Cancer and Metastasis Reviews

, Volume 33, Issue 4, pp 1043–1057 | Cite as

New approaches to selectively target cancer-associated matrix metalloproteinase activity

  • Marilena Tauro
  • Jeremy McGuire
  • Conor C. Lynch
Non-Thematic Review


Heightened matrix metalloproteinase (MMP) activity has been noted in the context of the tumor microenvironment for many years, and causal roles for MMPs have been defined across the spectrum of cancer progression. This is primarily due to the ability of the MMPs to process extracellular matrix (ECM) components and to regulate the bioavailability/activity of a large repertoire of cytokines and growth factors. These characteristics made MMPs an attractive target for therapeutic intervention but notably clinical trials performed in the 1990s did not fulfill the promise of preclinical studies. The reason for the failure of early MMP inhibitor (MMPI) clinical trials that are multifold but arguably principal among them was the inability of early MMP-based inhibitors to selectively target individual MMPs and to distinguish between MMPs and other members of the metzincin family. In the decades that have followed the MMP inhibitor trials, innovations in chemical design, antibody-based strategies, and nanotechnologies have greatly enhanced our ability to specifically target and measure the activity of MMPs. These advances provide us with the opportunity to generate new lines of highly selective MMPIs that will not only extend the overall survival of cancer patients, but will also afford us the ability to utilize heightened MMP activity in the tumor microenvironment as a means by which to deliver MMPIs or MMP activatable prodrugs.


Matrix metalloproteinase Extracellular matrix Activity-based protein probes Tumor microenvironment Cancer progression and metastasis 



We gratefully acknowledge the National Cancer Institute (RO1CA143094). We would also like to thank Barbara Fingleton at Vanderbilt University for her evaluation and critique of the manuscript.


  1. 1.
    Overall, C. M., & Lopez-Otin, C. (2002). Strategies for MMP inhibition in cancer: Innovations for the post-trial era. Nature Reviews Cancer, 2(9), 657–72. doi: 10.1038/nrc884.PubMedGoogle Scholar
  2. 2.
    Egeblad, M., & Werb, Z. (2002). New functions for the matrix metalloproteinases in cancer progression. Nature Reviews Cancer, 2(3), 161–74.PubMedGoogle Scholar
  3. 3.
    Nagase, H., & Woessner, J. F., Jr. (1999). Matrix metalloproteinases. Journal Biological Chemistry, 274(31), 21491–4.Google Scholar
  4. 4.
    Khokha, R., Murthy, A., & Weiss, A. (2013). Metalloproteinases and their natural inhibitors in inflammation and immunity. Nature Reviews Immunology, 13(9), 649–65. doi: 10.1038/nri3499.PubMedGoogle Scholar
  5. 5.
    Liotta, L. A., Tryggvason, K., Garbisa, S., Hart, I., Foltz, C. M., & Shafie, S. (1980). Metastatic potential correlates with enzymatic degradation of basement membrane collagen. Nature, 284(5751), 67–8.PubMedGoogle Scholar
  6. 6.
    Devel, L., Czarny, B., Beau, F., Georgiadis, D., Stura, E., & Dive, V. (2010). Third generation of matrix metalloprotease inhibitors: Gain in selectivity by targeting the depth of the S1′ cavity. Biochimie, 92(11), 1501–8. doi: 10.1016/j.biochi.2010.07.017.PubMedGoogle Scholar
  7. 7.
    Coussens, L. M., Fingleton, B., & Matrisian, L. M. (2002). Matrix metalloproteinase inhibitors and cancer: Trials and tribulations. Science, 295(5564), 2387–92.PubMedGoogle Scholar
  8. 8.
    Fingleton, B. (2007). Matrix metalloproteinases as valid clinical targets. Current Pharmaceutical Design, 13(3), 333–46.PubMedGoogle Scholar
  9. 9.
    Lopez-Otin, C., & Overall, C. M. (2002). Protease degradomics: a new challenge for proteomics. Nature Reviews Molecular Cell Biology, 3(7), 509–19. doi: 10.1038/nrm858.PubMedGoogle Scholar
  10. 10.
    Zucker, S., & Cao, J. (2009). Selective matrix metalloproteinase (MMP) inhibitors in cancer therapy: Ready for prime time? Cancer Biology and Therapy, 8(24), 2371–3.PubMedCentralPubMedGoogle Scholar
  11. 11.
    Roy, R., Yang, J., & Moses, M. A. (2009). Matrix metalloproteinases as novel biomarkers and potential therapeutic targets in human cancer. Journal of Clinical Oncology, 27(31), 5287–97. doi: 10.1200/JCO.2009.23.5556.PubMedCentralPubMedGoogle Scholar
  12. 12.
    Rodriguez, D., Morrison, C. J., & Overall, C. M. (2010). Matrix metalloproteinases: what do they not do? New substrates and biological roles identified by murine models and proteomics. Biochimica et Biophysica Acta, 1803(1), 39–54. doi: 10.1016/j.bbamcr.2009.09.015.PubMedGoogle Scholar
  13. 13.
    Overall, C. M., & Blobel, C. P. (2007). In search of partners: Linking extracellular proteases to substrates. Nature Reviews Molecular Cell Biology, 8(3), 245–57. doi: 10.1038/nrm2120.PubMedGoogle Scholar
  14. 14.
    Lopez-Otin, C., & Matrisian, L. M. (2007). Emerging roles of proteases in tumour suppression. Nature Reviews Cancer, 7(10), 800–8. doi: 10.1038/nrc2228.PubMedGoogle Scholar
  15. 15.
    Gonzalo, P., Guadamillas, M. C., Hernandez-Riquer, M. V., Pollan, A., Grande-Garcia, A., Bartolome, R. A., et al. (2010). MT1-MMP is required for myeloid cell fusion via regulation of Rac1 signaling. Developmental Cell, 18(1), 77–89. doi: 10.1016/j.devcel.2009.11.012.PubMedCentralPubMedGoogle Scholar
  16. 16.
    Correia, A. L., Mori, H., Chen, E. I., Schmitt, F. C., & Bissell, M. J. (2013). The hemopexin domain of MMP3 is responsible for mammary epithelial invasion and morphogenesis through extracellular interaction with HSP90beta. Genes and Development, 27(7), 805–17. doi: 10.1101/gad.211383.112.PubMedCentralPubMedGoogle Scholar
  17. 17.
    Saghatelian, A., Jessani, N., Joseph, A., Humphrey, M., & Cravatt, B. F. (2004). Activity-based probes for the proteomic profiling of metalloproteases. Proceedings of the National Academy of Sciences of the United States of America, 101(27), 10000–5. doi: 10.1073/pnas.0402784101.PubMedCentralPubMedGoogle Scholar
  18. 18.
    Browner, M. F., Smith, W. W., & Castelhano, A. L. (1995). Matrilysin-inhibitor complexes: Common themes among metalloproteases. Biochemistry, 34(20), 6602–10.PubMedGoogle Scholar
  19. 19.
    Puerta, D. T., Lewis, J. A., & Cohen, S. M. (2004). New beginnings for matrix metalloproteinase inhibitors: Identification of high-affinity zinc-binding groups. Journal of the American Chemical Society, 126(27), 8388–9. doi: 10.1021/ja0485513.PubMedGoogle Scholar
  20. 20.
    Quantin, B., Murphy, G., & Breathnach, R. (1989). Pump-1 cDNA codes for a protein with characteristics similar to those of classical collagenase family members. Biochemistry, 28(13), 5327–34.PubMedGoogle Scholar
  21. 21.
    Chandler, S., Cossins, J., Lury, J., & Wells, G. (1996). Macrophage metalloelastase degrades matrix and myelin proteins and processes a tumour necrosis factor-alpha fusion protein. Biochemical and Biophysical Research Communications, 228(2), 421–9. doi: 10.1006/bbrc.1996.1677.PubMedGoogle Scholar
  22. 22.
    Tochowicz, A., Maskos, K., Huber, R., Oltenfreiter, R., Dive, V., Yiotakis, A., et al. (2007). Crystal structures of MMP-9 complexes with five inhibitors: Contribution of the flexible Arg424 side-chain to selectivity. Journal of Molecular Biology, 371(4), 989–1006. doi: 10.1016/j.jmb.2007.05.068.PubMedGoogle Scholar
  23. 23.
    Tao, P., Fisher, J. F., Mobashery, S., & Schlegel, H. B. (2009). DFT studies of the ring-opening mechanism of SB-3CT, a potent inhibitor of matrix metalloproteinase 2. Organic Letters, 11(12), 2559–62. doi: 10.1021/ol9008393.PubMedCentralPubMedGoogle Scholar
  24. 24.
    Kleifeld, O., Kotra, L. P., Gervasi, D. C., Brown, S., Bernardo, M. M., Fridman, R., et al. (2001). X-ray absorption studies of human matrix metalloproteinase-2 (MMP-2) bound to a highly selective mechanism-based inhibitor. Comparison with the latent and active forms of the enzyme. Journal of Biological Chemistry, 276(20), 17125–31.PubMedGoogle Scholar
  25. 25.
    Weinspach, D., Seubert, B., Schaten, S., Honert, K., Sebens, S., Altevogt, P., et al. (2014). Role of L1 cell adhesion molecule (L1CAM) in the metastatic cascade: Promotion of dissemination, colonization, and metastatic growth. Clinical and Experimental Metastasis, 31(1), 87–100. doi: 10.1007/s10585-013-9613-6.PubMedGoogle Scholar
  26. 26.
    Bonfil, R. D., Sabbota, A., Nabha, S., Bernardo, M. M., Dong, Z., Meng, H., et al. (2006). Inhibition of human prostate cancer growth, osteolysis and angiogenesis in a bone metastasis model by a novel mechanism-based selective gelatinase inhibitor. International Journal of Cancer, 118(11), 2721–6.Google Scholar
  27. 27.
    Gooyit, M., Song, W., Mahasenan, K. V., Lichtenwalter, K., Suckow, M. A., Schroeder, V. A., et al. (2013). O-phenyl carbamate and phenyl urea thiiranes as selective matrix metalloproteinase-2 inhibitors that cross the blood–brain barrier. Journal of Medicinal Chemistry, 56(20), 8139–50. doi: 10.1021/jm401217d.PubMedGoogle Scholar
  28. 28.
    Puerta, D. T., Griffin, M. O., Lewis, J. A., Romero-Perez, D., Garcia, R., Villarreal, F. J., et al. (2006). Heterocyclic zinc-binding groups for use in next-generation matrix metalloproteinase inhibitors: Potency, toxicity, and reactivity. Journal of Biological Inorganic Chemistry: JBIC: a Publication of the Society of Biological Inorganic Chemistry, 11(2), 131–8. doi: 10.1007/s00775-005-0053-x.Google Scholar
  29. 29.
    Rubino, M. T., Agamennone, M., Campestre, C., Campiglia, P., Cremasco, V., Faccio, R., et al. (2011). Biphenyl sulfonylamino methyl bisphosphonic acids as inhibitors of matrix metalloproteinases and bone resorption. ChemMedChem, 6(7), 1258–68. doi: 10.1002/cmdc.201000540.PubMedGoogle Scholar
  30. 30.
    Thiolloy, S., Edwards, J. R., Fingleton, B., Rifkin, D. B., Matrisian, L. M., & Lynch, C. C. (2012). An osteoblast-derived proteinase controls tumor cell survival via TGF-beta activation in the bone microenvironment. PloS One, 7(1), e29862. doi: 10.1371/journal.pone.0029862PONE-D-11-14696.PubMedCentralPubMedGoogle Scholar
  31. 31.
    Tauro, M., Laghezza, A., Loiodice, F., Agamennone, M., Campestre, C., Tortorella, P. (2013). Arylamino methylene bisphosphonate derivatives as bone seeking matrix metalloproteinase inhibitors. Bioorganic & Medicinal Chemistry, 21(21), 6456–6465.Google Scholar
  32. 32.
    Kolb, H. C., & Sharpless, K. B. (2003). The growing impact of click chemistry on drug discovery. Drug Discovery Today, 8(24), 1128–37.PubMedGoogle Scholar
  33. 33.
    Lewis, W. G., Green, L. G., Grynszpan, F., Radic, Z., Carlier, P. R., Taylor, P., et al. (2002). Click chemistry in situ: acetylcholinesterase as a reaction vessel for the selective assembly of a femtomolar inhibitor from an array of building blocks. Angewandte Chemie, 41(6), 1053–7.PubMedGoogle Scholar
  34. 34.
    Hu, M., Li, J., & Yao, S. Q. (2008). In situ “click” assembly of small molecule matrix metalloprotease inhibitors containing zinc-chelating groups. Organic Letters, 10(24), 5529–31. doi: 10.1021/ol802286g.PubMedGoogle Scholar
  35. 35.
    Scherer, R. L., McIntyre, J. O., & Matrisian, L. M. (2008). Imaging matrix metalloproteinases in cancer. Cancer and Metastasis Reviews, 27(4), 679–90. doi: 10.1007/s10555-008-9152-9.PubMedGoogle Scholar
  36. 36.
    Howat, S., Park, B., Oh, I. S., Jin, Y. W., Lee, E. K., & Loake, G. J. (2014). Paclitaxel: Biosynthesis, production and future prospects. New Biotechnology, 31(3), 242–5. doi: 10.1016/j.nbt.2014.02.010.PubMedGoogle Scholar
  37. 37.
    Payne, J. B., & Golub, L. M. (2011). Using tetracyclines to treat osteoporotic/osteopenic bone loss: from the basic science laboratory to the clinic. Pharmacological Research: The Official Journal of the Italian Pharmacological Society, 63(2), 121–9. doi: 10.1016/j.phrs.2010.10.006.Google Scholar
  38. 38.
    Fingleton, B. (2003). CMT-3. CollaGenex. Current Opinion in Investigational Drugs, 4(12), 1460–7.PubMedGoogle Scholar
  39. 39.
    Furlow, B. (2006). COL-3 benefits patients with AIDS-related Kaposi’s sarcoma. The Lancet Oncology, 7(5), 368.PubMedGoogle Scholar
  40. 40.
    Zhang, C., & Kim, S. K. (2012). Antimetastasis effect of anthraquinones from marine fungus, Microsporum sp. Advances in Food and Nutrition Research, 65, 415–21. doi: 10.1016/B978-0-12-416003-3.00027-5.PubMedGoogle Scholar
  41. 41.
    Miyata, Y., Sato, T., Yano, M., & Ito, A. (2004). Activation of protein kinase C betaII/epsilon-c-Jun NH2-terminal kinase pathway and inhibition of mitogen-activated protein/extracellular signal-regulated kinase 1/2 phosphorylation in antitumor invasive activity induced by the polymethoxy flavonoid, nobiletin. Molecular Cancer Therapeutics, 3(7), 839–47.PubMedGoogle Scholar
  42. 42.
    Rooprai, H. K., Kandanearatchi, A., Maidment, S. L., Christidou, M., Trillo-Pazos, G., Dexter, D. T., et al. (2001). Evaluation of the effects of swainsonine, captopril, tangeretin and nobiletin on the biological behaviour of brain tumour cells in vitro. Neuropathology and Applied Neurobiology, 27(1), 29–39.PubMedGoogle Scholar
  43. 43.
    Kawabata, K., Murakami, A., & Ohigashi, H. (2006). Citrus auraptene targets translation of MMP-7 (matrilysin) via ERK1/2-dependent and mTOR-independent mechanism. FEBS Letters, 580(22), 5288–94. doi: 10.1016/j.febslet.2006.08.072.PubMedGoogle Scholar
  44. 44.
    Minagawa, A., Otani, Y., Kubota, T., Wada, N., Furukawa, T., Kumai, K., et al. (2001). The citrus flavonoid, nobiletin, inhibits peritoneal dissemination of human gastric carcinoma in SCID mice. Japanese Journal of Cancer Research: Gann, 92(12), 1322–8.PubMedGoogle Scholar
  45. 45.
    Shao, Z. M., Wu, J., Shen, Z. Z., & Barsky, S. H. (1998). Genistein inhibits both constitutive and EGF-stimulated invasion in ER-negative human breast carcinoma cell lines. Anticancer Research, 18(3A), 1435–9.PubMedGoogle Scholar
  46. 46.
    Kousidou, O. C., Mitropoulou, T. N., Roussidis, A. E., Kletsas, D., Theocharis, A. D., & Karamanos, N. K. (2005). Genistein suppresses the invasive potential of human breast cancer cells through transcriptional regulation of metalloproteinases and their tissue inhibitors. International Journal of Oncology, 26(4), 1101–9.PubMedGoogle Scholar
  47. 47.
    Agarwal, C., Tyagi, A., Kaur, M., & Agarwal, R. (2007). Silibinin inhibits constitutive activation of Stat3, and causes caspase activation and apoptotic death of human prostate carcinoma DU145 cells. Carcinogenesis, 28(7), 1463–70. doi: 10.1093/carcin/bgm042.PubMedGoogle Scholar
  48. 48.
    Agarwal, R., Agarwal, C., Ichikawa, H., Singh, R. P., & Aggarwal, B. B. (2006). Anticancer potential of silymarin: from bench to bed side. Anticancer Research, 26(6B), 4457–98.PubMedGoogle Scholar
  49. 49.
    Dell’Aica, I., Caniato, R., Biggin, S., & Garbisa, S. (2007). Matrix proteases, green tea, and St. John’s wort: biomedical research catches up with folk medicine. Clinica Chimica Acta; International Journal of Clinical Chemistry, 381(1), 69–77. doi: 10.1016/j.cca.2007.02.022.PubMedGoogle Scholar
  50. 50.
    Yamakawa, S., Asai, T., Uchida, T., Matsukawa, M., Akizawa, T., & Oku, N. (2004). (−)-Epigallocatechin gallate inhibits membrane-type 1 matrix metalloproteinase, MT1-MMP, and tumor angiogenesis. Cancer Letters, 210(1), 47–55. doi: 10.1016/j.canlet.2004.03.008.PubMedGoogle Scholar
  51. 51.
    Cao, Y., Fu, Z. D., Wang, F., Liu, H. Y., & Han, R. (2005). Anti-angiogenic activity of resveratrol, a natural compound from medicinal plants. Journal of Asian Natural Products Research, 7(3), 205–13. doi: 10.1080/10286020410001690190.PubMedGoogle Scholar
  52. 52.
    Tang, Z., Liu, X. Y., & Zou, P. (2007). Resveratrol inhibits the secretion of vascular endothelial growth factor and subsequent proliferation in human leukemia U937 cells. Journal of Huazhong University of Science and Technology Medical sciences =Hua zhong ke ji da xue xue bao Yi xue Ying De wen ban =Huazhong keji daxue xuebao Yixue Yingdewen ban, 27(5), 508–12. doi: 10.1007/s11596-007-0508-0.Google Scholar
  53. 53.
    Woo, J. H., Lim, J. H., Kim, Y. H., Suh, S. I., Min, D. S., Chang, J. S., et al. (2004). Resveratrol inhibits phorbol myristate acetate-induced matrix metalloproteinase-9 expression by inhibiting JNK and PKC delta signal transduction. Oncogene, 23(10), 1845–53. doi: 10.1038/sj.onc.1207307.PubMedGoogle Scholar
  54. 54.
    Vayalil, P. K., Mittal, A., & Katiyar, S. K. (2004). Proanthocyanidins from grape seeds inhibit expression of matrix metalloproteinases in human prostate carcinoma cells, which is associated with the inhibition of activation of MAPK and NF kappa B. Carcinogenesis, 25(6), 987–95. doi: 10.1093/carcin/bgh095.PubMedGoogle Scholar
  55. 55.
    Bodet, C., Chandad, F., & Grenier, D. (2007). Inhibition of host extracellular matrix destructive enzyme production and activity by a high-molecular-weight cranberry fraction. Journal of Periodontal Research, 42(2), 159–68. doi: 10.1111/j.1600-0765.2006.00929.x.PubMedGoogle Scholar
  56. 56.
    Banerji, A., Chakrabarti, J., Mitra, A., & Chatterjee, A. (2004). Effect of curcumin on gelatinase A (MMP-2) activity in B16F10 melanoma cells. Cancer Letters, 211(2), 235–42. doi: 10.1016/j.canlet.2004.02.007.PubMedGoogle Scholar
  57. 57.
    Lin, L. I., Ke, Y. F., Ko, Y. C., & Lin, J. K. (1998). Curcumin inhibits SK-Hep-1 hepatocellular carcinoma cell invasion in vitro and suppresses matrix metalloproteinase-9 secretion. Oncology (Williston Park), 55(4), 349–53.Google Scholar
  58. 58.
    Chen, H. W., Yu, S. L., Chen, J. J., Li, H. N., Lin, Y. C., Yao, P. L., et al. (2004). Anti-invasive gene expression profile of curcumin in lung adenocarcinoma based on a high throughput microarray analysis. Molecular Pharmacology, 65(1), 99–110. doi: 10.1124/mol.65.1.99.PubMedGoogle Scholar
  59. 59.
    Chen, H., Yan, X., Lin, J., Wang, F., & Xu, W. (2007). Depolymerized products of lambda-carrageenan as a potent angiogenesis inhibitor. Journal of Agricultural and Food Chemistry, 55(17), 6910–7. doi: 10.1021/jf070183+.PubMedGoogle Scholar
  60. 60.
    Kim, J. A., Ahn, B. N., Kong, C. S., Park, S. H., Park, B. J., & Kim, S. K. (2012). Antiphotoaging effect of chitooligosaccharides on human dermal fibroblasts. Photodermatology, Photoimmunology & Photomedicine, 28(6), 299–306. doi: 10.1111/phpp.12004.Google Scholar
  61. 61.
    Mannello, F. (2006). Natural bio-drugs as matrix metalloproteinase inhibitors: New perspectives on the horizon? Recent Patents on Anti-Cancer Drug Discovery, 1(1), 91–103.PubMedGoogle Scholar
  62. 62.
    Dredge, K. (2004). AE-941 (AEterna). Current Opinion in Investigational Drugs, 5(6), 668–77.PubMedGoogle Scholar
  63. 63.
    Tsao, R. (2010). Chemistry and biochemistry of dietary polyphenols. Nutrients, 2(12), 1231–46. doi: 10.3390/nu2121231.PubMedCentralPubMedGoogle Scholar
  64. 64.
    Babu, P. V., & Liu, D. (2008). Green tea catechins and cardiovascular health: an update. Current Medicinal Chemistry, 15(18), 1840–50.PubMedCentralPubMedGoogle Scholar
  65. 65.
    Annabi, B., Lachambre, M. P., Bousquet-Gagnon, N., Page, M., Gingras, D., & Beliveau, R. (2002). Green tea polyphenol (−)-epigallocatechin 3-gallate inhibits MMP-2 secretion and MT1-MMP-driven migration in glioblastoma cells. Biochimica et Biophysica Acta, 1542(1–3), 209–20.PubMedGoogle Scholar
  66. 66.
    Demeule, M., Brossard, M., Page, M., Gingras, D., & Beliveau, R. (2000). Matrix metalloproteinase inhibition by green tea catechins. Biochimica et Biophysica Acta, 1478(1), 51–60.PubMedGoogle Scholar
  67. 67.
    Fujita, M., Nakao, Y., Matsunaga, S., Seiki, M., Itoh, Y., Yamashita, J., et al. (2003). Ageladine A: an antiangiogenic matrixmetalloproteinase inhibitor from the marine sponge Agelas nakamurai. Journal of the American Chemical Society, 125(51), 15700–1. doi: 10.1021/ja038025w.PubMedGoogle Scholar
  68. 68.
    Shengule, S. R., Loa-Kum-Cheung, W. L., Parish, C. R., Blairvacq, M., Meijer, L., Nakao, Y., et al. (2011). A one-pot synthesis and biological activity of ageladine A and analogues. Journal of Medicinal Chemistry, 54(7), 2492–503. doi: 10.1021/jm200039m.PubMedGoogle Scholar
  69. 69.
    Falardeau, P., Champagne, P., Poyet, P., Hariton, C., & Dupont, E. (2001). Neovastat, a naturally occurring multifunctional antiangiogenic drug, in phase III clinical trials. Seminars in Oncology, 28(6), 620–5.PubMedGoogle Scholar
  70. 70.
    Lu, C., Lee, J. J., Komaki, R., Herbst, R. S., Feng, L., Evans, W. K., et al. (2010). Chemoradiotherapy with or without AE-941 in stage III non-small cell lung cancer: a randomized phase III trial. Journal of the National Cancer Institute, 102(12), 859–65. doi: 10.1093/jnci/djq179.PubMedCentralPubMedGoogle Scholar
  71. 71.
    Loprinzi, C. L., Levitt, R., Barton, D. L., Sloan, J. A., Atherton, P. J., Smith, D. J., et al. (2005). Evaluation of shark cartilage in patients with advanced cancer: a north central cancer treatment group trial. Cancer, 104(1), 176–82. doi: 10.1002/cncr.21107.PubMedGoogle Scholar
  72. 72.
    Vacchelli, E., Aranda, F., Eggermont, A., Galon, J., Sautes-Fridman, C., Zitvogel, L., et al. (2014). Trial watch: Tumor-targeting monoclonal antibodies in cancer therapy. Oncoimmunology, 3(1), e27048. doi: 10.4161/onci.27048.PubMedCentralPubMedGoogle Scholar
  73. 73.
    Acharya, U. H., & Jeter, J. M. (2013). Use of ipilimumab in the treatment of melanoma. Clinical Pharmacology: Advances and Applications, 5(Suppl 1), 21–7. doi: 10.2147/CPAA.S45884.Google Scholar
  74. 74.
    Braghiroli, M. I., Sabbaga, J., & Hoff, P. M. (2012). Bevacizumab: Overview of the literature. Expert Review of Anticancer Therapy, 12(5), 567–80. doi: 10.1586/era.12.13.PubMedGoogle Scholar
  75. 75.
    Devy, L., Huang, L., Naa, L., Yanamandra, N., Pieters, H., Frans, N., et al. (2009). Selective inhibition of matrix metalloproteinase-14 blocks tumor growth, invasion, and angiogenesis. Cancer Research, 69(4), 1517–26. doi: 10.1158/0008-5472.CAN-08-3255.PubMedGoogle Scholar
  76. 76.
    Naito, S., Takahashi, T., Onoda, J., Yamauchi, A., Kawai, T., Kishino, J., et al. (2012). Development of a neutralizing antibody specific for the active form of matrix metalloproteinase-13. Biochemistry, 51(44), 8877–84. doi: 10.1021/bi301228d.PubMedGoogle Scholar
  77. 77.
    Shiryaev, S. A., Remacle, A. G., Golubkov, V. S., Ingvarsen, S., Porse, A., Behrendt, N., et al. (2013). A monoclonal antibody interferes with TIMP-2 binding and incapacitates the MMP-2-activating function of multifunctional, pro-tumorigenic MMP-14/MT1-MMP. Oncogenesis, 2, e80. doi: 10.1038/oncsis.2013.44.PubMedCentralPubMedGoogle Scholar
  78. 78.
    Fingleton, B., Powell, W. C., Crawford, H. C., Couchman, J. R., & Matrisian, L. M. (2007). A rat monoclonal antibody that recognizes pro- and active MMP-7 indicates polarized expression in vivo. Hybridoma (Larchmt), 26(1), 22–7. doi: 10.1089/hyb.2006.028.Google Scholar
  79. 79.
    Lolmede, K., Campana, L., Vezzoli, M., Bosurgi, L., Tonlorenzi, R., Clementi, E., et al. (2009). Inflammatory and alternatively activated human macrophages attract vessel-associated stem cells, relying on separate HMGB1- and MMP-9-dependent pathways. Journal of Leukocyte Biology, 85(5), 779–87. doi: 10.1189/jlb.0908579.PubMedGoogle Scholar
  80. 80.
    Sela-Passwell, N., Kikkeri, R., Dym, O., Rozenberg, H., Margalit, R., Arad-Yellin, R., et al. (2012). Antibodies targeting the catalytic zinc complex of activated matrix metalloproteinases show therapeutic potential. Nature Medicine, 18(1), 143–7. doi: 10.1038/nm.2582.Google Scholar
  81. 81.
    Pei, D., Kang, T., & Qi, H. (2000). Cysteine array matrix metalloproteinase (CA-MMP)/MMP-23 is a type II transmembrane matrix metalloproteinase regulated by a single cleavage for both secretion and activation. The Journal of Biological Chemistry, 275(43), 33988–97. doi: 10.1074/jbc.M006493200.PubMedGoogle Scholar
  82. 82.
    Sato, H., Okada, Y., & Seiki, M. (1997). Membrane-type matrix metalloproteinases (MT-MMPs) in cell invasion. Thrombosis and Haemostasis, 78(1), 497–500.PubMedGoogle Scholar
  83. 83.
    Itoh, Y., & Seiki, M. (2006). MT1-MMP: a potent modifier of pericellular microenvironment. Journal of Cellular Physiology, 206(1), 1–8. doi: 10.1002/jcp.20431.PubMedGoogle Scholar
  84. 84.
    Ota, I., Li, X. Y., Hu, Y., & Weiss, S. J. (2009). Induction of a MT1-MMP and MT2-MMP-dependent basement membrane transmigration program in cancer cells by Snail1. Proceedings of the National Academy of Sciences of the United States of America, 106(48), 20318–23. doi: 10.1073/pnas.0910962106.PubMedCentralPubMedGoogle Scholar
  85. 85.
    Deu, E., Verdoes, M., & Bogyo, M. (2012). New approaches for dissecting protease functions to improve probe development and drug discovery. Nature Structural & Molecular Biology, 19(1), 9–16. doi: 10.1038/nsmb.2203.Google Scholar
  86. 86.
    Olson, E. S., Jiang, T., Aguilera, T. A., Nguyen, Q. T., Ellies, L. G., Scadeng, M., et al. (2010). Activatable cell penetrating peptides linked to nanoparticles as dual probes for in vivo fluorescence and MR imaging of proteases. Proceedings of the National Academy of Sciences of the United States of America, 107(9), 4311–6. doi: 10.1073/pnas.0910283107.PubMedCentralPubMedGoogle Scholar
  87. 87.
    Akers, W. J., Xu, B., Lee, H., Sudlow, G. P., Fields, G. B., Achilefu, S., et al. (2012). Detection of MMP-2 and MMP-9 activity in vivo with a triple-helical peptide optical probe. Bioconjugate Chemistry, 23(3), 656–63. doi: 10.1021/bc300027y.PubMedCentralPubMedGoogle Scholar
  88. 88.
    Turk, B. E., Huang, L. L., Piro, E. T., & Cantley, L. C. (2001). Determination of protease cleavage site motifs using mixture-based oriented peptide libraries. Nature Biotechnology, 19(7), 661–7. doi: 10.1038/90273.PubMedGoogle Scholar
  89. 89.
    Scherer, R. L., VanSaun, M. N., McIntyre, J. O., & Matrisian, L. M. (2008). Optical imaging of matrix metalloproteinase-7 activity in vivo using a proteolytic nanobeacon. Molecular Imaging, 7(3), 118–31.PubMedCentralPubMedGoogle Scholar
  90. 90.
    Zhang, H. (2004). Pyro-Gly-Pro-Leu-Gly-Leu-Ala-Arg-Lys (BHQ3). Molecular Imaging and Contrast Agent Database (MICAD). Bethesda (MD).Google Scholar
  91. 91.
    Fudala R, Rich R, Mukerjee A, Ranjan AP, Vishwanatha JK, Kurdowska AK, et al. (2012). Fluorescence detection of MMP-9.II. Ratiometric FRET-based sensing with dually labeled specific peptide. Current Pharmaceutical Biotechnology.Google Scholar
  92. 92.
    Lee, S., Xie, J., & Chen, X. (2010). Peptides and peptide hormones for molecular imaging and disease diagnosis. Chemical Reviews, 110(5), 3087–111. doi: 10.1021/cr900361p.PubMedCentralPubMedGoogle Scholar
  93. 93.
    Meyer, B. S., & Rademann, J. (2012). Extra- and intracellular imaging of human matrix metalloprotease 11 (hMMP-11) with a cell-penetrating FRET substrate. Journal of Biological Chemistry, 287(45), 37857–67. doi: 10.1074/jbc.M112.371500.PubMedCentralPubMedGoogle Scholar
  94. 94.
    Jabaiah, A., & Daugherty, P. S. (2011). Directed evolution of protease beacons that enable sensitive detection of endogenous MT1-MMP activity in tumor cell lines. Chemistry & Biology, 18(3), 392–401. doi: 10.1016/j.chembiol.2010.12.017.Google Scholar
  95. 95.
    Zhu, L., Ma, Y., Kiesewetter, D. O., Wang, Y., Lang, L., Lee, S., et al. (2013). Rational design of matrix metalloproteinase-13 activatable probes for enhanced specificity. ACS Chemical Biology. doi: 10.1021/cb400698s.PubMedCentralGoogle Scholar
  96. 96.
    Chien, M. P., Carlini, A. S., Hu, D., Barback, C. V., Rush, A. M., Hall, D. J., et al. (2013). Enzyme-directed assembly of nanoparticles in tumors monitored by in vivo whole animal imaging and ex vivo super-resolution fluorescence imaging. Journal of the American Chemical Society. doi: 10.1021/ja408182p.PubMedGoogle Scholar
  97. 97.
    Remacle, A. G., Shiryaev, S. A., Golubkov, V. S., Freskos, J. N., Brown, M. A., Karwa, A. S., et al. (2013). Non-destructive and selective imaging of the functionally active, pro-invasive membrane type-1 matrix metalloproteinase (MT1-MMP) enzyme in cancer cells. Journal of Biological Chemistry, 288(28), 20568–80. doi: 10.1074/jbc.M113.471508.PubMedCentralPubMedGoogle Scholar
  98. 98.
    Yu, S. S., Lau, C. M., Thomas, S. N., Jerome, W. G., Maron, D. J., Dickerson, J. H., et al. (2012). Size- and charge-dependent non-specific uptake of PEGylated nanoparticles by macrophages. International Journal of Nanomedicine, 7, 799–813. doi: 10.2147/IJN.S28531.PubMedCentralPubMedGoogle Scholar
  99. 99.
    Thorek, D. L., Ogirala, A., Beattie, B. J., & Grimm, J. (2013). Quantitative imaging of disease signatures through radioactive decay signal conversion. Nature Medicine, 19(10), 1345–50. doi: 10.1038/nm.3323.PubMedCentralPubMedGoogle Scholar
  100. 100.
    Kim, Y. P., Daniel, W. L., Xia, Z., Xie, H., Mirkin, C. A., & Rao, J. (2010). Bioluminescent nanosensors for protease detection based upon gold nanoparticle-luciferase conjugates. Chemical communications (Cambridge), 46(1), 76–8. doi: 10.1039/b915612g.Google Scholar
  101. 101.
    Samuelson, L. E., Scherer, R. L., Matrisian, L. M., McIntyre, J. O., & Bornhop, D. J. (2013). Synthesis and in vitro efficacy of MMP9-activated NanoDendrons. Molecular Pharmaceutics, 10(8), 3164–74. doi: 10.1021/mp4002206.PubMedGoogle Scholar
  102. 102.
    Shi, N. Q., Gao, W., Xiang, B., & Qi, X. R. (2012). Enhancing cellular uptake of activable cell-penetrating peptide-doxorubicin conjugate by enzymatic cleavage. International Journal of Nanomedicine, 7, 1613–21. doi: 10.2147/IJN.S30104.PubMedCentralPubMedGoogle Scholar
  103. 103.
    Li, R., Wu, W., Liu, Q., Wu, P., Xie, L., Zhu, Z., et al. (2013). Intelligently targeted drug delivery and enhanced antitumor effect by gelatinase-responsive nanoparticles. PloS One, 8(7), e69643. doi: 10.1371/journal.pone.0069643.PubMedCentralPubMedGoogle Scholar
  104. 104.
    Tredan, O., Galmarini, C. M., Patel, K., & Tannock, I. F. (2007). Drug resistance and the solid tumor microenvironment. Journal of the National Cancer Institute, 99(19), 1441–54. doi: 10.1093/jnci/djm135.PubMedGoogle Scholar
  105. 105.
    Danhier, F., Feron, O., & Preat, V. (2010). To exploit the tumor microenvironment: Passive and active tumor targeting of nanocarriers for anti-cancer drug delivery. Journal of Controlled Release: Official Journal of the Controlled Release Society, 148(2), 135–46. doi: 10.1016/j.jconrel.2010.08.027.Google Scholar
  106. 106.
    Burris, H. A., 3rd, Tibbitts, J., Holden, S. N., Sliwkowski, M. X., & Lewis Phillips, G. D. (2011). Trastuzumab emtansine (T-DM1): a novel agent for targeting HER2+ breast cancer. Clinical Breast Cancer, 11(5), 275–82. doi: 10.1016/j.clbc.2011.03.018.PubMedGoogle Scholar
  107. 107.
    Gu, G., Xia, H., Hu, Q., Liu, Z., Jiang, M., Kang, T., et al. (2013). PEG-co-PCL nanoparticles modified with MMP-2/9 activatable low molecular weight protamine for enhanced targeted glioblastoma therapy. Biomaterials, 34(1), 196–208. doi: 10.1016/j.biomaterials.2012.09.044.PubMedGoogle Scholar
  108. 108.
    Kondo, M., Asai, T., Katanasaka, Y., Sadzuka, Y., Tsukada, H., Ogino, K., et al. (2004). Anti-neovascular therapy by liposomal drug targeted to membrane type-1 matrix metalloproteinase. International Journal of Cancer, 108(2), 301–6. doi: 10.1002/ijc.11526.Google Scholar
  109. 109.
    Van Valckenborgh, E., Mincher, D., Di Salvo, A., Van Riet, I., Young, L., Van Camp, B., et al. (2005). Targeting an MMP-9-activated prodrug to multiple myeloma-diseased bone marrow: a proof of principle in the 5T33MM mouse model. Leukemia, 19(9), 1628–33. doi: 10.1038/sj.leu.2403866.PubMedGoogle Scholar
  110. 110.
    Ansari, C., Tikhomirov, G. A., Hong, S. H., Falconer, R. A., Loadman, P. M., Gill, J. H., et al. (2014). Development of novel tumor-targeted theranostic nanoparticles activated by membrane-type matrix metalloproteinases for combined cancer magnetic resonance imaging and therapy. Small, 10(3), 566–75. doi: 10.1002/smll.201301456.PubMedGoogle Scholar
  111. 111.
    Morell, M., Nguyen Duc, T., Willis, A. L., Syed, S., Lee, J., Deu, E., et al. (2013). Coupling protein engineering with probe design to inhibit and image matrix metalloproteinases with controlled specificity. Journal of the American Chemical Society, 135(24), 9139–48. doi: 10.1021/ja403523p.PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Marilena Tauro
    • 1
  • Jeremy McGuire
    • 1
  • Conor C. Lynch
    • 1
  1. 1.Departments of Tumor BiologyMoffitt Cancer Center and Research InstituteTampaUSA

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