Matrix Metalloproteinases and Cancer

Müfide Öncel 1 *
More Detail
1 Beyhekim Devlet Hastanesi Biyokimya Laboratuvarı, Konya
* Corresponding Author
EUR J BASIC MED SCI, Volume 2, Issue 3, pp. 91-100.
Download Full Text (PDF)


Extracellular proteolysis involves in tissue homeostasis. However in cancer, accelerating proteolysis leads to unregulated tumor growth, inflammation, tissue invasion, and metastasis. Matrix metalloproteinases represent the most prominent subclass of proteinases associated with tumorigenesis. In recent years by means of technological developments the roles of matrix metalloproteinases in development of tumorigenesis have been evaluated. Thus, matrix metalloproteinases have become critical therapeutic and diagnostic targets due to their roles in tumoroginesis.


Öncel M. Matrix Metalloproteinases and Cancer. Eur J Basic Med Sci. 2012;2(3):91-100.


  • Aliustaoğlu M. Temel Kanser Fizyopatolojisi. Klinik Gelişim 2009; 22(3): 46-9.
  • Liotta LA, Steeg PA, Stetler-Stevenson WG. Cancer metastasis and angiogenesis: an imbalance of positive andnegative regulation. Cell 1991; 64: 327-36.
  • Apakkan Aksun S, Bayındır O, Özmen D, Metalloproteinazlar, inhibitörleri ve ilişkili Fizyolojik ve Patolojik Durumlar. Türkiye Klinikleri Tıp Bilimleri 2001; 21: 332–42.
  • Hewitt R, Dan K. Stromal cell expression of components of matrixdegrading protease systems in human cancer. Enzyme Protein 1996; 49: 163–73.
  • Matrisian LM. Metalloproteinases and their inhibitors in matrix remodeling. Trends Genet 1990; 6(4):121–5
  • Sethi CS, Bailey TA, Luthert PJ, Chong NHV. Matrix metalloproteinase biology applied to vitreoretinal disorders. Br J Ophthalmol 2000; 84: 654–64.
  • Soydinç HO, Çamlıca H, Duranyılmaz D, et al. Matriks metalloproteinazlar ve akciğer kanseri. Türk Onkoloji Dergisi 2006;21(2):53–6.
  • Dollery CM, McEwan JR, Henney AM. Matrix metalloproteinases and cardiovascular disease. Circulation Research 1995; 77: 863–8.
  • Barret AJ, Rawlings ND. Clasification of peptidases Biol Chem 1992; 244: 353–73.
  • Hidalgo M, Eckhardt SG. Development of Matrix Metalloproteinase Inhibitors in Cancer Therapy. J. of Nation Cancer Ins. 2001; 93(3): 178–84.
  • Bourboulia D, Stetler-Stevenson WG. Matrix MetalloProteinases (MMPs) and Tissue Inhibitors of MetalloProteinases (TIMPs): positive and negative regulators intumor cell adhesion. Semin Cancer Biol. 2010; 20(3): 161–8.
  • Ray JM. Stetler-Stevenson WG. The role of matrix metalloproteases and their inhibitors in tumour invasion, metastasis and angiogenesis. Eur Respir J. 1994; 7: 2062–72.
  • Overall CM. Otin CL. Strategies for MMP inhibition in cancer: innovations fort pense he post –trial era. Nat Reviews 2002; 2: 657-72.
  • Curan S, Murray GI. Matrix Metalloproteinases in Tumour Invasion and Metastasis. J. Pathol 1999; 189: 300–8.
  • Krizkova S, Zitka O, Masarik M, et al. Clinical importance of matrix metalloproteinases. Bratisl Lek Lsty 2011; 112(8): 435-40.
  • Reel B. Matriks Metalloproteinaz Enzimleri ve Ateroskleroz. Türkiye Klinikleri J Med 2006; 26: 527–37.
  • Wosner JF. Matrix metalloproteinases and their inhibitors in connective tissue remodeling. Fabes J 1991; 5: 2145–54.
  • Kessenbrock K, Plaks V, Werb Z. Matrix Metalloproteinases: Regulators of the Tumor Microenvironment. NIH Public Access 2010; 141(1): 52–67.
  • Amelina C, Caruntu ID, Gıuşca SE, Balan RA. Matrix metalloproteinases involvement in pathologic conditions. Rom J of Morphol Embryol 2010; 51(2):215–28.
  • Christofori G. Changing neighbours, changing behaviour: cell adhesion molecule-mediated signalling during tumour progression. Embo J.2003; 22: 2318–23.
  • Deryugina EI, Ratnikov BI, Postnova TI, et al. Processing of integrin alpha(v) subunit by membrane type 1 matrix metalloproteinase stimulates migration of breast carcinoma cells on vitronectin and enhances tyrosine phosphorylation of focal adhesion kinase. J Biol Chem 2002; 277: 9749–56.
  • Ho AT, Voura EB, Soloway PD, et al. MMP inhibitors augment fibroblast adhesion through stabilisation of focal adhesion contacts and up-regulation of cadherin function. J Biol Chem 2001; 276: 40215–24.
  • Birchmeier C, Birchmeier W, Brand-Saberi B. Epithelial–mesenchymal transitions in cancer progression. Acta Anat (Basel) 1996; 156: 217–26.
  • Noe V, Fingleton B, Jacobs K, et al. Release of an invasion promoter E-cadherin fragment by matrilysin and stromelysin-1. J Cell Sci 2001; 114: 111–8.
  • Lochter A, Galosy S, Muschler J, et al. 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 1997; 139: 1861– 72.
  • Nakahara H, Howard L, Thompson EW, et al. Transmembrane/cytoplasmic domain-mediated membrane type 1-matrix metalloprotease docking to invadopodia is required for cell invasion. Proc Natl Acad Sci 1997; 94: 7959–64.
  • Kajita M, Itoh Y, Chiba T, et al. Membrane-type 1 matrix metalloproteinase cleaves CD44 and promotes cell migration. J Cell Biol. 2001; 153: 893-904.
  • Powell WC, Fingleton B, Wilson CL, et al. The metalloproteinase matrilysin proteolytically generates active soluble Fas ligand and potentiates epithelial cell apoptosis. Curr Biol 1999; 9: 1441–7.
  • Yu WH, Woessner JF Jr, McNeish JD, Stamenkovic I. CD44 anchors the assembly of matrilysin/MMP-7 with heparinbinding epidermal growth factor precursor and ErbB4 and regulates female reproductive organ remodeling. Genes Dev 2002; 16: 307–23.
  • Alexander CM, Howard EW, Bissell MJ, Werb Z. Rescue of mammary epithelial cell apoptosis and entactin degradation by a tissue inhibitor of metalloproteinases-1 transgene. J Cell Biol 1996; 135: 1669–77.
  • Wu E, Mari BP, Wang F, et al. Stromelysin-3 suppresses tumor cell apoptosis in a murine model. J Cell Biochem 2001; 82: 549–55.
  • Fata JE, Leco KJ, Voura EB, et al. Accelerated apoptosis in the Timp-3-deficient mammary gland. J Clin Invest 2001; 108: 831–41.
  • Bond M, Fabunmi RP, Baker AH, Newby AC. Synergistic upregulation of metalloproteinase -9 by growth factors and inflammatory cytokines: an absolute requirement for transcription factor NF-kappa B. Febs Lett 1998; 435: 29–34.
  • Alexander CM, Selvarajan S, Mudgett J, Werb Z. Stromelysin-1 regulates adipogenesis during mammary gland involution. J. Cell Biol 2001; 152: 693–703.
  • Littlepage LE, Sternlicht MD, Rougier N, et al. Matrix metalloproteinases contribute distinct roles in neuroendocrine prostate carcinogenesis, metastasis, and angiogenesis progression. Cancer Res 2010; 70: 2224–34.
  • Unemori EN, Ferrara N, Bauer EA, et al. Vascular endothelial growth factor induces interstitial collagenase expression in human endothelial cells. J Cell Physiol 1992; 153: 557-562.
  • Lamoreaux WJ, Fitzgerald ME, Reiner A, et al. Vascular endothelial growth factor increases release of gelatinase A and decreases release of tissue inhibitor of metalloproteinases by microvascular endothelial cells in vitro. Microvasc Res 1998; 55: 29-42.
  • O’Reilly MS, Wiederschain D, Stetler- Stevenson WG, et al. Regulation of angiostatin production by matrix metalloproteinase-2 in a model of concomitant resistance. J Biol Chem 1999; 274: 29568-71.
  • Dong Z, Kumar R, Yang X, et al. Macrophagederived metalloelastase is responsible for the generation of angiostatin in Lewis lung carcinoma. Cell 1997; 88: 801-10.
  • Ribatti D. Endogenous inhibitors of angiogenesis: a historical review. Leuk Res 2009; 33: 638–44.
  • Heljasvaara R, Nyberg P, Luostarinen J, et al. Generation of biologically active endostatin fragments from human collagen XVIII by distinct matrix metalloproteases. Exp. Cell Res 2005; 307: 292–304.
  • Cornelius LA, Nehring LC, Harding E, et al. Matrix metalloproteinases generate angiostatin: effects on neovascularization. J. Immunol 1998; 161: 6845–52.
  • Patterson BC, Sang QA. Angiostatin-converting enzyme activities of human matrilysin (MMP-7) and gelatinase B/type IV collagenase (MMP-9). J. Biol. Chem 1997; 272: 28823–5.
  • Sounni NE, Dehne K, Van Kempen L, et al. Stromal regulation of vessel stability by MMP9 and TGFβ. Dis. Model. Mech. Published Dis Model Mech 2010; 3(5- 6): 317–32.
  • Kaplan RN, Riba RD, Zacharoulis S, et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 2005: 438; 820–7.
  • Boire A, Covic L, Agarwal A, et al. PAR1 is a matrix metalloprotease-1 receptor that promotes invasion and tumorigenesis of breast cancer cells. Cell 2005; 120: 303–13.
  • Lynch CC, Hikosaka A, Acuff HB, et al. MMP-7 promotes prostate cancer-induced osteolysis via the solubilization of RANKL. Cancer Cell 2005; 7: 485–96.
  • Lu X, Wang Q, Hu G, et al. ADAMTS1 and MMP1 proteolytically engage EGF-like ligands in an osteolytic signaling cascade for bone metastasis. Genes Dev 2009; 23: 1882–94.
  • Friedl P, Wolf K. Tube travel: the role of proteases in individual and collective cancer cell invasion. Cancer Res 2008; 68: 7247–9.
  • Agrawal S, Anderson P, Durbeej M, et al. Dystroglycan is selectively cleaved at the parenchymal basement membrane at sites of leukocyte extravasation in experimental autoimmune encephalomyelitis. J Exp Med 2006; 203: 1007–19.
  • Lin WW, Karin M. A cytokine-mediated link between innate immunity, inflammation, and cancer. J. Clin. Invest 2007; 117: 1175–83.
  • Manicone AM, Mc Guire JK. Matrix metalloproteinases as modulators of inflammation. Semin. Cell Dev Biol 2008; 19: 34–41.
  • Roy R, Yang J, Moses MA. Matrix Metalloproteinases As Novel Biomarkers and Potential Therapeutic Targets in Human Cancer. Journal of clinical oncology 2009; 27(31): 5287-97.
  • Wu ZS, Wu Q, Yang JH, et al. Prognostic significance of MMP-9 and TIMP-1 serum and tissue expression in breast cancer. Int J Cancer 2008; 122: 2050-6.
  • La Rocca G, Pucci-Minafra I, Marrazzo A, et al. Zymographic detection and clinical correlations of MMP-2 and MMP-9 in breast cancer sera. Br J Cancer 2004; 90: 1414-21.
  • Zhang B, Cao X, Liu Y, et al. Tumor-derived matrix metalloproteinase-13 (MMP-13) correlates with poor prognoses of invasive breast cancer. BMC Cancer 2008; 83: 1-10.
  • Pories SE, Zurakowski D, Roy R, et al. Urinary metalloproteinases: Noninvasive biomarkers for breast cancer risk assessment. Cancer Epidemiol Biomarkers Prev 2008; 17: 1034-42.
  • Poola I, DeWitty RL, Marshalleck JJ, et al. Identification of MMP-1 as a putative breast cancer predictive marker by global gene expression analysis. Nat Med 2005; 11: 481-3.
  • Ranuncolo SM, Armanasco E, Cresta C, et al. Plasma MMP-9 (92 kDa-MMP) activity is useful in the follow-up and in the assessment of prognosis in breast cancer patients. Int J Cancer 2003 ;106:745-51.
  • Tetu B, Brisson J, Wang CS, et al. The influence of MMP-14, TIMP- 2 and MMP-2 expression on breast cancer prognosis. Breast Cancer Res R 2006; 28: 1-9.
  • Tian M, Cui YZ, Song GH. et al. Proteomic analysis identifies MMP-9, DJ-1 and A1BG as overexpressed proteins in pancreatic juice from pancreatic ductal adenocarcinoma patients. BMC Cancer 2008; 241: 1-11.
  • Yokoyama M, Ochi K, Ichimura M, et al. Matrix metalloproteinase-2 in pancreatic juice for diagnosis of pancreatic cancer. Pancreas 2002; 24: 344-7.
  • Kuhlmann KF, Van Till JW, Boermeester MA, et al. Evaluation of matrix metalloproteinase 7 in plasma and pancreatic juice as a biomarker for pancreatic cancer. Cancer Epidemiol Biomarkers Prev 2007; 16: 886-91.
  • Jumper C, Cobos E, Lox C. Determination of the serum matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) in patients with either advanced small-cell lung cancer or non-small-cell lung cancer prior to treatment. Respir Med 2004; 98: 173-7.
  • Koc M, Ediger D, Budak F, et al. Matrix metalloproteinase-9 (MMP-9) elevated in serum but not in bronchial lavage fluid in patients with lung cancer. Tumori 2006; 92: 149-54.
  • Liu D, Nakano J, Ishikawa S, et al. Overexpression of matrix metalloproteinase-7 (MMP-7) correlates with tumor proliferation, and a poor prognosis in non-small cell lung cancer. Lung Cancer 2007; 58: 384-91.
  • Schutz A, Schneidenbach D, Aust G, et al. Differential expression and activity status of MMP-1, MMP-2 and MMP-9 in tumor and stromal cells of squamous cell carcinomas of the lung. Tumour Biol 2002; 23:179-84.
  • Su L, Zhou W, Park S, et al. Matrix metalloproteinase-1 promoter polymorphism and lung cancer risk. Cancer Epidemiol Biomarkers Prev 2005; 14: 567-70.
  • Gerhards S, Jung K, Koenig F, et al. Excretion of matrix metalloproteinases 2 and 9 in urine is associated with a high stage and grade of bladder carcinoma. Urology 2001; 57: 675-9.
  • Hilska M, Roberts PJ, Collan YU, et al. Prognostic significance of matrix metalloproteinases-1, -2, -7 and -13 and tissue inhibitors of metalloproteinases-1, -2, -3 and -4 in colorectal cancer. Int J Cancer 2007; 121: 714-23.
  • Langenskiold M, Holmdahl L, Falk P, et al. Increased plasma MMP-2 protein expression in lymph node-positive patients with colorectal cancer. Int J Colorectal Dis 2005; 20: 245-52,
  • Cho YB, Lee WY, Song SY, et al. Matrix metalloproteinase-9 activity is associated with poor prognosis in T3-T4 node-negative colorectal cancer. Hum Pathol 2007; 38: 1603-10.
  • Tutton MG, George ML, Eccles SA, et al. Use of plasma MMP-2 and MMP-9 levels as a surrogate for tumour expression in colorectal cancer patients. Int J Cancer 2003; 107: 541-50.
  • Maurel J, Nadal C, Garcia-Albeniz X, et al. Serum matrix metalloproteinase 7 levels identifies poor prognosis advanced colorectal cancer patients. Int J Cancer 2007; 121: 1066-71.
  • Lengyel E, Schmalfeldt B, Konik E, et al. Expression of latent matrix metalloproteinase 9 (MMP-9) predicts survival in advanced ovarian cancer. Gynecol Oncol 2001; 82: 291-8.
  • Kamat AA, Fletcher M, Gruman LM, et al: The clinical relevance of stromal matrix metalloproteinase expression in ovarian cancer. Clin Cancer Res 2006; 12: 1707-14.
  • Perigny M, Bairati I, Harvey I, et al. Role of immunohistochemical overexpression of matrix metalloproteinases MMP-2 and MMP-11 in the prognosis of death by ovarian cancer. Am J Clin Pathol 2008; 129: 226-31.
  • Wood M, Fudge K, Mohler JL, et al. In situ hybridization studies of metalloproteinases 2 and 9 and TIMP-1 and TIMP-2 expression in human prostate cancer. Clin Exp Metastasis 1997;15: 246-58.
  • Sauer CG, Kappeler A, Spath M, et al. Expression and activity of matrix metalloproteinases- 2 and -9 in serum, core needle biopsies and tissue specimens of prostate cancer patients. Virchows Arch 2004; 444: 518-26.
  • Riddick AC, Shukla CJ, Pennington CJ, et al. Identification of degradome components associated with prostate cancer progression by expression analysis of human prostatic tissues. Br J Cancer 2005: 92; 2171-80.
  • Morgia G, Falsaperla M, Malaponte G, et al. Matrix metalloproteinases as diagnostic (MMP-13) and prognostic (MMP-2, MMP-9) markers of prostate cancer. Urol Res 2005;33: 44-50.
  • Kuniyasu H, Ukai R, Johnston D, et al. The relative mRNA expression levels of matrix metalloproteinase to E-cadherin in prostate biopsy specimens distinguishes organ-confined from advanced prostate cancer at radical prostatectomy. Clin Cancer Res 2003; 9: 2185-94.
  • Sawaya RE, Yamamoto M, Gokaslan ZL, et al. Expression and localization of 72 kDa type IV collagenase (MMP-2) in human malignant gliomas in vivo. Clin Exp Metastasis 1996; 14: 35-42.
  • Jaalinoja J, Herva R, Korpela M, et al. Matrix metalloproteinase 2 (MMP-2) immunoreactive protein is associated with poor grade and survival in brain neoplasms. J Neurooncol 2000; 46: 81-90.
  • Zucker S, Cao J, Chen WT. Critical appraisal of the use of matrix metalloproteinase inhibitors in cancer treatmentOncogene 2000; 19: 6642-50.
  • Brown PD, Matrix metalloproteinase inhibitors, Angiogenesis, 1998; 1(2):142–54.
  • Batist G, Patenaude F, Champagne P, et al. Neovastat (AE-941) in refractory renal cell carcinoma patients: Report of a phase II trial with two dose levels. Ann Oncol; 2002; 13: 1259-63.
  • Betz M, Huxley P, Davies SJ, et al. 1.8-A crystal structure of the catalytic domain of human neutrophil collagenase (matrix metalloproteinase- 8) complexed with a peptidomimetic hydroxamate primed-side inhibitor with a distinct selectivity profile. Eur J Biochem1997; 247: 356-63.
  • Papathoma AS, Petraki C, Grigorakis A, et al. Prognostic significance of matrix metalloproteinases 2 and 9 in bladder cancer. Anticancer Res 2000; 20: 2009-13.
  • Folkman J. New perspectives in clinical oncology from angiogenesis research, Eur J Cancer, 1996; 32A(14):2535–9.
  • Golub LM, Mcnamara TF, D’angelo G, et al. A non-antibacterial chemically-modified tetracycline inhibits mammalian collagenase activity, J Dent Res 1987; 66(8): 1310–4.
  • Golub LM, Ramamurthy NS, McNamara TF, et al. Tetracyclines inhibit connective tissue breakdown: New therapeutic implications for an old family of drugs. Crit Rev Oral Biol Med1991; 2: 297-321.
  • Acharya MR, Venitz J, Figg WD, et al. Chemically modified tetracyclines as inhibitors of matrix metalloproteinases. Drug Resist Updat 2004; 7: 195-208.
  • Sapadin AN, Fleischmajer R. Tetracyclines: Nonantibiotic properties and their clinical implications. J Am Acad Dermatol 2006; 54: 258-65.
  • Fernandez CA, Butterfield C, Jackson G, et al. Structural and functional uncoupling of the enzymatic and angiogenic inhibitory activities of tissue inhibitor of metalloproteinase-2 (TIMP-2): Loop 6 is a novel angiogenesis inhibitor. J Biol Chem 2003; 278: 40989-95.
  • Seo DW, Li H, Guedez L, et al. TIMP -2 mediated inhibition of angiogenesis: An MMP independent mechanism. Cell 2003; 114: 171-80.