Abstract
Matrix metalloproteinases (MMPs) are a family of more than 28 enzymes that were initially identified on the basis of their ability to cleave most elements of the extracellular matrix (ECM) but have subsequently been found to be upregulated in nearly every tumor type. As digestion of the ECM is essential for tumor invasion and metastasis, MMPs have been studied for their role in these later stages of tumor development. More recently, exposure to these enzymes has been found to impact cellular signaling pathways that stimulate cell growth at early stages of tumor progression. MMPs have also been found to cleave intracellular targets and so inducing mitotic abnormalities and genomic instability. Emerging evidence indicates that tumor-associated MMPs can also stimulate processes associated with epithelial-mesenchymal transition (EMT), a developmental process that is activated in tumor cells during cell invasion and metastasis. Investigations of potential therapeutic MMP inhibitors aimed at blocking the protumorigenic tissue alterations induced by MMPs have been complicated by the side effects associated with nonspecific inhibition of normal physiological processes; recent investigations have shown how delineation of the extracellular targets and intracellular signaling pathways by which MMP action on cancer cells can induce EMT provides insight into novel therapeutic targets. Here, we provide an overview of recent findings of MMP action in tumors and the mechanisms by which MMPs induce both phenotypic and genotypic alterations that facilitate tumor progression.
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References
Sieweke MH, Bissell MJ (1994) The tumor-promoting effect of wounding: a possible role for TGF-beta-induced stromal alterations. Crit Rev Oncog 5(2–3):297–311
Sternlicht MD, Werb Z (2001) How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol 17:463–516
Bissell MJ, Radisky D (2001) Putting tumours in context. Nat Rev Cancer 1(1):46–54
Thiery JP, Sleeman JP (2006) Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol 7(2):131–142
Overall CM, Lopez-Otin C (2002) Strategies for MMP inhibition in cancer: innovations for the post-trial era. Nat Rev Cancer 2(9):657–672
Matrisian LM (1994) Matrix metalloproteinase gene expression. Ann N Y Acad Sci 732:42–50
Westermarck J, Kahari VM (1999) Regulation of matrix metalloproteinase expression in tumor invasion. Faseb J 13(8):781–792
Jones LE, Humphreys MJ, Campbell F et al (2004) Comprehensive analysis of matrix metalloproteinase and tissue inhibitor expression in pancreatic cancer: increased expression of matrix metalloproteinase-7 predicts poor survival. Clin Cancer Res 10(8):2832–2845
Liu D, Nakano J, Ishikawa S et al (2007) Overexpression of matrix metalloproteinase-7 (MMP-7) correlates with tumor proliferation, and a poor prognosis in non-small cell lung cancer. Lung Cancer 58(3):384–391
Morgia G, Falsaperla M, Malaponte G et al (2005) Matrix metalloproteinases as diagnostic (MMP-13) and prognostic (MMP-2, MMP-9) markers of prostate cancer. Urol Res 33(1):44–50
Wu CY, Wu MS, Chiang EP et al (2007) Plasma matrix metalloproteinase-9 level is better than serum matrix metalloproteinase-9 level to predict gastric cancer evolution. Clin Cancer Res 13(7):2054–2060
Mook OR, Frederiks WM, Van Noorden CJ (2004) The role of gelatinases in colorectal cancer progression and metastasis. Biochim Biophys Acta 1705(2):69–89
Somiari SB, Somiari RI, Heckman CM et al (2006) Circulating MMP2 and MMP9 in breast cancer—potential role in classification of patients into low risk, high risk, benign disease and breast cancer categories. Int J Cancer 119(6):1403–1411
Tetu B, Brisson J, Wang CS et al (2006) The influence of MMP-14, TIMP-2 and MMP-2 expression on breast cancer prognosis. Breast Cancer Res 8(3):R28
Yoshida H, Ishiko O, Sumi T et al (2001) Survivin, bcl-2 and matrix metalloproteinase-2 enhance progression of clear cell- and serous-type ovarian carcinomas. Int J Oncol 19(3):537–542
Katayama A, Bandoh N, Kishibe K et al (2004) Expressions of matrix metalloproteinases in early-stage oral squamous cell carcinoma as predictive indicators for tumor metastases and prognosis. Clin Cancer Res 10(2):634–640
Kerkela E, Saarialho-Kere U (2003) Matrix metalloproteinases in tumor progression: focus on basal and squamous cell skin cancer. Exp Dermatol 12(2):109–125
Illman SA, Lehti K, Keski-Oja J et al (2006) Epilysin (MMP-28) induces TGF-beta mediated epithelial to mesenchymal transition in lung carcinoma cells. J Cell Sci 119(Pt 18):3856–3865
Radisky DC, Levy DD, Littlepage LE et al (2005) Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability. Nature 436(7047):123–127
Lochter A, Sternlicht MD, Werb Z et al (1998) The significance of matrix metalloproteinases during early stages of tumor progression. Ann N Y Acad Sci 857:180–193
Noel A, Boulay A, Kebers F et al (2000) Demonstration in vivo that stromelysin-3 functions through its proteolytic activity. Oncogene 19(12):1605–1612
McGuire JK, Li Q, Parks WC (2003) Matrilysin (matrix metalloproteinase-7) mediates E-cadherin ectodomain shedding in injured lung epithelium. Am J Pathol 162(6):1831–1843
Song W, Jackson K, McGuire PG (2000) Degradation of type IV collagen by matrix metalloproteinases is an important step in the epithelial-mesenchymal transformation of the endocardial cushions. Dev Biol 227(2):606–617
Karsdal MA, Larsen L, Engsig MT et al (2002) Matrix metalloproteinase-dependent activation of latent transforming growth factor-beta controls the conversion of osteoblasts into osteocytes by blocking osteoblast apoptosis. J Biol Chem 277(46):44061–44067
Iida J, McCarthy JB (2007) Expression of collagenase-1 (MMP-1) promotes melanoma growth through the generation of active transforming growth factor-beta. Melanoma Res 17(4):205–213
Yu Q, Stamenkovic I (2000) Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis. Genes Dev 14(2):163–176
Yu WH, Woessner JF Jr, McNeish JD et al (2002) CD44 anchors the assembly of matrilysin/MMP-7 with heparin-binding epidermal growth factor precursor and ErbB4 and regulates female reproductive organ remodeling. Genes Dev 16(3):307–323
Cheng K, Xie G, Raufman JP (2007) Matrix metalloproteinase-7-catalyzed release of HB-EGF mediates deoxycholyltaurine-induced proliferation of a human colon cancer cell line. Biochem Pharmacol 73(7):1001–1012
Manes S, Llorente M, Lacalle RA et al (1999) The matrix metalloproteinase-9 regulates the insulin-like growth factor-triggered autocrine response in DU-145 carcinoma cells. J Biol Chem 274(11):6935–6945
Shubayev VI, Myers RR (2000) Upregulation and interaction of TNFalpha and gelatinases A and B in painful peripheral nerve injury. Brain Res 855(1):83–89
Ito A, Mukaiyama A, Itoh Y et al (1996) Degradation of interleukin 1beta by matrix metalloproteinases. J Biol Chem 271(25):14657–14660
Fishman DA, Bafetti LM, Stack MS (1996) Membrane-type matrix metalloproteinase expression and matrix metalloproteinase-2 activation in primary human ovarian epithelial carcinoma cells. Invasion Metastasis 16(3):150–159
Du B, Wang P, Guo X et al (1999) Expression of membrane type 1-matrix metalloproteinase in laryngeal carcinoma. Pathol Oncol Res 5(3):214–217
Uchibori M, Nishida Y, Nagasaka T et al (2006) Increased expression of membrane-type matrix metalloproteinase-1 is correlated with poor prognosis in patients with osteosarcoma. Int J Oncol 28(1):33–42
Jiang WG, Davies G, Martin TA et al (2006) Expression of membrane type-1 matrix metalloproteinase, MT1-MMP in human breast cancer and its impact on invasiveness of breast cancer cells. Int J Mol Med 17(4):583–590
Sounni NE, Noel A (2005) Membrane type-matrix metalloproteinases and tumor progression. Biochimie 87(3–4):329–342
Tam EM, Morrison CJ, Wu YI et al (2004) Membrane protease proteomics: Isotope-coded affinity tag MS identification of undescribed MT1-matrix metalloproteinase substrates. Proc Natl Acad Sci USA 101(18):6917–6922
Gilles C, Polette M, Seiki M et al (1997) Implication of collagen type I-induced membrane-type 1-matrix metalloproteinase expression and matrix metalloproteinase-2 activation in the metastatic progression of breast carcinoma. Lab Invest 76(5):651–660
Ha HY, Moon HB, Nam MS et al (2001) Overexpression of membrane-type matrix metalloproteinase-1 gene induces mammary gland abnormalities and adenocarcinoma in transgenic mice. Cancer Res 61(3):984–990
Masson R, Lefebvre O, Noel A et al (1998) In vivo evidence that the stromelysin-3 metalloproteinase contributes in a paracrine manner to epithelial cell malignancy. J Cell Biol 140(6):1535–1541
Mudgett JS, Hutchinson NI, Chartrain NA et al (1998) Susceptibility of stromelysin 1-deficient mice to collagen-induced arthritis and cartilage destruction. Arthritis Rheum 41(1):110–121
Vu TH, Shipley JM, Bergers G et al (1998) MMP-9/gelatinase B is a key regulator of growth plate angiogenesis and apoptosis of hypertrophic chondrocytes. Cell 93(3):411–422
Itoh T, Tanioka M, Matsuda H et al (1999) Experimental metastasis is suppressed in MMP-9-deficient mice. Clin Exp Metastasis 17(2):177–181
Holmbeck K, Bianco P, Caterina J et al (1999) MT1-MMP-deficient mice develop dwarfism, osteopenia, arthritis, and connective tissue disease due to inadequate collagen turnover. Cell 99(1):81–921
Wolf K, Wu YI, Liu Y et al (2007) Multi-step pericellular proteolysis controls the transition from individual to collective cancer cell invasion. Nat Cell Biol 9(8):893–904
Hotary KB, Allen ED, Brooks PC et al (2003) Membrane type I matrix metalloproteinase usurps tumor growth control imposed by the three-dimensional extracellular matrix. Cell 114(1):33–45
Nabeshima K, Inoue T, Shimao Y et al (2002) Matrix metalloproteinases in tumor invasion: role for cell migration. Pathol Int 52(4):255–264
Dumin JA, Dickeson SK, Stricker TP et al (2001) Pro-collagenase-1 (matrix metalloproteinase-1) binds the alpha(2)beta(1) integrin upon release from keratinocytes migrating on type I collagen. J Biol Chem 276(31):29368–29374
Stefanidakis M, Ruohtula T, Borregaard N et al (2004) Intracellular and cell surface localization of a complex between alphaMbeta2 integrin and promatrix metalloproteinase-9 progelatinase in neutrophils. J Immunol 172(11):7060–7068
Nisato RE, Hosseini G, Sirrenberg C et al (2005) Dissecting the role of matrix metalloproteinases (MMP) and integrin alpha(v)beta3 in angiogenesis in vitro: absence of hemopexin C domain bioactivity, but membrane-type 1-MMP and alpha(v)beta3 are critical. Cancer Res 65(20):9377–9387
Thomas GJ, Lewis MP, Hart IR et al (2001) AlphaVbeta6 integrin promotes invasion of squamous carcinoma cells through up-regulation of matrix metalloproteinase-9. Int J Cancer 92(5):641–650
Hamidi S, Salo T, Kainulainen T et al (2000) Expression of alpha(v)beta6 integrin in oral leukoplakia. Br J Cancer 82(8):1433–1440
Impola U, Uitto VJ, Hietanen J et al (2004) Differential expression of matrilysin-1 (MMP-7), 92 kD gelatinase (MMP-9), and metalloelastase (MMP-12) in oral verrucous and squamous cell cancer. J Pathol 202(1):14–22
Brooks PC, Stromblad S, Sanders LC et al (1996) Localization of matrix metalloproteinase MMP-2 to the surface of invasive cells by interaction with integrin alpha v beta 3. Cell 85(5):683–693
Ellerbroek SM, Fishman DA, Kearns AS et al (1999) Ovarian carcinoma regulation of matrix metalloproteinase-2 and membrane type 1 matrix metalloproteinase through beta1 integrin. Cancer Res 59(7):1635–1641
Symowicz J, Adley BP, Gleason KJ et al (2007) Engagement of collagen-binding integrins promotes matrix metalloproteinase-9-dependent E-cadherin ectodomain shedding in ovarian carcinoma cells. Cancer Res 67(5):2030–2039
Ratnikov BI, Rozanov DV, Postnova TI et al (2002) An alternative processing of integrin alpha(v) subunit in tumor cells by membrane type-1 matrix metalloproteinase. J Biol Chem 277(9):7377–7385
von Bredow DC, Nagle RB, Bowden GT et al (1997) Cleavage of beta 4 integrin by matrilysin. Exp Cell Res 236(1):341–345
Murray D, Morrin M, McDonnell S (2004) Increased invasion and expression of MMP-9 in human colorectal cell lines by a CD44-dependent mechanism. Anticancer Res 24(2A):489–494
Thanakit V, Sampatanukul P, Ruangvejvorachai P et al (2005) The association of co-expression of CD44v4/MMP-9 with different nodal status in high-grade breast carcinoma patients. J Med Assoc Thai 88(Suppl 4):S30–S35
Gabison EE, Hoang-Xuan T, Mauviel A et al (2005) EMMPRIN/CD147, an MMP modulator in cancer, development and tissue repair. Biochimie 87(3–4):361–368
Tang Y, Kesavan P, Nakada MT et al (2004) Tumor-stroma interaction: positive feedback regulation of extracellular matrix metalloproteinase inducer (EMMPRIN) expression and matrix metalloproteinase-dependent generation of soluble EMMPRIN. Mol Cancer Res 2(2):73–80
Thomasset N, Lochter A, Sympson CJ et al (1998) Expression of autoactivated stromelysin-1 in mammary glands of transgenic mice leads to a reactive stroma during early development. Am J Pathol 153(2):457–467
Lochter A, Galosy S, Muschler J et al (1997) Matrix metalloproteinase stromelysin-1 triggers a cascade of molecular alterations that leads to stable epithelial-to-mesenchymal conversion and a premalignant phenotype in mammary epithelial cells. J Cell Biol 139(7):1861–1872
Bergers G, Coussens LM (2000) Extrinsic regulators of epithelial tumor progression: metalloproteinases. Curr Opin Genet Dev 10(1):120–127
Lee KH, Choi EY, Hyun MS et al (2007) Association of extracellular cleavage of E-cadherin mediated by MMP-7 with HGF-induced in vitro invasion in human stomach cancer cells. Eur Surg Res 39(4):208–215
Covington MD, Burghardt RC, Parrish AR (2006) Ischemia-induced cleavage of cadherins in NRK cells requires MT1-MMP (MMP-14). Am J Physiol Renal Physiol 290(1):F43–F51
Mei JM, Borchert GL, Donald SP et al (2002) Matrix metalloproteinase(s) mediate(s) NO-induced dissociation of beta-catenin from membrane bound E-cadherin and formation of nuclear beta-catenin/LEF-1 complex. Carcinogenesis 23(12):2119–2122
Golubkov VS, Strongin AY (2007) Proteolysis-driven oncogenesis. Cell Cycle 6(2):147–150
Golubkov VS, Chekanov AV, Savinov AY et al (2006) Membrane type-1 matrix metalloproteinase confers aneuploidy and tumorigenicity on mammary epithelial cells. Cancer Res 66(21):10460–10465
Golubkov VS, Chekanov AV, Doxsey SJ et al (2005) Centrosomal pericentrin is a direct cleavage target of membrane type-1 matrix metalloproteinase in humans but not in mice: potential implications for tumorigenesis. J Biol Chem 280(51):42237–42241
Si-Tayeb K, Monvoisin A, Mazzocco C et al (2006) Matrix metalloproteinase 3 is present in the cell nucleus and is involved in apoptosis. Am J Pathol 169(4):1390–1401
Limb GA, Matter K, Murphy G et al (2005) Matrix metalloproteinase-1 associates with intracellular organelles and confers resistance to lamin A/C degradation during apoptosis. Am J Pathol 166(5):1555–1563
Egeblad M, Werb Z (2002) New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2(3):161–174
Sillanpaa S, Anttila M, Voutilainen K et al (2007) Prognostic significance of matrix metalloproteinase-9 (MMP-9) in epithelial ovarian cancer. Gynecol Oncol 104(2):296–303
Zhang Q, Chen X, Zhou J et al (2006) CD147, MMP-2, MMP-9 and MVD-CD34 are significant predictors of recurrence after liver transplantation in hepatocellular carcinoma patients. Cancer Biol Ther 5(7):808–814
Cardillo MR, Di Silverio F, Gentile V (2006) Quantitative immunohistochemical and in situ hybridization analysis of metalloproteinases in prostate cancer. Anticancer Res 26(2A):973–982
Ohtani H, Motohashi H, Sato H et al (1996) Dual over-expression pattern 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(5):565–570
McCawley LJ, Crawford HC, King LE Jr et al (2004) A protective role for matrix metalloproteinase-3 in squamous cell carcinoma. Cancer Res 64(19):6965–6972
Owen JL, Iragavarapu-Charyulu V, Gunja-Smith Z et al (2003) Up-regulation of matrix metalloproteinase-9 in T lymphocytes of mammary tumor bearers: role of vascular endothelial growth factor. J Immunol 171(8):4340–4351
Coussens LM, Tinkle CL, Hanahan D et al (2000) MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis. Cell 103(3):481–490
Tse JC, Kalluri R (2007) Mechanisms of metastasis: epithelial-to-mesenchymal transition and contribution of tumor microenvironment. J Cell Biochem 101(4):816–829
Sternlicht MD, Lochter A, Sympson CJ et al (1999) The stromal proteinase MMP3/stromelysin-1 promotes mammary carcinogenesis. Cell 98(2):137–146
Sympson CJ, Bissell MJ, Werb Z (1995) Mammary gland tumor formation in transgenic mice overexpressing stromelysin-1. Semin Cancer Biol 6(3):159–163
Lochter A, Srebrow A, Sympson CJ et al (1997) Misregulation of stromelysin-1 expression in mouse mammary tumor cells accompanies acquisition of stromelysin-1-dependent invasive properties. J Biol Chem 272(8):5007–5015
Jordan P, Brazao R, Boavida MG et al (1999) Cloning of a novel human Rac1b splice variant with increased expression in colorectal tumors. Oncogene 18(48):6835–6839
Schnelzer A, Prechtel D, Knaus U et al (2000) Rac1 in human breast cancer: overexpression, mutation analysis, and characterization of a new isoform, Rac1b. Oncogene 19(26):3013–3020
Singh A, Karnoub AE, Palmby TR et al (2004) Rac1b, a tumor associated, constitutively active Rac1 splice variant, promotes cellular transformation. Oncogene 23(58):9369–9380
Feig DI, Reid TM, Loeb LA (1994) Reactive oxygen species in tumorigenesis. Cancer Res 54(7 Suppl):1890s–1894s
Dong R, Wang Q, He XL et al (2007) Role of nuclear factor kappa B and reactive oxygen species in the tumor necrosis factor-a-induced epithelial-mesenchymal transition of MCF-7 cells. Braz J Med Biol Res 40(8):1071–1078
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Orlichenko, L.S., Radisky, D.C. Matrix metalloproteinases stimulate epithelial-mesenchymal transition during tumor development. Clin Exp Metastasis 25, 593–600 (2008). https://doi.org/10.1007/s10585-008-9143-9
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DOI: https://doi.org/10.1007/s10585-008-9143-9