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MMPs

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Cancer Therapeutic Targets
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Abstract

Matrix metalloproteinases (MMPs) are a family of endopeptidases that have long been associated with tumor invasion and metastasis. Several small molecule inhibitors were developed in the 1980s and 1990s, but all failed in large-scale clinical trials. While these failures undoubtedly dampened enthusiasm for further consideration of MMPs as important targets in cancer, continuing research has uncovered multiple roles for these proteases in many cancers as well as other diseases. Lessons learned from the early clinical failures have informed development of more specific reagents such as antibodies targeted to particular family members. Additionally, the strong association between MMP activity and tumor progression has stirred interest in the development of MMP-activated imaging agents that may be particularly useful for assessing response to other types of cancer therapy. Tumor-associated MMP activity has also been harnessed as a methodology for localized activation of pro-drugs, with the intention of reducing the toxic side effects of systemic chemotherapy. Overall, although broad-spectrum inhibition of MMPs is a failed clinical approach, there are still many potentially beneficial uses of targeting MMP activity in the cancer setting.

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References

  • Acuff HB, Sinnamon M, Fingleton B, Boone B, Levy SE, Chen X, Pozzi A, Carbone DP, Schwartz DR, Moin K, et al. Analysis of host- and tumor-derived proteinases using a custom dual species microarray reveals a protective role for stromal matrix metalloproteinase-12 in non-small cell lung cancer. Cancer Res. 2006;66:7968–75.

    Article  CAS  PubMed  Google Scholar 

  • Ahmann FR, Saad F, Mercier R, Huddart RA, Roberts JT, Collier M, Bettencourt LA, Zhang M, Clendeninn NJ. Interim results of a phase III study of matrix metalloproteinase inhibitor prinomastat in patients having metastatic, hormone refractory prostate cancer (HRPC). Proc Am Soc Clin Oncol. 2001;20: Abstr 692.

    Google Scholar 

  • Al Aqeel A, Al Sewairi W, Edress B, Gorlin RJ, Desnick RJ, Martignetti JA. Inherited multicentric osteolysis with arthritis: a variant resembling Torg syndrome in a Saudi family. Am J Med Genet. 2000;93:11–8.

    Article  CAS  PubMed  Google Scholar 

  • Al Rawashdeh W, Arns S, Gremse F, Ehling J, Knuchel-Clarke R, Kray S, Spoler F, Kiessling F, Lederle W. Optical tomography of MMP activity allows a sensitive noninvasive characterization of the invasiveness and angiogenesis of SCC xenografts. Neoplasia. 2014;16:235–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Albright CF, Graciani N, Han W, Yue E, Stein R, Lai Z, Diamond M, Dowling R, Grimminger L, Zhang SY, et al. Matrix metalloproteinase-activated doxorubicin prodrugs inhibit HT1080 xenograft growth better than doxorubicin with less toxicity. Mol Cancer Ther. 2005;4:751–60.

    Article  CAS  PubMed  Google Scholar 

  • auf dem Keller U, Bellac CL, Li Y, Lou Y, Lange PF, Ting R, Harwig C, Kappelhoff R, Dedhar S, Adam MJ, et al. Novel matrix metalloproteinase inhibitor [18F]marimastat-aryltrifluoroborate as a probe for in vivo positron emission tomography imaging in cancer. Cancer Res. 2010;70:7562–9.

    Article  CAS  PubMed  Google Scholar 

  • Bergers G, Brekken R, McMahon G, Vu TH, Itoh T, Tamaki K, Tanzawa K, Thorpe P, Itohara S, Werb Z, et al. Matrix Metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol. 2000;2:737–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bissett D, O’Byrne K, von Pawel J, Gatzemeier U, Price A, Nicolson M, Mercier R, Mazabel E, Penning C, Zhang, et al. Phase III study of matrix metalloproteinase inhibitor in non-small cell lung cancer. J Clin Oncol. 2005;23:842–9.

    Article  CAS  PubMed  Google Scholar 

  • Coussens LM, Fingleton B, Matrisian LM. Matrix metalloproteinase inhibitors and cancer: trials and tribulations. Science. 2002;295:2387–92.

    Article  CAS  PubMed  Google Scholar 

  • Crisp JL, Savariar EN, Glasgow HL, Ellies LG, Whitney MA, Tsien RY. Dual targeting of integrin alphavbeta3 and matrix metalloproteinase-2 for optical imaging of tumors and chemotherapeutic delivery. Mol Cancer Ther. 2014;13:1514–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dangi-Garimella S, Krantz SB, Barron MR, Shields MA, Heiferman MJ, Grippo PJ, Bentrem DJ, Munshi HG. Three-dimensional collagen I promotes gemcitabine resistance in pancreatic cancer through MT1-MMP-mediated expression of HMGA2. Cancer Res. 2011;71:1019–28.

    Article  CAS  PubMed  Google Scholar 

  • Daniel KB, Major Jourden JL, Negoescu KE, Cohen SM. Activation of sulfonate ester based matrix metalloproteinase proinhibitors by hydrogen peroxide. J Biol Inorg Chem. 2011;16:313–23.

    Article  CAS  PubMed  Google Scholar 

  • Devy L, Huang L, Naa L, Yanamandra N, Pieters H, Frans N, Chang E, Tao Q, Vanhove M, Lejeune A, et al. Selective inhibition of matrix metalloproteinase-14 blocks tumor growth, invasion, and angiogenesis. Cancer Res. 2009;69:1517–26.

    Article  CAS  PubMed  Google Scholar 

  • Egeblad M, Werb Z. New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer. 2002;2:161–74.

    Article  CAS  PubMed  Google Scholar 

  • Erler JT, Bennewith KL, Cox TR, Lang G, Bird D, Koong A, Le QT, Giaccia AJ. Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. Cancer Cell. 2009;15:35–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Failes TW, Hambley TW. Towards bioreductively activated prodrugs: Fe(III) complexes of hydroxamic acids and the MMP inhibitor marimastat. J Inorg Biochem. 2007;101:396–403.

    Article  CAS  PubMed  Google Scholar 

  • Fingleton B. Matrix metalloproteinase inhibitors for cancer therapy: the current situation and future prospects. Expert Opin Ther Targets. 2003;7:385–97.

    Article  CAS  PubMed  Google Scholar 

  • Fingleton B. Matrix metalloproteinases: roles in cancer and metastasis. Front Biosci. 2006;11:479–91.

    Article  CAS  PubMed  Google Scholar 

  • Fingleton B, Vargo-Gogola T, Crawford HC, Matrisian LM. Matrilysin expression selects for cells with reduced sensitivity to apoptosis. Neoplasia. 2001;3:459–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gill SE, Kassim SY, Birkland TP, Parks WC. Mouse models of MMP and TIMP function. Methods Mol Biol. 2010;622:31–52.

    Article  CAS  PubMed  Google Scholar 

  • Godefroy E, Moreau-Aubry A, Diez E, Dreno B, Jotereau F, Guilloux Y. alpha v beta3-dependent cross-presentation of matrix metalloproteinase-2 by melanoma cells gives rise to a new tumor antigen. J Exp Med. 2005;202:61–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang Y, Shi J, He Q, Sheikh MS. The promise of paclitaxel-peptide conjugates for MMP-2-targeted drug delivery. Cancer Biol Ther. 2010;9:204–5.

    Article  PubMed  Google Scholar 

  • Jia WR, Chai WM, Tang L, Wang Y, Fei XC, Han BS, Chen M. Three dimensional contrast enhanced ultrasound score and dynamic contrast-enhanced magnetic resonance imaging score in evaluating breast tumor angiogenesis: correlation with biological factors. Eur J Radiol. 2014;83:1098–105.

    Article  PubMed  Google Scholar 

  • Kaplan RN, Riba RD, Zacharoulis S, Bramley AH, Vincent L, Costa C, MacDonald DD, Jin DK, Shido K, Kerns SA, et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature. 2005;438:820–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kessenbrock K, Plaks V, Werb Z. Matrix metalloproteinases: regulators of the tumor microenvrionment. Cell. 2010;141:52–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kleiner DE, Stetler-Stevenson WG. Quantitative zymography: detection of picogram quantities of gelatinases. Anal Biochem. 1994;218:325–9.

    Article  CAS  PubMed  Google Scholar 

  • Lee S, Jilani SM, Nikolova GV, Carpizo D, Iruela-Arispe ML. Processing of VEGF-A by matrix metalloproteinases regulates bioavailability and vascular patterning in tumors. J Cell Biol. 2005;169:681–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liotta LA, Tryggvason K, Garbisa S, Hart I, Foltz CM, Shafie S. Metastatic potential correlates with enzymatic degradation of basement membrane. Nature. 1980;284:67–8.

    Article  CAS  PubMed  Google Scholar 

  • Lombard C, Saulnier J, Wallach J. Assays of matrix metalloproteinases (MMPs) activities: a review. Biochimie. 2005;87:265–72.

    Article  CAS  PubMed  Google Scholar 

  • Lopez-Otin C, Overall CM. Protease degradomics: a new challenge for proteomics. Nat Rev Mol Cell Biol. 2002;3:509–19 [Review] [50 Refs].

    Article  CAS  PubMed  Google Scholar 

  • Lopez-Otin C, Palavalli LH, Samuels Y. Protective roles of matrix metalloproteinases: from mouse models to human cancer. Cell Cycle. 2009;8:3657–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lynch CC, Matrisian LM. Matrix metalloproteinases in tumor-host cell communication. Differentiation. 2002;70:561–73.

    Article  CAS  PubMed  Google Scholar 

  • Lynch CC, Hikosaka A, Acuff HB, Martin MD, Kawai N, Singh RK, Vargo-Gogola TC, Begtrup JL, Peterson TE, Fingleton B, et al. MMP-7 promotes prostate cancer-induced ostolysis via the solubilization of RANKL. Cancer Cell. 2005;7:485–96.

    Article  CAS  PubMed  Google Scholar 

  • Mansour AM, Drevs J, Esser N, Hamada FM, Badary OA, Unger C, Fichtner I, Kratz F. A new approach for the treatment of malignant melanoma: enhanced antitumor efficacy of an albumin-binding doxorubicin prodrug that is cleaved by matrix metalloproteinase 2. Cancer Res. 2003;63:4062–6.

    CAS  PubMed  Google Scholar 

  • Martin MD, Matrisian LM. The other side of MMPs: protective roles in tumor progression. Cancer Metastasis Rev. 2007;26:717–24.

    Article  CAS  PubMed  Google Scholar 

  • Murray GI, Duncan ME, O’Neill P, Melvin WT, Fothergill JE. Matrix metalloproteinase-1 is associated with poor prognosis in colorectal cancer. Nat Med. 1996;2:461–2.

    Article  CAS  PubMed  Google Scholar 

  • Nguyen QT, Olson ES, Aguilera TA, Jiang T, Scadeng M, Ellies LG, Tsien RY. Surgery with molecular fluorescence imaging using activatable cell-penetrating peptides decreases residual cancer and improves survival. Proc Natl Acad Sci U S A. 2010;107:4317–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Overall CM, Kleifeld O. Tumour microenvironment – opinion: validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy. Nat Rev Cancer. 2006;6:227–39.

    Article  CAS  PubMed  Google Scholar 

  • Peinado H, Aleckovic M, Lavotshkin S, Matei I, Costa-Silva B, Moreno-Bueno G, Hergueta-Redondo M, Williams C, Garcia-Santos G, Ghajar C, et al. Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat Med. 2012;18:883–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Radisky DC, Levy DD, Littlepage LE, Liu H, Nelson CM, Fata JE, Leake D, Godden EL, Albertson DG, Nieto MA, et al. Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability. Nature. 2005;436:123–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Redondo-Munoz J, Ugate-Berzal E, Terol MJ, Van den Steen PE, Hernandez del Cerro M, Roderfeld M, Roeb E, Opdenakker G, Garcia-Marco JA, Garcia-Pardo A. Matrix metalloproteinase-9 promotes chronic lymphocytic leukemia B cell survival through its hemopexin domain. Cancer Cell. 2010;17:160–72.

    Article  CAS  PubMed  Google Scholar 

  • Rigas JR, Denham CA, Rinaldi DA, Moore TD, Smith JW, Winston RD, Sridhar KS, Valera S.-ZB, Humphrey R, Sorensen JM. Randomized placebo controlled trials for the matrix metalloproteinase inhibitor (MMPI) BAY12-9566 as adjuvent therapy for patients with small cell and non-small cell lung cancer. Proc Am Soc Clin Oncol. 2003;22: Abstr 2525.

    Google Scholar 

  • Roy R, Yang J, Moses MA. Matrix metalloproteinases as novel biomarkers and potential therapeutic targets in human cancer. J Clin Oncol. 2009;27:5287–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sabeh F, Ota I, Holmbeck K, Birkedal-Hansen H, Soloway P, Balbìn M, Lûpez-Otìn C, Shapiro S, Inada M, Krane S, et al. Tumor cell traffic through the extracellular matrix is controlled by the membrane-anchored collagenase MT1-MMP. J Cell Biol. 2004;167:769–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Scherer RL, McIntyre JO, Matrisian L. Imaging matrix metalloproteinases in cancer. Cancer Metastasis Rev. 2008;27:679–90.

    Article  PubMed  Google Scholar 

  • Smylie M, Mercier R, Aboulafia D, Tucker R, Bonomi P, Collier M, Keller M, Stuart-Smith J, Knowles M, Clendeninn NJ, Shepherd F. Phase III study of the matrix metalloproteinase (MMP) inhibitor prinomastat in patients having advanced non-small cell lung cancer. Proc Am Soc Clin Oncol. 2001;20: Abstr 1226.

    Google Scholar 

  • Sternlicht MD, Lochter A, Sympson CJ, Huey B, Rougier JP, Gray JW, Pinkel D, Bissell MJ, Werb Z. The stromal proteinase MMP-3/stromelysin-1 promotes mammary carcinogenesis. Cell. 1999;98:137–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tauro BJ, Mathias RA, Greening DW, Gopal SK, Ji H, Kapp EA, Coleman BM, Hill AF, Kusebauch U, Hallows JL, et al. Oncogenic H-ras reprograms Madin-Darby canine kidney (MDCK) cell-derived exosomal proteins following epithelial-mesenchymal transition. Mol Cell Proteomics. 2013;12:2148–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vargo-Gogola T, Fingleton B, Crawford HC, Matrisian LM. Matrilysin (matrix metalloproteinase-7) selects for apoptosis-resistant mammary cells in vivo. Cancer Res. 2002;62:5559–63.

    CAS  PubMed  Google Scholar 

  • Vartak DG, Gemeinhart RA. Matrix metalloproteases: underutilized targets for drug delivery. J Drug Target. 2007;15:1–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wagner S, Breyholz HJ, Holtke C, Faust A, Schober O, Schafers M, Kopka K. A new 18F-labelled derivative of the MMP inhibitor CGS 27023A for PET: radiosynthesis and initial small-animal PET studies. Appl Radiat Isot. 2009;67:606–10.

    Article  CAS  PubMed  Google Scholar 

  • Wilson CL, Heppner KJ, Labosky PA, Hogan BL, Matrisian LM. Intestinal tumorigenesis is suppressed in mice lacking the metalloproteinase matrilysin. Proc Natl Acad Sci U S A. 1997;94:1402–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Witty JP, Lempka T, Coffey Jr RJ, Matrisian LM. Decreased tumor formation in 7,12-dimethylbenzanthracene-treated stromelysin-1 transgenic mice is associated with alterations in mammary epithelial cell apoptosis. Cancer Res. 1995;55:1401–6.

    CAS  PubMed  Google Scholar 

  • Zankl A, Bonafe L, Calcaterra V, Di Rocco M, Superti-Furga A. Winchester syndrome caused by a homozygous mutation affecting the active site of matrix metalloproteinase 2. Clin Genet. 2005;67:261–6.

    Article  CAS  PubMed  Google Scholar 

  • Zankl A, Pachman L, Poznanski A, Bonafe L, Wang F, Shusterman Y, Fishman DA, Superti-Furga A. Torg syndrome is caused by inactivating mutations in MMP2 and is allelic to NAO and Winchester syndrome. J Bone Miner Res. 2007;22:329–33.

    Article  CAS  PubMed  Google Scholar 

  • Zheng QH, Fei X, Liu X, Wang JQ, Bin Sun H, Mock BH, Lee Stone K, Martinez TD, Miller KD, Sledge GW, et al. Synthesis and preliminary biological evaluation of Mmp inhibitor radiotracers [11c]Methyl-Halo-Cgs 27023a analogs, new potential pet breast cancer imaging agents. Nucl Med Biol. 2002;29:761–70.

    Article  CAS  PubMed  Google Scholar 

  • Zhou S, Wang F, Hsieh TC, Wu JM, Wu E. Thalidomide – a notorious sedative to a wonder anti-cancer drug. Curr Med Chem. 2013;20:4012–8.

    Google Scholar 

  • Zucker S, Cao J. Measurement of matrix metalloproteinases in serum of patients with melanoma: snarled in technical pitfalls. Clin Cancer Res. 2005;11:5069–70.

    Article  CAS  PubMed  Google Scholar 

  • Zucker S, Hymowitz M, Conner C, Zarrabi HM, Hurewitz AN, Matrisian L, Boyd D, Nicolson G, Montana S. Measurement of matrix metalloproteinases and tissue inhibitors of metalloproteinases in blood and tissues. Clinical and experimental applications. Ann N Y Acad Sci. 1999;878:212–27.

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Barbara Fingleton .

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Fingleton, B. (2017). MMPs. In: Marshall, J. (eds) Cancer Therapeutic Targets. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-0717-2_21

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