Summary
The matrix metalloproteinase MMP-2 is up-regulated in epithelial cancers and its mRNA localizes to stromal fibroblasts. In this paper we show that co-culture of ovarian carcinoma cells with fibroblasts resulted in an enhanced release of proMMP-2 and TIMP-2 into the culture medium. Cell–cell interaction was a major factor in this response and carcinoma cells stimulated proMMP-2 release from fibroblasts but not vice versa. Collagen I, in a dose-dependent fashion, induced activation of proMMP-2 by tumour-derived, but not normal, fibroblasts. Antibody to β1 integrin also induced proMMP-2 activation by tumour-derived fibroblasts. The activation involved the processing of proMMP-2 by a membrane-bound metalloproteinase. We propose that, in the ovarian tumour microenvironment, interaction between tumour cells and fibroblasts may enhance fibroblast production of the proMMP-2 and TIMP-2. Collagen I, also present in the ovarian tumours, then induces these fibroblasts to activate proMMP-2 even in the presence of TIMP-2. This active MMP-2 can associate with the cell surface of tumour cells and fibroblasts and is used in the processes of tissue remodelling and invasion.
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References
Afzal, S., Lalani, E-L, Foulkes, W. D., Boyce, B., Tickle, S., Cardillo, M-R, Baker, T., Pignatelli, M. & Stamp, G. W. H. (1996). Matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-2 expression and synthetic matrix metalloproteinase-2 inhibitor binding in ovarian carcinomas and tumour cell lines. Lab Invest 2: 406–421.
Atkinson, S. J., Crabbe, T., Cowell, S., Ward, R., Butler, M. J., Sato, H., Seiki, M., Reynolds, J. J. & Mutphy, G. (1995). Intermolecular autolytic cleavage can contribute to the activation of progelatinase A by cell membranes. J Biol Chem 270: 30479–30485.
Autio-Harmainen, H., Karttunen, T., Hurskainen, T., Hoyhtya, M. & Kauppila, A. (1993). Expression of 72 kilodalton type IV collagenase (gelatinase A) in benign and malignant ovarian tumours. Lab Invest 69: 312–321.
Azzam, H. S. & Thompson, E. W. (1992). Collagen-induced activation of the Mr 72 type IV collagenase in normal and malignant human fibroblastoid cells. Cancer Res 52: 4540–4544.
Baramova, E. N., Bajou, K., Remacle, A., Líhoir, C., Krell, H. W., Weidle, U. H., Noel, A. & Foidart, J. M. (1997). Involvement of PA/plasmin system in the processing of pro-MMP-9 and in the second step of proMMP-2 activation. FEBS Letts 405: 157–162.
Birkedal-Hansen, H. (1995). Proteolytic remodeling of extracellular matrix. Curr Opin Cell Biol 7: 728–735.
Bordier, C. (1981). Phase separation of integral membrane proteins in Triton X-114 solution. J Biol Chem 256: 1604–1607.
Campo, E., Merino, M. J., Tavassoli, F. A., Charonis, A. S. & Stetler-Stevenson, W. G. (1992). Evaluation of basement membrane components and the 72 kDa type IV collagenase in serous tumours of the ovary. Am J Surg Pathol 16: 500–507.
Fishman, D. A., Bafetti, L. M. & Stack, M. S. (1997). Membrane-type matrix metalloproteinase expression and matrix metalloproteinase-2 activation in primary human ovarian epithelial carcinoma cells. Inv Metastasis 16: 150–159.
Garzetti, G., Ciavattini, A., Lucarini, G., Goteri, G., Nictolis, M. D., Garbisa, S., Masiero, L., Romanini, C. & Graziella, B. (1995). Tissue and serum metalloproteinase (MMP-2) expression in advanced ovarian serous cystodenocarcinomas: clinical and prognostic implications. Anticancer Res 15: 2799–2804.
Gilles, C., Polette, M., Seiki, M., Birembaut, P. & Thompson, E. W. (1997). Implication of collagen type-1 induced membrane-type 1-matrox metalloproteinase expression and matrix metalloproteinase-2 activation in the metastatic progression of breast carcinoma. Lab Invest 76: 651–660.
Greene, J., Wang, M., Liu, Y. I., Raymond, L. A., Rosen, C. & Shi, Y. I. (1996). Molecular cloning and characterization of human tissue inhibitor of metalloproteinase 4. J Biol Chem 271: 30375–30378.
Ito, A., Nakajima, S., Sasaguri, Y., Nagase, H. & Mori, Y. (1995). Co-culture of human breast adenocarcinoma MCF-7 cells and human dermal fibroblasts enhances the production of matrix metalloproteinases 1, 2 and 3 in fibroblasts. Br J Cancer 71: 1039–1045.
Kataoka, H., Decastro, R., Zucker, S. & Biswas, C. (1993). Tumour cell-derived collagenase-stimulatory factor increases expression of interstitial collagenase, stromeolysin, and 72 kDa gelatinase. Cancer Res 53: 3154–3158.
Kikkawa, F., Tamakoshi, K., Nawa, K., Shibata, K., Yamagata, S., Yamagata, T. & Suganuma, N. (1997). Positive correlation between inhibitors of matrix metalloproteinase 1 and matrix metalloproteinases in malignant ovarian tumour tissues. Cancer Letts 120: 109–115.
Kolenbrock, H., Hecker-Kia, A., Orgel, D., Ulbrich, N. & Will, H. (1997). Activation of progelatinase A and progelatinase A/TIMP-2 complex by membrane type 2-matrix metalloproteinase. J Biol Chem 378: 71–76.
Kubota, S., Ito, H. & Seyama, Y. (1997). Anti-alpha3 integrin antibody induces the activated form of matrix metalloprotease-2 (MMP-2) with concomitant stimulation of invasion through matrigel by human rhabdomyosarcoma cells. Int J Cancer 70: 106–111.
Kuwashima, Y., Uehara, T., Kurosumi, M., Kishi, K., Shironizu, K., Matsuzawa, M. & Takayama, S. (1995). Basement membrane status I undifferentiated carcinomas of the ovary: immunohistochemical distribution of type IV collagen and laminin. Eur J Gynaecol Oncol 16: 181–186.
Leber, T. M. & Balkwill, F. R. (1997). Zymography: a single-step staining method for quantitation of proteolytic activity on substrate gels. Anal Biochem 249: 24–28.
Lee, A. Y., Akers, K. T., Collier, M., Li, L., Eisen, A. Z. & Louise-Seltzer, J. (1997). Intracellular activation of gelatinase A (72-kDa type IV collagenase) by normal fibroblasts. Proc Natl Acad Sci USA 94: 4424–4429.
Lewalle, J. M., Munaut, C., Pichot, B., Cataldo, D., Baramova, E. & Foidart, J. M. (1995). Plasma membrane-dependent activation of gelatinase A in human vascular endothelial cells. J Cell Physiol 165: 475–483.
Liabakk, N-B, Talbot, I., Smith, R. A., Wilkinson, K. & Balkwil, F. B. (1996). Matrix metalloprotease 2 (MMP-2) and matrix metalloprotease 9 (MMP-9) type IV collagenases in colorectal cancer. Cancer Res 56: 190–196.
Liotta, L. A., Steeg, P. S. & Steteler-Stevenson, W. G. (1991). Cancer metastasis and angiogenesis: an imbalance of positive and negative regulation. Cancer Res 64: 327–336.
Lohi, J., Lehti, K., Westermarck, J., Kahari, V-M & Keski-Oja, J. (1996). Regulation of membrane-type matrix metalloprotease-1 expression by growth factors and phorbol 12-myristate 13-acetate. Eur J Biochem 239: 239–247.
Moser, T. L., Young, T. N., Rodriguez, G. C., Pizzo, S. V., Bast, R. C. & Stack, M. S. (1994). Secretion of extracellular matrix-degrading proteinases is increased in epithelial ovarian carcinoma. Int J Cancer 56: 552–559.
Naylor, M. S., Stamp, G. W., Davies, B. D. & Balkwill, F. R. (1994). Expression and activity of MMPs and their regulators in ovarian cancer. Int J Cancer 58: 50–56.
Niedbala, M. J., Crickard, K. & Bernacki, R. J. (1987). In vitro degradation of extracellular matrix by human ovarian carcinoma cells. Clin Exp Metastasis 5: 181–197.
Noel, A., Munaut, C., Boulvain, A., Calberg-Bacq, C. M., Nusgens, B., Lapiere, C. M. & Foidart, J. M. (1992). Modulation of collagen and fibronectin synthesis in fibroblasts by normal and malignant cells. J Cell Biochem 48: 150–161.
Noel, A., Polette, M., Lewalle, J-M, Munaut, C., Emonard, H. P., Birembaut, P. & Foidart, J-M (1994). Co-ordinate enhancement of gelatinase A mRNA and activity levels in human fibroblasts in response to breast-adenocarcinoma cells. Int J Cancer 56: 331–336.
Ohtani, H., Motohashi, H., Sato, H., Seiki, M. & Nagura, H. (1996). Dual overexpression of membrane-type metalloproteinase-1 in cancer and stromal cells in human gastrointestinal carcinoma revealed by in situ hybridization and immunoelectron microscopy. Int J Cancer 68: 565–570.
Okada, A., Bellocq, J-P, Rouyer, N., Chenard, M-P, Rio, M-C, Chambon, P. & Basset, P. (1995). Membrane-type metalloproteinase (MT-MMP) gene is expressed in stromal cells of human colon, breast, and head and neck carcinomas. Proc Natl Acad Sci USA 92: 2730–2734.
Ray, J. M. & Stetler-Stevenson, W. G. (1995). Gelatinase A activity directly modulates melanoma cell adhesion and spreading. EMBO J 14: 908–917.
Sato, H., Takino, T., Okada, O., Kada, O., Cao, J., Shinagawa, A., Yamamoto, E. & Seiki, M. (1994). A matrix metalloproteinase expressed on the surface of invasive tumour cells. Nature 370: 61–65.
Seltzer, J. L., Lee, A-Y, Akers, K. T., Sudbeck, B., Eileen, A., Southon, E. A., Wayner, E. A. & Eisen, A. Z. (1994). Activation of 72-kDa collagenase/gelatinase by normal fibroblasts in collagen lattices is mediated by integrin receptors but is not related to lattice contraction. Exp Cell Res 213: 365–374.
Shofuda, K., Yasumitsu, H., Nishihashi, A., Miki, K. & Miyazaki, K. (1997). Expression of three matrix metalloproteinases (MT-MMPs) in rat vascular smooth muscle cells and characterization of MT3-MMPs with and without transmembrane domain. J Biol Chem 272: 9749–9754.
Stetler-Stevenson, W. G., Krutzsch, H. C., Wacher, M. P., Maraguliies, I. M. K. & Liotta, I. A. (1989a). The activation of human type IV collagenase proenzyme: sequence identification of the major conversion product following organo-mecurial activation. J Biol Chem 264: 1353–1360.
Stetler-Stevenson, W. G., Krutzsch, H. C. & Liotta, I. A. (1989b). Tissue inhibitors of metalloproteinase (TIMP-2): a new member of the metalloproteinase inhibitor family. J Biol Chem 264: 17374–17378.
Strongin, A. Y., Cillier, I., Bannikov, G., Marmer, B. L., Grant, G. A. & Goldberg, G. I. (1995). Mechanism of cell surface activation of 72 kDa type IV collagenase. J Biol Chem 270: 5331–5338.
Tamakoshi, K., Kikkawa, F., Nawa, A., Ishikawa, H., Mizuno, K., Tamakoshi, A., Yamagata, S., Suganuma, N. & Tomoda, Y. (1995). Characterisation of extracellular matrix-degrading proteinase and its inhibitor in gynecologic cancer tissues with clinically different metastatic form. Cancer 76: 2565–2571.
Westerlund, A., Hujanen, E., Puistola, U. & Turpeenniemi-Hujanen, T. (1997). Fibroblasts stimulate human ovarian cancer cell invasion and expression of 72-kDa gelatinase A (MMP-2). Gynecol Oncol 67: 76–82.
Ueno, H., Nakamura, H., Inoue, M., Imai, M., Imai, K., Noguchi, M., Sato, H., Seiki, M. & Okada, Y. (1997). Expression and tissue localization of membrane-types 1, 2 and 3 matrix metalloproteinases in human invasive breast carcinomas. Cancer Res 57: 2055–2060.
Zhu, G-G, Risteli, L., Risteli, J., Kauppila, M. & Stenback, F. (1994). Immunohistochemical study of type I collagen and type I pH-collagen in benign and malignant neoplasms. Cancer 75: 1010–1017.
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Boyd, R., Balkwill, F. MMP-2 release and activation in ovarian carcinoma: the role of fibroblasts. Br J Cancer 80, 315–321 (1999). https://doi.org/10.1038/sj.bjc.6690357
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DOI: https://doi.org/10.1038/sj.bjc.6690357
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