Home Membrane-type I matrix metalloproteinase-dependent ectodomain shedding of mucin16/ CA-125 on ovarian cancer cells modulates adhesion and invasion of peritoneal mesothelium
Article
Licensed
Unlicensed Requires Authentication

Membrane-type I matrix metalloproteinase-dependent ectodomain shedding of mucin16/ CA-125 on ovarian cancer cells modulates adhesion and invasion of peritoneal mesothelium

  • Lana Bruney , Kaitlynn C. Conley , Natalie M. Moss , Yueying Liu and M. Sharon Stack EMAIL logo
Published/Copyright: September 5, 2014

Abstract

Mucin16 [MUC16/cancer antigen 125 (CA-125)], a high-molecular-weight glycoprotein expressed on the ovarian tumor cell surface, potentiates metastasis via selective binding to mesothelin on peritoneal mesothelial cells. Shed MUC16/CA-125 is detectable in sera from ovarian cancer patients. We investigated the potential role of membrane type 1 matrix metalloproteinase (MT1-MMP, MMP-14), a transmembrane collagenase highly expressed in ovarian cancer cells, in MUC16/CA-125 ectodomain shedding. An inverse correlation between MT1-MMP and MUC16 immunoreactivity was observed in human ovarian tumors and cells. Further, when MUC16-expressing OVCA433 cells were engineered to overexpress MT1-MMP, surface expression of MUC16/CA-125 was lost, whereas cells expressing the inactive E240A mutant retained surface MUC16/CA-125. As a functional consequence, decreased adhesion of cells expressing catalytically active MT1-MMP to three-dimensional meso-mimetic cultures and intact ex vivo peritoneal tissue explants was observed. Nevertheless, meso-mimetic invasion is enhanced in MT1-MMP-expressing cells. Together, these data support a model wherein acquisition of catalytically active MT1-MMP expression in ovarian cancer cells induces MUC16/CA-125 ectodomain shedding, reducing adhesion to meso-mimetic cultures and to intact peritoneal explants. However, proteolytic clearing of MUC16/CA-125, catalyzed by MT1-MMP, may then expose integrins for high-affinity cell binding to peritoneal tissues, thereby anchoring metastatic lesions for subsequent proliferation within the collagen-rich sub-mesothelial matrix.


Corresponding author: M. Sharon Stack, Department of Chemistry and Biochemistry and Harper Cancer Research Institute, University of Notre Dame, A200D Harper Hall, South Bend, IN 46617, USA, e-mail:

Acknowledgments

The authors gratefully acknowledge financial support from National Institutes of Health/National Cancer Institute grants F31 CA159804 (L.B.), RO1 CA109545 (M.S.S.), and RO1 CA086984 (M.S.S.).

References

Ahmed, N., Riley, C., Rice, G., and Quinn, M. (2005). Role of integrin receptors for fibronectin, collagen and laminin in the regulation of ovarian carcinoma functions in response to a matrix microenvironment. Clin. Exp. Metastasis 22, 391–402.Search in Google Scholar

Auersperg, N., Pan, J., Grove, B.D., Peterson, T., Fisher, J., Maines-Bandiera, S., Somasiri, A., and Roskelley, C.D. (1999). E-cadherin induces mesenchymal-to-epithelial transition in human ovarian surface epithelium. Proc. Natl. Acad. Sci. USA 96, 6249–6254.Search in Google Scholar

Auersperg, N., Wong, A.S., Choi, K.C., Kang, S.K., and Leung, P.C. (2001). Ovarian surface epithelium: biology, endocrinology, and pathology. Endocr. Rev. 22, 255–288.Search in Google Scholar

Barbolina, M.V., Adley, B.P., Ariztia, E.V., Liu, Y., and Stack, M.S. (2007). Microenvironmental regulation of membrane type 1 matrix metalloproteinase activity in ovarian carcinoma cells via collagen-induced EGR1 expression. J. Biol. Chem. 282, 4924–4931.Search in Google Scholar

Barbolina, M.V., Moss, N.M., Westfall, S.D., Liu, Y., Burkhalter, R.J., Marga, F., Forgacs, G., Hudson, L.G., and Stack, M.S. (2009). Microenvironmental regulation of ovarian cancer metastasis. Cancer Treat. Res. 149, 319–334.Search in Google Scholar

Barbolina, M.V., Liu, Y., Gurler, H., Kim, M., Kajdacsy-Balla, A.A., Rooper, L.,Shepard, J., Weiss, M., Shea, L.D., Penzes, P., et al. (2013). Matrix rigidity activates Wnt signaling through down-regulation of Dickkopf-1 protein. J. Biol. Chem. 288, 141–151.Search in Google Scholar

Bast, R.C., Klug, T.L., St John, E., Jenison, E., Niloff, J.M., Lazarus, H., Berkowitz, R.S., Leavitt, T., Griffiths, C.T., Parker, L., et al. (1983). A radioimmunoassay using a monoclonal antibody to monitor the course of epithelial ovarian cancer. N. Engl. J. Med. 309, 883–887.Search in Google Scholar

Berns, E.M.J.J. and Bowtell, D.D. (2012). The changing view of high-grade serous ovarian cancer. Cancer Res. 72, 2701–2704.Search in Google Scholar

Burleson, K.M., Casey, R.C., Skubitz, K.M., Pambuccian, S.E., Oegema, T.R., and Skubitz, A.P.N. (2004a). Ovarian carcinoma ascites spheroids adhere to extracellular matrix components and mesothelial cell monolayers. Gynecol. Oncol. 93, 170–181.Search in Google Scholar

Burleson, K.M., Hansen, L.K., and Skubitz, A.P.N. (2004b). Ovarian carcinoma spheroids disaggregate on type I collagen and invade live human mesothelial cell monolayers. Clin. Exp. Metastasis. 21, 685–697.Search in Google Scholar

Cannistra, S.A. (2004). Cancer of the ovary. N. Engl. J. Med. 351, 2519–2529.Search in Google Scholar

Casey, R.C., Burleson, K.M., Skubitz, K.M., Pambuccian, S.E., Oegema, T.R., Ruff, L.E., and Skubitz, A.P. (2001). Beta 1-integrins regulate the formation and adhesion of ovarian carcinoma multicellular spheroids. Am. J. Pathol. 159, 2071–2080.Search in Google Scholar

Chen, S.-H., Hung, W.-C., Wang, P., Paul, C., and Konstantopoulos, K. (2013). Mesothelin binding to CA125/MUC16 promotes pancreatic cancer cell motility and invasion via MMP-7 activation. Sci. Rep. 3, 1870.Search in Google Scholar

Cramer, D.W., Bast, R.C., Berg, C.D., Diamandis, E.P., Godwin, A.K., Hartge, P., Hartge P, Lokshin, A.E., Lu, K.H., McIntosh, M.W., et al. (2011). Ovarian cancer biomarker performance in prostate, lung, colorectal, and ovarian cancer screening trial specimens. Cancer Prev. Res. (Phila.) 4, 365–374.Search in Google Scholar

Desgrosellier, J.S. and Cheresh, D.A. (2010). Integrins in cancer: biological implications and therapeutic opportunities. Nat. Rev. Cancer 10, 9–22.Search in Google Scholar

Devine, P.L., McGuckin, M.A., and Ward, B.G. (1992). Circulating mucins as tumor markers in ovarian cancer (review). Anticancer Res. 12, 709–717.Search in Google Scholar

Doi, T., Maniwa, Y., Tanaka, Y., Tane, S., Hashimoto, S., Ohno, Y., Nishio, W., Nishimura, Y., Ohbayashi, C., Okita, Y., et al. (2011). MT1-MMP plays an important role in an invasive activity of malignant pleural mesothelioma cell. Exp. Mol. Pathol. 90, 91–96.Search in Google Scholar

Dubeau, L. (2008). The cell of origin of ovarian epithelial tumours. Lancet Oncol. 9, 1191–1197.Search in Google Scholar

Egeblad, M. and Werb, Z. (2002). New functions for the matrix metalloproteinases in cancer progression. Nat. Rev. Cancer 2, 161–174.Search in Google Scholar

Ellerbroek, S.M., Wu, Y.I., Overall, C.M., and Stack, M.S. (2001). Functional interplay between type I collagen and cell surface matrix metalloproteinase activity. J. Biol. Chem. 276, 24833–28342.Search in Google Scholar

Fathalla, M.F. (1971). Incessant ovulation – a factor in ovarian neoplasia? Lancet ii, 163.Search in Google Scholar

Goodell, C.A., Belisle, J.A., Gubbels, J.A., Migneault, M., Rancourt, C., Connor, J., Kunnimalaiyaan, M., Kravitz, R., Tucker, W., Zwick, M., et al. (2009). Characterization of the tumor marker muc16 (ca125) expressed by murine ovarian tumor cell lines and identification of a panel of cross-reactive monoclonal antibodies. J. Ovarian Res. 2, 8.Search in Google Scholar

Gubbels, J.A.A., Belisle, J., Onda, M., Rancourt, C., Migneault, M., Ho, M., Bera, T.K., Connor, J., Sathyanarayana, B.K., Lee, B., et al. (2006). Mesothelin-MUC16 binding is a high affinity, N-glycan dependent interaction that facilitates peritoneal metastasis of ovarian tumors. Mol. Cancer 5, 50.Search in Google Scholar

Hillier, S.G. (2012). Nonovarian origins of ovarian cancer. Proc. Natl. Acad. Sci. USA 109, 3608–3609.Search in Google Scholar

Howlader, N., Noone, A., Krapcho, M., Garshell, J., Neyman, N., Altekruse, S., Kosary, C.L., Yu, M., Ruhl, J., Tatalovich, Z., et al., eds. (2013). SEER Cancer Statistics Review, 1975–2010 (Bethesda, MD: National Cancer Institute).Search in Google Scholar

Hudson, L.G., Zeineldin, R., and Stack, M.S. (2008). Phenotypic plasticity of neoplastic ovarian epithelium: unique cadherin profiles in tumor progression. Clin. Exp. Metastasis 25, 643–655.Search in Google Scholar

Husseinzadeh, N. (2011). Status of tumor markers in epithelial ovarian cancer has there been any progress? A review. Gynecol. Oncol. 120, 152–157.Search in Google Scholar

Jemal, A., Bray, F., and Ferlay, J. (2011). Global cancer statistics. CA Cancer J. Clin. 61, 69–90.Search in Google Scholar

Kaimal, R., Aljumaily, R., Tressel, S.L., Pradhan, R.V., Covic, L., Kuliopulos, A., Zarwan, C., Kim, Y.B., Sharifi, S., and Agarwal, A. (2013). Selective blockade of matrix metalloprotease-14 with a monoclonal antibody abrogates invasion, angiogenesis, and tumor growth in ovarian cancer. Cancer Res. 73, 2457–2467.Search in Google Scholar

Kaneko, O., Gong, L., Zhang, J., Hansen, J.K., Hassan, R., Lee, B., and Ho, M. (2009). A binding domain on mesothelin for CA125/MUC16. J. Biol. Chem. 284, 3739–3749.Search in Google Scholar

Kim, J., Coffey, D.M., Creighton, C.J., Yu, Z., Hawkins, S.M., and Matzuk, M.M. (2012). High-grade serous ovarian cancer arises from fallopian tube in a mouse model. Proc. Natl. Acad. Sci. USA 109, 3921–3926.Search in Google Scholar

Kui Wong, N., Easton, R.L., Panico, M., Sutton-Smith, M., Morrison, J.C., Lattanzio, F.A., Morris, H.R., Clark, G.F., Dell, A., and Patankar, M.S. (2003). Characterization of the oligosaccharides associated with the human ovarian tumor marker CA125. J. Biol. Chem. 278, 28619–28634.Search in Google Scholar

Lengyel, E., Burdette, J.E., Kenny, H.A., Matei, D., Pilrose, J., Haluska, P., Nephew, K.P., Hales, D.B., and Stack, M.S. (2013). Epithelial ovarian cancer experimental models. Oncogene 1–15. DOI: 10.1038/onc.2013.321 [Epub ahead of print].Search in Google Scholar

Lessan, K., Aguiar, D.J., Oegema, T., Siebenson, L., and Skubitz, A.P. (1999). CD44 and beta1 integrin mediate ovarian carcinoma cell adhesion to peritoneal mesothelial cells. Am. J. Pathol. 154, 1525–1537.Search in Google Scholar

Mai, P.L., Wentzensen, N., and Greene, M.H. (2011). Challenges related to developing serum-based biomarkers for early ovarian cancer detection. Cancer Prev. Res. (Phila.) 4, 303–306.Search in Google Scholar

Marth, C., Fuith, L.C., Böck, G., and Dapunt, O. (1989). Modulation of ovarian carcinoma tumor marker CA-125 by γ modulation of ovarian carcinoma tumor marker CA-125 by 7-interferon. Cancer Res. 105, 6538–6542.Search in Google Scholar

Marth, C., Egle, D., Auer, D., Rössler, J., Zeimet, A.G., Vergote, I., and Daxenbichler, G. (2007). Modulation of CA-125 tumor marker shedding in ovarian cancer cells by erlotinib or cetuximab. Gynecol. Oncol. 105, 716–721.Search in Google Scholar

Moore, R.G., MacLaughlan, S., and Bast, R.C. (2010). Current state of biomarker development for clinical application in epithelial ovarian cancer. Gynecol. Oncol. 116, 240–245.Search in Google Scholar

Moser, T.L., Pizzo, S.V., Bafetti, L.M., Man, D.A.F., and Sharon, M. (1996). Evidence for preferential adhesion of ovarian epithelial carcinoma cells to type I collagen mediated by the alpha2beta1 integrin. Int. J. Cancer 701, 695–701.Search in Google Scholar

Moss, N.M., Barbolina, M.V., Liu, Y., Sun, L., Munshi, H.G., and Stack, M.S. (2009a). Ovarian cancer cell detachment and multicellular aggregate formation are regulated by membrane type 1 matrix metalloproteinase: a potential role in I.p. metastatic dissemination. Cancer Res. 69, 7121–7129.Search in Google Scholar

Moss, N.M., Wu, Y.I., Liu, Y., Munshi, H.G., and Stack, M.S. (2009b). Modulation of the membrane type 1 matrix metalloproteinase cytoplasmic tail enhances tumor cell invasion and proliferation in three-dimensional collagen matrices. J. Biol. Chem. 284, 19791–19799.Search in Google Scholar

Patankar, M.S., Jing, Y., Morrison, J.C., Belisle, J.A., Lattanzio, F.A., Deng, Y., Wong, N.K., Morris, H.R., Dell, A., and Clark, G.F. (2005). Potent suppression of natural killer cell response mediated by the ovarian tumor marker CA125. Gynecol. Oncol. 99, 704–713.Search in Google Scholar

Rump, A., Morikawa, Y., Tanaka, M., Minami, S., Umesaki, N., Takeuchi, M., and Miyajima, A. (2004). Binding of ovarian cancer antigen CA125/MUC16 to mesothelin mediates cell adhesion. J. Biol. Chem. 279, 9190–9198.Search in Google Scholar

Sakata, K., Shigemasa, K., Nagai, N., and Ohama, K. (2000). Expression of matrix metalloproteinases (MMP-2, MMP-9, MT1-MMP) and their inhibitors (TIMP-1, TIMP-2) in common epithelial tumors of the ovary. Int. J. Oncol. 17, 673–381.Search in Google Scholar

Scholler, N. and Urban, N. (2007). CA125 in ovarian cancer. Biomark. Med. 1, 513–523.Search in Google Scholar

Scholler, N., Garvik, B., Hayden-Ledbetter, M., Kline, T., and Urban, N. (2007). Development of a CA125-mesothelin cell adhesion assay as a screening tool for biologics discovery. Cancer Lett. 247, 130–136.Search in Google Scholar

Sounni, N.E., Devy, L., Hajitou, A., Frankenne, F., Munaut, C., Gilles, C., Deroanne, C., Thompson, E.W., Foidart, J.M., and Noel, A. (2002). MT1-MMP expression promotes tumor growth and angiogenesis through an up-regulation of vascular endothelial growth factor expression. FASEB J. 16, 555–564.Search in Google Scholar

Strauss, R., Li, Z.-Y., Liu, Y., Beyer, I., Persson, J., Sova, P., Möller, T., Pesonen, S., Hemminki, A., Hamerlik, P., et al. (2011). Analysis of epithelial and mesenchymal markers in ovarian cancer reveals phenotypic heterogeneity and plasticity. PLoS One 6, e16186.Search in Google Scholar

Strobel, T. and Cannistra, S.A. (1999). Beta1-integrins partly mediate binding of ovarian cancer cells to peritoneal mesothelium in vitro. Gynecol. Oncol. 73, 362–367.Search in Google Scholar

Thériault, C., Pinard, M., Comamala, M., Migneault, M., Beaudin, J., Matte, I., Boivin, M., Piché, A., and Rancourt C. (2011). MUC16 (CA125) regulates epithelial ovarian cancer cell growth, tumorigenesis and metastasis. Gynecol. Oncol. 121, 434–443.Search in Google Scholar

Tuxen, M.K., Sölétormos, G., and Dombernowsky, P. (1995). Tumor markers in the management of patients with ovarian cancer. Cancer Treat. Rev. 21, 215–245.Search in Google Scholar

Vergote, I.B., Onsrud, M., Børmer, O.P., Sert, B.M., and Moen, M. (1992). CA125 in peritoneal fluid of ovarian cancer patients. Gynecol. Oncol. 44, 161–165.Search in Google Scholar

Yin, B.W. and Lloyd, K.O. (2001). Molecular cloning of the CA125 ovarian cancer antigen: identification as a new mucin, MUC16. J. Biol. Chem. 276, 27371–27375.Search in Google Scholar

Yin, B.W.T., Dnistrian, A., and Lloyd, K.O. (2002). Ovarian cancer antigen CA125 is encoded by the MUC16 mucin gene. Int. J. Cancer 98, 737–740.Search in Google Scholar

Zeimet, A.G., Marth, C., Offner, F.A., Obrist, P., Uhl-Steidl, M., Feichtinger, H., Stadlmann, S., Daxenbichler, G., and Dapunt, O. (1996). Human peritoneal mesothelial cells are more potent than ovarian cancer cells in producing tumor marker CA-125. Gynecol. Oncol. 62, 384–389.Search in Google Scholar

Received: 2014-2-27
Accepted: 2014-6-2
Published Online: 2014-9-5
Published in Print: 2014-10-1

©2014 by De Gruyter

Downloaded on 19.11.2025 from https://www.degruyterbrill.com/document/doi/10.1515/hsz-2014-0155/html
Scroll to top button