironment.    Mol. Cancer Res., 5: 443-454, 2007.

Victor, B.C. and Sloane, B.F.:  Cysteine cathepsin noninhibitory binding partners:  modulating intracellular trafficking and function.  Biol. Chem. 388: 1131-1140, 2007.

Jedeszko, C., Sameni, M., Olive, M.B., Moin, K. and Sloane, B.F.: Visualizing protease activity in living cells: from 2D to 4D.  Curr. Protocols Cell Biol., in press, 2008.

Moin, K., Sameni, M., Jedeszko, C., Li, Q., Olive, M.B., Mattingly, R.R. and Sloane, B.F.: Images of cleavage: tumor proteases in action.   In: The Cancer Degradome --- Proteases and Cancer Biology.  D.R. Edwards, G.F. Hoyer-Hansen, F. Blasi and B.F. Sloane, eds.), Springer, New York, in press, 2008.

Schwartz, D.R., Moin, K., Weber, E. and Sloane, B.F.:  The Hu/Mu ProtIn chip: a custom dual-species oligonucleotide microarray for profiling degradome gene expression in tumors and their microenvironment. In: The Cancer Degradome --- Proteases and Cancer Biology.  D.R. Edwards, G.F. Hoyer-Hansen, F. Blasi and B.F. Sloane, eds.), Springer, New York, in press, 2008.

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Anil Wali, Ph.D.
Proteases and Metastasis
Ph.D., Post-Graduate Institute of Medical Education and Research, India, 1990

http://www.karmanos.org/view_news.asp?id=408

Dr. Wali's research work is part of the multi-disciplinary Thoracic Oncology Research Program of Karmanos Cancer Institute and Veterans Affairs Medical Center, Wayne State University. The main objective of his laboratory is to delineate molecular mechanisms associated with novel target genes involved in the pathogenesis of Lung Cancer and Malignant Pleural Mesothelioma (MPM). His laboratory has employed several state-of-the-art methodologies in genomics and proteomics such as cDNA microarrays, Affymetrix high density oligonucleotide chips, 2D-PAGE-MS/MS analysis to identify several potential biomarkers for lung related malignancies. Current projects include tissue inhibitor of metalloproteinase (TIMP-1) and Intelectin. The hypothesis is that altered TIMP-1 and Intelectin gene expression influences tumorigenicity and invasiness of malignant pleural mesothelioma (MPM), that can be exploited as early detection biomarkers for this disease. To validate and find the molecular mechanisms associated with the alterations in TIMP-1 and Intelectin gene expression in archived MPM tumors and available corresponding cell lines, we plan on using RT-PCR, western blot, soft agar assays and tissue immunohistochemical studies. Another project in his laboratory is to evaluate serum and pleural effusions from archived specimens, as well as prospective high risk group of individuals by ELISA and correlate TIMP-1 and Intelectin expression with the known clinical outcomes for these patients. The proposed studies have the potential to clarify the importance of TIMP-1 and Intelectin in the pathogenesis of MPM and to define novel early detection strategies that could provide valuable insight into the future chemopreventive and/or therapeutic interventions for this disease.

Selected Publications

HI Pass, Z Liu, A Wali, R Bueno, S Land, D Lott, F Lonardo, M Carbone, and S Draghici. Gene expression profiles predict survival and progression of pleural mesothelioma. Clinical Cancer Research 10: 849-859, 2004.

Siddiq F, FH Sarkar, A Wali, HI Pass, and F Lonardo. Increased osteonectin expression is associated with malignant transformation and tumor associated fibrosis in the lung. Lung Cancer 45: 197-205, 2004.

Pass HI, Lott D, Lonardo F, Harbut M, Liu Z, Tang N, Carbone M, Webb C, and Wali A. Asbestos exposure, Pleural mesothelioma, and Serum osteopontin levels. New Engl J Med. 353:1564-73, 2005.

Wali A, PJ Morin, CD Hough, F Lonardo M Carbone, T Seya, and HI Pass. Identification of Intelectin in malignant pleural mesothelioma by serial analysis of gene expression (SAGE). Lung Cancer. 48: 19-29, 2005.

Rishi, AK; Zhang, L.; Yu, Y.; Jiang, Y.; Nautiyal, J; Wali, A; Fontana, JA; Levi, E; Majumdar, AP Cell cycle- and apoptosis-regulatory protein-1 is involved in apoptosis signaling by epidermal growth factor receptor. J Biol Chem. 281: 13188-98, 2006.

Rishi, AK; Parikh, R.; Wali, A.; Durko, L; Zhang, I; Yu, Y; Majumdar, AP: EGF receptor-related protein (ERRP) inhibits invasion of colon cancer cells and tubule formation by endothelial cells in vitro. Anticancer Res. 26: 1029-37, 2006.

Cortese, JF; Gowda, AL; Wali, A; Eliason, JF; Pass, HI; Everson, RB: Common EGFR mutations conferring sensitivity to gefitinib in lung adenocarcinoma are not prevalent in human malignant mesothelioma. Int J Cancer.  118: 521-2, 2006.

Frey, AB; Wali, A; Pass, H; Lonardo, F:Osteopontin is linked to p65 and MMP-9 expression in pulmonary adenocarcinoma but not in malignant pleural mesothelioma. Histopathology. 50: 720-726, 2007.

Zhang, L; Levi, E; Majumdar, P; Yu, Y; Aboukameel, A; Du, J; Xu, H; Mohammad, R; Hatfield, JS; Wali, A; Adsay, V; Majumdar, APN; Rishi, AK: Transactivation of transcription-tagged cell cycle and apoptosis regulatory protein-1 peptides suppress the growth of human breast cancer cells in vitro and in vivo. Mol Cancer Ther. 6: 1661-1672, 2007.

Zhang L, Wali A, Ramana CV, Rishi AK. Cell growth inhibition by
okadaic acid involves gut-enriched kruppel-like factor-mediated enhanced expression of c-myc. Cancer Res 67: 10198-10206, 2007.

Tsou JA, Galler JS, Wali A, Ye W, Siegmund KD, Groshen S, Laird
PW, Turla S, Koss MN, Pass HI, Laird-Offringa IA. DNA methylation
profile of 28 potential marker loci in malignant mesothelioma. Lung
Cancer 58: 220-230, 2007.

Pass HI, Wali A, Tang N, Ivanova A, Ivanov S, Harbut M, Carbone
M, Allard J. Soluble mesothelin related peptide level elevation in
mesothelioma serum and pleural effusions. Annals of Thoracic Surgery. (In press), 2008.

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