JCT  Vol.6 No.9 , September 2015
Integrin Alpha-V Beta-3-Matrix Metalloproteinase-2 (MMP-2), Cross-Talk
The present study aimed to detect comparative expression of integrin αVβ3 and its involvement in expression and activation of matrix metalloproteinase-2 (MMP-2) in 25 malignant human breast tumor and adjacent normal breast tissues from different clinical TNM stages (DCIS to T4) of the disease and possible involvement of known regulating parameters of MMP-2 like TIMP-2, MT1-MMP and EMPRIN. Integrin αVβ3 was highly expressed in tumors than adjacent normal breast tissues. Pro-MMP-2(72-KD) was mainly expressed in adjacent normal tissues compared to tumors. The mature forms of MMP-2 (68 KD and 64 KD) were found only in tumors. Appreciable expression of TIMP-2 and induction of MT1-MMP and EMPRIN in T2-T4 stages suggested their possible role in MMP-2 activation. Over expression Integrin αVβ3 in tumors than adjacent normal breast tissues was an indication of cancer progression with involvement of integrin signaling. We conclude that, the co-precipitation of MMP-2 with αvβ3 by anti-αv antibody is a strong indication that integrin αvβ3 is a surface receptor for MMP-2 and αvβ3-MMP-2 complex on the surface of tumor cells may play a very important role in determining the invasive property and malignant behavior of tumor tissues. The positive expression of endogenous inhibitor of MMP-2, TIMP-2 may have an appreciable role in activation of this protease and risk of malignancy in advanced stage of the disease. The enhanced expression of MT1-MMP and EMPRIN suggested a role for these factors in gelatinase regulation. However the exact mechanism(s) remains to be investigated. Finally, evaluation of integrin αVβ3 associated MMP-2 expression and activity may add valuable information and can possibly be therapeutic target. The clinical exploitation of integrins will provide oncologists with novel therapeutic strategies for the treatment of malignancy in breast cancer.

Cite this paper
Sil, H. and Chatterjee, A. (2015) Integrin Alpha-V Beta-3-Matrix Metalloproteinase-2 (MMP-2), Cross-Talk. Journal of Cancer Therapy, 6, 793-802. doi: 10.4236/jct.2015.69087.
[1]   Albelda, S.M. (1993) Biology of the Disease. Role of Integrins and Other Cell Adhesion Molecules in Tumor Progression and Metastasis. Laboratory Investigation, 68, 4-17.

[2]   Hynes, R.O. (1987) Integrins: A Family of Cell Surface Receptors. Cell, 48, 549-554.

[3]   Cheresh, D. (1993) Integrins, Structure, Function and Biological Properties. Advances in Molecular and Cell Biology, 6, 225-252.

[4]   Guadango, T.M., Ohtsubo, M., Roberts, J.M. and Assoian, R.K. (1993) A Link between Cyclin A Expression and Adhesion Dependent Cell Proliferation. Science, 262, 1572-1575.

[5]   Varner, J.A., Emerson, D.A. and Juliano, R.L. (1995) Integrin α5β1 Expression in Negatively Regulates Cell Growth: Reversal by Attachment to Fibronectin. Molecular Biology of the Cell, 6, 725-740.

[6]   Juliano, R.L. and Haskill, S. (1993) Signal Transduction from the Extracellular Matrix. The Journal of Cell Biology, 120, 577-585.

[7]   Montgomery, A.M.P., Reisfels, R.A. and Cheresh, D.A. (1994) Integrin αvβ3 Rescues Melanoma Cells from Apoptosis in Three Dimensional Dermal Collagen. Proceedings of the National Academy of Sciences of the United States of America, 91, 8856-8860.

[8]   Boudreau, N., Sympson, C.J. and Werb, Z. (1995) Bissel. Suppression of ICE and Appoptosis in Mammery Epithelial Cells by Extracellular Matrix. Science, 267, 891-893.

[9]   Thomas, G.J., Jones, J., Speight, P.M. (1997) Integrin and Oral Cancer. Oral Oncology, 33, 381-388.

[10]   Blanchine, P.J., Burd, P.R. and Metcalf, D.D. (1992) IL-3 Dependent Mast Cells Attach to Plate Bound Vitronectin. Demonstration of Augmented Proliferation in Response to Signals Transduced via Cell Surface Vitronectin Receptors. The Journal of Immunology, 149, 3665-3671.

[11]   Albelda, S.M., Mette, S.A., Elder, D.E., Stewart, R., Damianovich, L., Herlyn, M. and Buck, C.A. (1990) Integrin Distribution in Malignant Melanoma: Association of the β3 Subunit with Tumor Progression. Cancer Research, 50, 6757-6764.

[12]   Lafrenie, R.M., Podor, T.J., Buchanan, M.R. and Orr, F.W. (1992) Upregulated Biosynthesis and Expression of Endothelial Cell Vitronectin Receptor Enhances Cancer Cell Adhesion. Cancer Research, 52, 2202-2208.

[13]   Marchall, J.F., Nesbitt, S.A., Helfrich, M.H., Horton, M.A., Palakova, K. and Hart, I.R. (1991) Integrin Expression in Human Melanoma Cell Lines: Heterogenicity of Vitronectin Receptor Composition and Function. International Journal of Cancer, 49, 924-931.

[14]   Monsky, W.L., Kelly, T., Lin, C.Y., Yeh, Y., Stetler-Stevenson, W.G., Mueller, S.C. and Chen, W.T. (1993) Binding and Localization of M(r) 72,000 Matrix Metalloproteinase at Cell Surface Invadopodia. Cancer Research, 53, 3159-3164.

[15]   Partridge, C.A., Phillips, P.G., Niedbala, M.J. and Jeffrey, J.J. (1997) Localization and Activation of Type IV Collagenase/Gelatinase at Endothelial Focal Contacts. American Journal of Physiology, 272, L813-L822.

[16]   Koyama, S. (2004) Enhanced Cell Surface Expression of Matrix Metalloproteinases and Their Inhibitors, and Tumor-Induced Host Response in Progression of Human Gastric Carcinoma. Digestive Diseases and Sciences, 49, 1621-1630.

[17]   Brooks, P.C., Stromblad, S., Sanders, L., Von Schalscha, T.L., Aimes, R.T., Stetlar-Stevenson, W.G., Quigley, J.P. and Chesesh, D.A. (1996) Localization of Matrix Metalloproteinase-2 to the Surface of Invasive Cells by Interaction with αvβ3. Cell, 85, 683-693.

[18]   Brooks, P.C., Silletti, S., Von Schalscha, T.L., Friedlander, M. and Cheresh, D.A. (1998) Disruption of Angiogenesis by PEX, a Noncatalytic Metalloproteinase Fragment with Integrin Binding Activity. Cell, 92, 391-400.

[19]   Liotta, L.A. and Stetler-Stevenson, W.G. (1990) Metalloproteinases and Cancer Invasion. Seminars in Cancer Biology, 1, 99-106.

[20]   Monteagudo, C., Merino, M.J., San-Juan, J., Liotta, L.A. and Stetler-Stevenson, W.G. (1990) Immunohistochemical Distribution of Type IV Collagenase in Normal, Benign, and Malignant Breast Tissue. American Journal of Pathology, 136, 585-592.

[21]   D’Errico, A., Garbisa, S., Liotta, L.A., Castronovo, R., Stetler-Stevenson, W. and Grigioni, W.F. (1991) Augmentation of Type IV Collagenase and Laminin Receptors Immunoreactivity Associated with Human Breast, Colon and Gastric Carcinoma Progression. Modern Pathology, 4, 239-246.

[22]   Chattopadhyay, N. and Chatterjee, A. (2001) Studies on the Expression of Alpha(v)Beta3 Integrin Receptors in Non-Malignant and Malignant Human Cervical Tumor Tissues. Journal of Experimental & Clinical Cancer Research, 20, 269-275.

[23]   Zhao, Y., Bachelier, R., Treilleux, I., Pujuguet, P., Peyruchaud, O., Baron, R., Clément-Lacroix, P. and Clézardin, P. (2007) Tumor αvβ3 Is a Therapeutic Target for Breast Cancer Bone Metastasis. Cancer Research, 67, 5821-5830.

[24]   Seftor, R.E., Seftor, E.A., Stetler Stevenson, W.G. and Hendrix, M.J.C. (1993) The 72 kD Type IV Collagenase Is Modulated via Differential Expression of αvβ3 and α5β1 Integrins in Human Melanoma Cell Invasion. Cancer Research, 53, 3411-3415.

[25]   Philippe, C. (2011) Therapeutic Targets for Bone Metastases in Breast Cancer. Breast Cancer Research, 13, 207.

[26]   Felding-Habbermann, B., Fransvea, E., O’toole, T.E., Manzuk, L., Faha, B. and Hensler, M. (2002) Involvement of Tumor Cell Integrin αvβ3 in Hemaogenous Metastasis of Human Melanoma Cells. Clinical and Experimental Metastasis, 19, 427-436.

[27]   Gehlsen, K.R., Davis, G.E. and Sriramarao, P. (1992) Integrin Expression in Human Melanoma Cells with Differing Invasive and Metastatic Properties. Clinical and Experimental Metastasis, 10, 111-120.

[28]   Nip, J., Shibata, H., Loskutoff, D.J., Cheresh, D.A. and Brodt, P. (1992) Human Melanoma Cells Derived from Lymphatic Metastases Use Alpha-V Beta-3 to Adhere to Lymph Node Vitronectin. Journal of Clinical Investigation, 90, 1406-1413.

[29]   Gasparini, G, Brooks, P.C., Beganzoli, E., Vermulen, P.B., Bonoldi, E., Dirx, L.Y., Ranjeri, G., Miceli, R. and Cheresh, D.A. (1998) Vascular Integrin αvβ3: A New Prognostic Indicator in Breast Cancer. Clinical Cancer Research, 4, 2625-2624.

[30]   Brooks, P.C., Stromblad, S., Klemke, R., Vissocher, D.F., Sarkar, H. and Cheresh, D.A. (1995) Antiintegrin αvβ3 Blocks Human Breast Cancer Growth and Angiogenesis in Human Skin. Journal of Clinical Investigation, 96, 1815-1822.

[31]   Davies, B., Miles, D.W., Happerfield, L.C., Naylor, M.S., Bobrow, L.G., Rubens, R.D. and Balkwill, F.R. (1993) Activity of Type IV Collagenases in Benign and Malignant Breast Disease. British Journal of Cancer, 67, 1126-1133.

[32]   Tryggvason, K., Hoyhtya, M. and Pyke, C. (1993) Type IV Collagenase in Invasive Tumors. Breast Cancer Research and Treatment, 24, 209-218.

[33]   Talvensaari-Mattila, A., Paakko, P., Hoyhtya, M., Blanco-Sequeiros, G. and Turpeenniemi-Hujanen, T. (1998) Matrix Metalloproteinase-2 Immunoreactive Protein, a Marker of Aggressiveness in Breast Carcinoma. Cancer, 83, 1153-1162.

[34]   Hoodn, J.D. and Cheresh, D.A. (2002) Role of Integrins in Cell Invasion and Migration. Nature Reviews Cancer, 2, 91-100.

[35]   Lisa, M., Bafetti Timothy, N., Young, Yoshifumi, I. and Sharon Stack, M. (1998) Intact Vitronectin Induces Matrix Metalloproteinase-2 and Tissue Inhibitor of Metalloproteinases-2 Expression and Enhanced Cellular Invasion by Melanoma Cells. Journal of Biological Chemistry, 273, 143-149.

[36]   Nguyen, M., Arkell, J. and Jackson, C.J. (2000) Activated Protein C Directly Activates Human Endothelial Gelatinase A. Journal of Biological Chemistry, 275, 9095-9098.

[37]   Morrison, C.J., Butler, G.S., Bigg, H.F., Roberts, C.R., Soloway, P.D. and Overall, C.M. (2001) Cellular Activation of MMP-2 (Gelatinase A) by MT2-MMP Occurs via a TIMP-2-Independent Pathway. Journal of Biological Chemistry, 276, 47402-47410.

[38]   Zahradka, P., Harding, G., Litchie, B., Thomas, S., Werner, J.P., Wilson, D.P. and Yurkova, N. (2004) Activation of MMP-2 in Response to Vascular Injury Is Mediated by Phosphatidylinositol 3-Kinase-Dependent Expression of MT1-MMP. American Journal of Physiology: Heart and Circulatory Physiology, 287, H2861-H2870.

[39]   Corcoran, M.L., Emmert-Buck, M.R., McClanahan, J.L., Pelina-Parker, M. and Stetler-Stevenson, W.G. (1996) TIMP-2 Mediates Cell Surface Binding of MMP-2. Advances in Experimental Medicine and Biology, 389, 295-304.

[40]   Puyraimond, A., Fridman, R., Lemesle, M., Arbeille, B. and Menashi, S. (2001) MMP-2 Colocalizes with Caveolae on the Surface of Endothelial Cells. Experimental Cell Research, 262, 28-36.

[41]   Garbett, E.A., Reed, M.W., Stephenson, T.J. and Brown, N.J. (2000) Proteolysis in Human Breast Cancer. Molecular Pathology, 53, 99-106.

[42]   Ree, A.H., Florenes, V.A., Berg, J.P., Maelandsmo, G.M., Nesland, J.M. and Fodstad, O. (1997) High Levels of Messenger RNAs for Tissue Inhibitors of Metalloproteinases (TIMP-1 and TIMP-2) in Primary Breast Carcinomas Are Associated with Development of Distant Metastases. Clinical Cancer Research, 3, 1623-1628.

[43]   Deryugina, E.I., Ratnikov, B., Monosov, E., Postnova, T.I., Discipio, R., Smith, J.W. and Strongin, A.Y. (2001) MT1-MMP Initiates Activation of Pro-MMP-2 and Integrin αvβ3 Promotes Maturation of MMP-2 in Breast Carcinoma Cells. Experimental Cell Research, 263, 209-223.

[44]   Ellis, S.M., Nabeshima, K. and Biswas, C. (1989) Monoclonal Antibody Preparation and Purification of a Tumor Cell Collagenase Stimulatory Factor. Cancer Research, 49, 3385-3391.

[45]   Guo, H., Zucke, R.S., Gordon, M.K., Toole, B.P. and Biswas, C. (1997) Stimulation of Matrix Metalloproteinase Production by Recombinant Extracellular Matrix Metalloproteinase Inducer from Transfected Chinese Hamster Ovary Cells. Journal of Biological Chemistry, 272, 24-27.

[46]   Kataoka, H., DeCastro, R., Zucker, S. and Biswas, C. (1993) Tumor Cell-Derived Collagenase-Stimulatory Factor Increases Expression of Interstitial Collagenase, Stromelysin, and 72-kDa Gelatinase. Cancer Research, 53, 3154-3158.

[47]   Sameshima, T., Nabeshima, K., Toole, B.P., Yokogami, K., Okada, Y., Goya, T., Koono, M. and Wakisaka, S. (2000) Glioma Cell Extracellular Matrix Metalloproteinase Inducer (EMMPRIN) (CD147) Stimulates Production of Membrane-Type Matrix Metalloproteinases and Activated Gelatinase A in Co-Cultures with Brain-Derived Fibroblasts. Cancer Letters, 157, 177-184.

[48]   Chattopadhyay, N., Mitra, A., Frei, E. and Chatterjee, A. (2001) Human Cervical Tumor Cell (Siha) Surface αvβ3 Integrin Receptor Has Associated Matrix Metalloproteinase (MMP-2) Activity. Journal of Cancer Research and Clinical Oncology, 127, 653-658.

[49]   Mitra, A., Chakrabarti, J., Chattopadhyay, N. and Chatterjee, A. (2003) Membrane-Associated MMP-2 in Human Cervical Cancer. Journal of Environmental Pathology, Toxicology and Oncology, 22, 93-100.