Analysis of the MMP-dependent and independent functions of tissue inhibitor of metalloproteinase-2 on the invasiveness of breast cancer cells
Tóm tắt
Matrix metalloproteinases (MMPs) are secreted endopeptidases that play an essential role in remodeling the extracellular matrix (ECM). MMPs are primarily active during development, when the majority of ECM remodeling events occurs. In adults, elevated MMP activity has been observed in many pathological conditions such as cancer and osteoarthritis. The proteolytic activity of MMPs is controlled by their natural inhibitors - the tissue inhibitor of metalloproteinases (TIMPs). In addition to blocking MMP-mediated proteolysis, TIMPs have a number of MMP-independent functions including binding to cell surface proteins thereby stimulating signaling cascades. TIMP-2, the most studied member of the family, can both inhibit and activate MMPs directly, as well as inhibit MMP activity indirectly by upregulating expression of RECK, a membrane anchored MMP regulator. While TIMP-2 has been shown to play important roles in breast cancer, we describe how the MMP-independent effects of TIMP-2 can modulate the invasiveness of MCF-7, T47D and MDA-MB-231 breast cancer cells. Using an ALA + TIMP-2 mutant which is devoid of MMP inhibition, but still capable of initiating specific cell signaling cascades, we show that TIMP-2 can differentially affect MMP activity and cellular invasiveness in both an MMP dependent and independent manner. More specifically, MMP activity and invasiveness is increased with the addition of exogenous TIMP-2 in poorly invasive cell lines whereas it is decreased in highly invasive cells lines (MDA-MB-231). Conversely, the addition of ALA + TIMP-2 resulted in decreased invasiveness regardless of cell line.
Tài liệu tham khảo
Abdallah MA, Abdullah HI, Kang S, Taylor DD, Nakajima ST, Gercel-Taylor C (2007) Effects of the components of hormone therapy on matrix metalloproteinases in breast-cancer cells: an in vitro study. Fertil Steril 87:978–981
Alakus H, Grass G, Hennecken JK, Bollschweiler E, Schulte C, Drebber U, Baldus SE, Metzger R, Hölscher AH, Mönig SP (2008) Clinicopathological significance of MMP-2 and its specific inhibitor TIMP-2 in gastric cancer. Histol Histopathol 23:917–923
Balduyck M, Zerimech F, Gouyer V, Lemaire R, Hemon B, Grard G, Thiebaut C, Lemaire V, Dacquembronne E, Duhem T, Lebrun A, Dejonghe MJ, Huet G (2000) Specific expression of matrix metalloproteinases 1, 3, 9 and 13 associated with invasiveness of breast cancer cells in vitro. Clin Exp Metastasis 18:171–178
Bartsch JE, Staren ED, Appert HE (2003) Matrix metalloproteinase expression in breast cancer. J Surg Res 110:383–392
Dove A (2002) MMP inhibitors: glimmers of hope amidst clinical failures. Nat Med 8:95
Ehrenfeld P, Conejeros I, Pavicic MF, Matus CE, Gonzalez CB, Quest AF, Bhoola KD, Poblete MT, Burgos RA, Figueroa CD (2011) Activation of kinin B1 receptor increases the release of metalloproteases-2 and -9 from both estrogen-sensitive and -insensitive breast cancer cells. Cancer Lett 301:106–118
Figueira RC, Gomes LR, Neto JS, Silva FC, Silva ID, Sogayar MC (2009) Correlation between MMPs and their inhibitors in breast cancer tumor tissue specimens and in cell lines with different metastatic potential. BMC Cancer 9:20
Gill SE, Kassim SY, Birkland TP, Parks WC (2010) Mouse models of MMP and TIMP function. Methods Mol Biol 622:31–52
Hancox RA, Allen MD, Holliday DL, Edwards DR, Pennington CJ, Guttery DS, Shaw JA, Walker RA, Pringle JH, Jones JL (2009) Tumour-associated tenascin-C isoforms promote breast cancer cell invasion and growth by matrix metalloproteinase-dependent and independent mechanisms. Breast Cancer Res 11:R24
Janowska-Wieczorek A, Marquez-Curtis LA, Wysoczynski M, Ratajczak MZ (2006) Enhancing effect of platelet-derived microvesicles on the invasive potential of breast cancer cells. Transfusion 46:1199–1209
Jones JL, Shaw JA, Pringle JH, Walker RA (2003) Primary breast myoepithelial cells exert an invasion-suppressor effect on breast cancer cells via paracrine down-regulation of MMP expression in fibroblasts and tumour cells. J Pathol 201:562–572
Lambert V, Wielockx B, Munaut C, Galopin C, Jost M, Itoh T, Werb Z, Baker A, Libert C, Krell HW, Foidart JM, Noël A, Rakic JM (2003) MMP-2 and MMP-9 synergize in promoting choroidal neovascularization. FASEB J 17:2290–2302
Lambert E, Dasse E, Haye B, Petitfrere E (2004) TIMPs as multifacial proteins. Crit Rev Oncol Hematol 49:187–198
Larsen MB, Stephens RW, Brunner N, Nielsen HJ, Engelholm LH, Christensen IJ, Stetler-Stevenson WG, Hoyer-Hansen G (2005) Quantification of tissue inhibitor of metalloproteinases 2 in plasma from healthy donors and cancer patients. Scand J Immunol 61:449–460
Lauber SN, Gooderham NJ (2011) The cooked meat-derived mammary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine promotes invasive behaviour of breast cancer cells. Toxicology 279:139–145
Mott JD, Werb Z (2004) Regulation of matrix biology by matrix metalloproteinases. Curr Opin Cell Biol 16:558–564
Noda M, Takahashi C (2007) Recklessness as a hallmark of aggressive cancer. Cancer Sci 98:1659–1665
Oh J, Seo DW, Diaz T, Wei B, Ward Y, Ray JM, Morioka Y, Shi S, Kitayama H, Takahashi C, Noda M, Stetler-Stevenson WG (2004) Tissue inhibitors of metalloproteinase 2 inhibits endothelial cell migration through increased expression of RECK. Cancer Res 64:9062–9069
Ra HJ, Parks WC (2007) Control of matrix metalloproteinase catalytic activity. Matrix Biol 26:587–956
Ratnikov BI, Deryugina EI, Strongin AY (2002) Gelatin zymography and substrate cleavage assays of matrix metalloproteinase-2 in breast carcinoma cells overexpressing membrane type-1 matrix metalloproteinase. Lab Invest 82(11):1583–90
Rhee JS, Coussens LM (2002) RECKing MMP function: implications for cancer development. Trends Cell Biol 12:209–211
Seo DW, Li H, Guedez L, Wingfield PT, Diaz T, Salloum R, Wei BY, Stetler-Stevenson WG (2003) TIMP-2 mediated inhibition of angiogenesis: an MMP-independent mechanism. Cell 114:171–180
Stetler-Stevenson WG (2008) The tumor microenvironment: regulation by MMP-independent effects of tissue inhibitor of metalloproteinases-2. Cancer Metastasis Rev 27:57–66
Stetler-Stevenson WG, Seo DW (2005) TIMP-2: an endogenous inhibitor of angiogenesis. Trends Mol Med 11:97–103
Svagzdys S, Lesauskaite V, Pangonyte D, Saladzinskas Z, Tamelis A, Pavalkis D (2011) Matrix metalloproteinase-9 is a prognostic marker to predict survival of patients who underwent surgery due to rectal carcinoma. Tohoku J Exp Med 223:67–73
Toth M, Fridman R (2001) Assessment of gelatinases (MMP-2 and MMP-9 by gelatin zymography. Methods Mol Med 57:163–174
van't Veer LJ, Dai H, van de Vijver MJ, He YD, Hart AA, Mao M, Peterse HL, van der Kooy K, Marton MJ, Witteveen AT, Schreiber GJ, Kerkhoven RM, Roberts C, Linsley PS, Bernards R, Friend SH (2002) Nature 415:530–536
Walsh LA, Carere DA, Cooper CA, Damjanovski S (2007) Membrane type-1 matrix metalloproteinases and tissue inhibitor of metalloproteinases-2 RNA levels mimic each other during Xenopus laevis metamorphosis. PLoS One 2:e1000
Walsh LA, Damjanovski S (2011) IGF-1 increases invasive potential of MCF 7 breast cancer cells and induces activation of latent TGF-β1 resulting in epithelial to mesenchymal transition. Cell Commun Signal 9:10
Wingfield PT, Sax JK, Stahl SJ, Kaufman J, Palmer I, Chung V, Corcoran ML, Kleiner DE, Stetler-Stevenson WG (1999) Biophysical and functional characterization of full-length, recombinant human tissue inhibitor of metalloproteinases-2 (TIMP-2) produced in Escherichia coli, Comparison of wild type and amino-terminal alanine appended variant with implications for the mechanism of TIMP functions. J Biol Chem 274:21362–21368
Yana I, Seiki M (2002) MT-MMPs play pivotal roles in cancer dissemination. Clin Exp Metastasis 19:209–215
Zhang A, Meng L, Wang Q, Xi L, Chen G, Wang S, Zhou J, Lu Y, Ma D (2006) Enhanced in vitro invasiveness of ovarian cancer cells through up-regulation of VEGF and induction of MMP-2. Oncol Rep 15:831–836
Zucker S, Drews M, Conner C, Foda HD, DeClerck YA, Langley KE, Bahou WF, Docherty AJ, Cao J (1998) Tissue inhibitor of metalloproteinase-2 (TIMP-2) binds to the catalytic domain of the cell surface receptor, membrane type 1-matrix metalloproteinase 1 (MT1-MMP). J Biol Chem 273:1216–1222