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Emerging roles of proteases in tumour suppression
Nature Reviews Cancervolume 7, pages800–808 (2007)Cite this article
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Abstract
Proteases have long been associated with cancer progression because of their ability to degrade extracellular matrices, which facilitates invasion and metastasis. However, recent studies have shown that these enzymes target a diversity of substrates and favour all steps of tumour evolution. Unexpectedly, the post-trial studies have also revealed proteases with tumour-suppressive effects. These effects are associated with more than 30 different enzymes that belong to three distinct protease classes. What are the clinical implications of these findings?
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References
Lopez-Otin, C. & Overall, C. M. Protease degradomics: a new challenge for proteomics.Nature Rev. Mol. Cell Biol.3, 509–519 (2002).
Turk, B. Targeting proteases: successes, failures and future prospects.Nature Rev. Drug Discov.5, 785–799 (2006).
Puente, X. S., Sanchez, L. M., Overall, C. M. & Lopez-Otin, C. Human and mouse proteases: a comparative genomic approach.Nature Rev. Genet.4, 544–558 (2003).
Puente, X. S. & Lopez-Otin, C. A genomic analysis of rat proteases and protease inhibitors.Genome Res.14, 609–622 (2004).
Fisher, A. Mechanism of the proteolytic activity of malignant tissue cells.Nature157, 442 (1946).
Egeblad, M. & Werb, Z. New functions for the matrix metalloproteinases in cancer progression.Nature Rev. Cancer2, 161–174 (2002).
Mohamed, M. M. & Sloane, B. F. Cysteine cathepsins: multifunctional enzymes in cancer.Nature Rev. Cancer6, 764–775 (2006).
Borgono, C. A. & Diamandis, E. P. The emerging roles of human tissue kallikreins in cancer.Nature Rev. Cancer4, 876–890 (2004).
Teitz, T. et al. Caspase 8 is deleted or silenced preferentially in childhood neuroblastomas with amplification of MYCN.Nature Med.6, 529–535 (2000).
Marino, G. et al. Human autophagins, a family of cysteine proteinases potentially implicated in cell degradation by autophagy.J. Biol. Chem.278, 3671–3678 (2003).
Hoeller, D., Hecker, C. M. & Dikic, I. Ubiquitin and ubiquitin-like proteins in cancer pathogenesis.Nature Rev. Cancer6, 776–788 (2006).
Coussens, L. M., Fingleton, B. & Matrisian, L. M. Matrix metalloproteinase inhibitors and cancer: trials and tribulations.Science295, 2387–2392 (2002).
Overall, C. M. & Lopez-Otin, C. Strategies for MMP inhibition in cancer: innovations for the post-trial era.Nature Rev. Cancer2, 657–672 (2002).
Balbin, M. et al. Loss of collagenase-2 confers increased skin tumor susceptibility to male mice.Nature Genet.35, 252–257 (2003).
McCawley, L. J., Crawford, H. C., King, L. E., Jr, Mudgett, J. & Matrisian, L. M. A protective role for matrix metalloproteinase-3 in squamous cell carcinoma.Cancer Res.64, 6965–6972 (2004).
Overall, C. M. & Kleifeld, O. Validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy.Nature Rev. Cancer6, 227–239 (2006).
Mandruzzato, S., Brasseur, F., Andry, G., Boon, T. & van der Bruggen, P. A CASP-8 mutation recognized by cytolytic T lymphocytes on a human head and neck carcinoma.J. Exp. Med.186, 785–793 (1997).
Soung, Y. H. et al.CASPASE-8 gene is inactivated by somatic mutations in gastric carcinomas.Cancer Res.65, 815–821 (2005).
Harada, K. et al. Deregulation of caspase 8 and 10 expression in pediatric tumors and cell lines.Cancer Res.62, 5897–5901 (2002).
Stupack, D. G. et al. Potentiation of neuroblastoma metastasis by loss of caspase-8.Nature439, 95–99 (2006).
Shin, M. S. et al. Inactivating mutations ofCASP10 gene in non-Hodgkin lymphomas.Blood99, 4094–4099 (2002).
Park, W. S. et al. Inactivating mutations of thecaspase-10 gene in gastric cancer.Oncogene21, 2919–2925 (2002).
Soung, Y. H. et al. Somatic mutations ofCASP3 gene in human cancers.Hum. Genet.115, 112–115 (2004).
Offman, J. et al. Repeated sequences inCASPASE-5 andFANCD2 but notNF1 are targets for mutation in microsatellite-unstable acute leukemia/myelodysplastic syndrome.Mol. Cancer Res.3, 251–260 (2005).
Lee, J. W. et al. Mutational analysis of theCASP6 gene in colorectal and gastric carcinomas.APMIS114, 646–650 (2006).
Soung, Y. H. et al. Inactivating mutations ofCASPASE-7 gene in human cancers.Oncogene22, 8048–8052 (2003).
Bignell, G. R. et al. Identification of the familial cylindromatosis tumour-suppressor gene.Nature Genet.25, 160–165 (2000).
Hellerbrand, C. et al. Reduced expression of CYLD in human colon and hepatocellular carcinomas.Carcinogenesis28, 21–27 (2007).
Massoumi, R., Chmielarska, K., Hennecke, K., Pfeifer, A. & Fassler, R. Cyld inhibits tumor cell proliferation by blocking Bcl-3-dependent NF-κB signaling.Cell125, 665–677 (2006).
Li, M. et al. Deubiquitination of p53 by HAUSP is an important pathway for p53 stabilization.Nature416, 648–653 (2002).
Masuya, D. et al. TheHAUSP gene plays an important role in non-small cell lung carcinogenesis through p53-dependent pathways.J. Pathol.208, 724–732 (2006).
Kim, J. H. et al. Roles of sumoylation of a reptin chromatin-remodelling complex in cancer metastasis.Nature Cell Biol.8, 631–639 (2006).
Levine, B. Cell biology: autophagy and cancer.Nature446, 745–747 (2007).
Marino, G. et al. Tissue-specific autophagy alterations and increased tumorigenesis in mice deficient in Atg4C/autophagin-3.J. Biol. Chem.282, 18573–18583 (2007).
Freije, J. M. et al. Matrix metalloproteinases and tumor progression.Adv. Exp. Med. Biol.532, 91–107 (2003).
Montel, V. et al. Altered metastatic behavior of human breast cancer cells after experimental manipulation of matrix metalloproteinase 8 gene expression.Cancer Res.64, 1687–1694 (2004).
Gorrin-Rivas, M. J. et al. Mouse macrophage metalloelastase gene transfer into a murine melanoma suppresses primary tumor growth by halting angiogenesis.Clin. Cancer Res.6, 1647–1654 (2000).
Acuff, H. B. 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.66, 7968–7975 (2006).
Houghton, A. M. et al. Macrophage elastase (matrix metalloproteinase-12) suppresses growth of lung metastases.Cancer Res.66, 6149–6155 (2006).
Gorrin-Rivas, M. J. et al. Implications of human macrophage metalloelastase and vascular endothelial growth factor gene expression in angiogenesis of hepatocellular carcinoma.Ann. Surg.231, 67–73 (2000).
Yang, W. et al. Human macrophage metalloelastase gene expression in colorectal carcinoma and its clinicopathologic significance.Cancer91, 1277–1283 (2001).
Hofmann, H. S. et al. Matrix metalloproteinase-12 expression correlates with local recurrence and metastatic disease in non-small cell lung cancer patients.Clin. Cancer Res.11, 1086–1092 (2005).
Kerkela, E. et al. Metalloelastase (MMP-12) expression by tumour cells in squamous cell carcinoma of the vulva correlates with invasiveness, while that by macrophages predicts better outcome.J. Pathol.198, 258–269 (2002).
Dong, Z., Kumar, R., Yang, X. & Fidler, I. J. Macrophage-derived metalloelastase is responsible for the generation of angiostatin in Lewis lung carcinoma.Cell88, 801–810 (1997).
Uria, J. A. & Lopez-Otin, C. Matrilysin-2, a new matrix metalloproteinase expressed in human tumors and showing the minimal domain organization required for secretion, latency, and activity.Cancer Res.60, 4745–4751 (2000).
Savinov, A. Y. et al. Matrix metalloproteinase 26 proteolysis of the NH2-terminal domain of the estrogen receptor β correlates with the survival of breast cancer patients.Cancer Res.66, 2716–2724 (2006).
Sternlicht, M. D. et al. The stromal proteinase MMP3/stromelysin-1 promotes mammary carcinogenesis.Cell98, 137–146 (1999).
Witty, J. P., Lempka, T., Coffey, R. J., Jr & Matrisian, L. M. Decreased tumor formation in 7,12-dimethylbenzanthracene-treated stromelysin-1 transgenic mice is associated with alterations in mammary epithelial cell apoptosis.Cancer Res.55, 1401–1406 (1995).
Coussens, L. M., Tinkle, C. L., Hanahan, D. & Werb, Z. MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis.Cell103, 481–490 (2000).
Scorilas, A. et al. Overexpression of matrix-metalloproteinase-9 in human breast cancer: a potential favourable indicator in node-negative patients.Br. J. Cancer84, 1488–1496 (2001).
Takeha, S. et al. Stromal expression of MMP-9 and urokinase receptor is inversely associated with liver metastasis and with infiltrating growth in human colorectal cancer: a novel approach from immune/inflammatory aspect.Jpn J. Cancer Res.88, 72–81 (1997).
Pozzi, A., LeVine, W. F. & Gardner, H. A. Low plasma levels of matrix metalloproteinase 9 permit increased tumor angiogenesis.Oncogene21, 272–281 (2002).
Hamano, Y. et al. Physiological levels of tumstatin, a fragment of collagen IV α3 chain, are generated by MMP-9 proteolysis and suppress angiogenesis via αVβ3 integrin.Cancer Cell3, 589–601 (2003).
Andarawewa, K. L. et al. Dual stromelysin-3 function during natural mouse mammary tumor virus–ras tumor progression.Cancer Res.63, 5844–5849 (2003).
Pendas, A. M. et al. Diet-induced obesity and reduced skin cancer susceptibility in matrix metalloproteinase 19-deficient mice.Mol. Cell Biol.24, 5304–5313 (2004).
Jost, M. et al. Earlier onset of tumoral angiogenesis in matrix metalloproteinase-19-deficient mice.Cancer Res.66, 5234–5241 (2006).
Porter, S., Clark, I. M., Kevorkian, L. & Edwards, D. R. The ADAMTS metalloproteinases.Biochem. J.386, 15–27 (2005).
Iruela-Arispe, M. L., Carpizo, D. & Luque, A. ADAMTS1: a matrix metalloprotease with angioinhibitory properties.Ann. NY Acad. Sci.995, 183–190 (2003).
Kuno, K., Bannai, K., Hakozaki, M., Matsushima, K. & Hirose, K. The carboxyl-terminal half region of ADAMTS-1 suppresses both tumorigenicity and experimental tumor metastatic potential.Biochem. Biophys. Res. Commun.319, 1327–1333 (2004).
Masui, T. et al. Expression of METH-1 and METH-2 in pancreatic cancer.Clin. Cancer Res.7, 3437–3443 (2001).
Liu, Y. J., Xu, Y. & Yu, Q. Full-length ADAMTS-1 and the ADAMTS-1 fragments display pro- and antimetastatic activity, respectively.Oncogene25, 2452–2467 (2006).
Luque, A., Carpizo, D. R. & Iruela-Arispe, M. L. ADAMTS1/METH1 inhibits endothelial cell proliferation by direct binding and sequestration of VEGF165.J. Biol. Chem.278, 23656–23665 (2003).
Lee, N. V. et al. ADAMTS1 mediates the release of antiangiogenic polypeptides from TSP1 and 2.EMBO J.25, 5270–5283 (2006).
Porter, S. et al. Dysregulated expression of adamalysin-thrombospondin genes in human breast carcinoma.Clin. Cancer Res.10, 2429–2440 (2004).
Rocks, N. et al. Expression of a disintegrin and metalloprotease (ADAM and ADAMTS) enzymes in human non-small-cell lung carcinomas (NSCLC).Br. J. Cancer94, 724–730 (2006).
Lind, G. E. et al.ADAMTS1,CRABP1, andNR3C1 identified as epigenetically deregulated genes in colorectal tumorigenesis.Cell Oncol.28, 259–272 (2006).
Dunn, J. R. et al. METH-2 silencing and promoter hypermethylation in NSCLC.Br. J. Cancer91, 1149–1154 (2004).
Dunn, J. R. et al. Expression ofADAMTS-8, a secreted protease with antiangiogenic properties, is downregulated in brain tumours.Br. J. Cancer94, 1186–1193 (2006).
Lo, P. H. et al. Identification of a tumor suppressive critical region mapping to 3p14.2 in esophageal squamous cell carcinoma and studies of a candidate tumor suppressor gene,ADAMTS9.Oncogene26, 148–157 (2007).
Sjoblom, T. et al. The consensus coding sequences of human breast and colorectal cancers.Science314, 268–274 (2006).
Jin, H. et al. Epigenetic identification ofADAMTS18 as a novel 16q23.1 tumor suppressor frequently silenced in esophageal, nasopharyngeal and multiple other carcinomas.Oncogene 4 June 2007 (doi: 10.1038/sj.onc.1210559).
Sumitomo, M., Shen, R. & Nanus, D. M. Involvement of neutral endopeptidase in neoplastic progression.Biochim. Biophys. Acta1751, 52–59 (2005).
Goodman, O. B., Jr et al. Neprilysin inhibits angiogenesis via proteolysis of fibroblast growth factor-2.J. Biol. Chem.281, 33597–33605 (2006).
Sumitomo, M. et al. Synergy in tumor suppression by direct interaction of neutral endopeptidase with PTEN.Cancer Cell5, 67–78 (2004).
Osman, I. et al. Loss of neutral endopeptidase and activation of protein kinase B (Akt) is associated with prostate cancer progression.Cancer107, 2628–2636 (2006).
Horiguchi, A. et al. Lentiviral vector neutral endopeptidase gene transfer suppresses prostate cancer tumor growth.Cancer Gene Ther. 6 April 2007 (doi: 10.1038/sj.cgt.7701047).
Ghosh, A., Wang, X., Klein, E. & Heston, W. D. Novel role of prostate-specific membrane antigen in suppressing prostate cancer invasiveness.Cancer Res.65, 727–731 (2005).
Zhang, P. et al. Identification ofcarboxypeptidase of glutamate like-B as a candidate suppressor in cell growth and metastasis in human hepatocellular carcinoma.Clin. Cancer Res.12, 6617–6625 (2006).
Takada, H. et al.ADAM23, a possible tumor suppressor gene, is frequently silenced in gastric cancers by homozygous deletion or aberrant promoter hypermethylation.Oncogene24, 8051–8060 (2005).
Wahlstrom, A. M. et al.Rce1 deficiency accelerates the development of K-RAS-induced myeloproliferative disease.Blood109, 763–768 (2007).
Reinheckel, T. et al. The lysosomal cysteine protease cathepsin L regulates keratinocyte proliferation by control of growth factor recycling.J. Cell Sci.118, 3387–3395 (2005).
Killian, C. S., Corral, D. A., Kawinski, E. & Constantine, R. I. Mitogenic response of osteoblast cells to prostate-specific antigen suggests an activation of latent TGF-β and a proteolytic modulation of cell adhesion receptors.Biochem. Biophys. Res. Commun.192, 940–947 (1993).
Lai, L. C., Erbas, H., Lennard, T. W. & Peaston, R. T. Prostate-specific antigen in breast cyst fluid: possible role of prostate-specific antigen in hormone-dependent breast cancer.Int. J. Cancer66, 743–746 (1996).
Fortier, A. H. et al. Recombinant prostate specific antigen inhibits angiogenesisin vitro andin vivo.Prostate56, 212–219 (2003).
Sher, Y. P. et al. Human kallikrein 8 protease confers a favorable clinical outcome in non-small cell lung cancer by suppressing tumor cell invasiveness.Cancer Res.66, 11763–11770 (2006).
Goyal, J. et al. The role for NES1 serine protease as a novel tumor suppressor.Cancer Res.58, 4782–4786 (1998).
Roman-Gomez, J. et al. The normal epithelial cell-specific 1 (NES1) gene, a candidate tumor suppressor gene on chromosome 19q13.3–4, is downregulated by hypermethylation in acute lymphoblastic leukemia.Leukemia18, 362–365 (2004).
Borgono, C. A. et al. Expression and functional characterization of the cancer-related serine protease, human tissue kallikrein 14.J. Biol. Chem.282, 2405–2422 (2007).
Hooper, J. D. et al. Testisin, a new human serine proteinase expressed by premeiotic testicular germ cells and lost in testicular germ cell tumors.Cancer Res.59, 3199–3205 (1999).
Chen, L. M. et al. Down-regulation of prostasin serine protease: a potential invasion suppressor in prostate cancer.Prostate48, 93–103 (2001).
Chen, L. M. & Chai, K. X. Prostasin serine protease inhibits breast cancer invasiveness and is transcriptionally regulated by promoter DNA methylation.Int. J. Cancer97, 323–329 (2002).
Manton, K. J. et al. Hypermethylation of the 5′ CpG island of the gene encoding the serine protease Testisin promotes its loss in testicular tumorigenesis.Br. J. Cancer92, 760–769 (2005).
Tang, T. et al. Testisin, a glycosyl-phosphatidylinositol- linked serine protease, promotes malignant transformationin vitro andin vivo.Cancer Res.65, 868–878 (2005).
Chen, M., Chen, L. M. & Chai, K. X. Androgen regulation of prostasin gene expression is mediated by sterol-regulatory element-binding proteins and SLUG.Prostate66, 911–920 (2006).
Wesley, U. V., Albino, A. P., Tiwari, S. & Houghton, A. N. A role for dipeptidyl peptidase IV in suppressing the malignant phenotype of melanocytic cells.J. Exp. Med.190, 311–322 (1999).
Kajiyama, H. et al. Dipeptidyl peptidase IV overexpression induces up-regulation of E-cadherin and tissue inhibitors of matrix metalloproteinases, resulting in decreased invasive potential in ovarian carcinoma cells.Cancer Res.63, 2278–2283 (2003).
Wesley, U. V., McGroarty, M. & Homoyouni, A. Dipeptidyl peptidase inhibits malignant phenotype of prostate cancer cells by blocking basic fibroblast growth factor signaling pathway.Cancer Res.65, 1325–1334 (2005).
Yamashita, K., Mimori, K., Inoue, H., Mori, M. & Sidransky, D. A tumor-suppressive role for trypsin in human cancer progression.Cancer Res.63, 6575–6578 (2003).
Marsit, C. J., Okpukpara, C., Danaee, H. & Kelsey, K. T. Epigenetic silencing of thePRSS3 putative tumor suppressor gene in non-small cell lung cancer.Mol. Carcinog.44, 146–150 (2005).
Marsit, C. J. et al. Carcinogen exposure and gene promoter hypermethylation in bladder cancer.Carcinogenesis27, 112–116 (2006).
Ramirez-Montagut, T. et al. FAPα, a surface peptidase expressed during wound healing, is a tumor suppressor.Oncogene23, 5435–5446 (2004).
Klezovitch, O. et al. Hepsin promotes prostate cancer progression and metastasis.Cancer Cell6, 185–195 (2004).
Srikantan, V., Valladares, M., Rhim, J. S., Moul, J. W. & Srivastava, S.HEPSIN inhibits cell growth/invasion in prostate cancer cells.Cancer Res.62, 6812–6816 (2002).
Merchan, J. R. et al. Protease activity of urokinase and tumor progression in a syngeneic mammary cancer model.J. Natl Cancer Inst.98, 756–764 (2006).
Overall, C. M. et al. Protease degradomics: mass spectrometry discovery of protease substrates and the CLIP-CHIP, a dedicated DNA microarray of all human proteases and inhibitors.Biol. Chem.385, 493–504 (2004).
Varela, I. et al. Accelerated ageing in mice deficient in Zmpste24 protease is linked to p53 signalling activation.Nature437, 564–568 (2005).
Desnick, R. J. & Schuchman, E. H. Enzyme replacement and enhancement therapies: lessons from lysosomal disorders.Nature Rev. Genet.3, 954–966 (2002).
Karikari, C. A. et al. Targeting the apoptotic machinery in pancreatic cancers using small-molecule antagonists of the X-linked inhibitor of apoptosis protein.Mol. Cancer Ther.6, 957–966 (2007).
Brummelkamp, T. R., Nijman, S. M., Dirac, A. M. & Bernards, R. Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-κB.Nature424, 797–801 (2003).
DiPaola, R. S. et al. Characterization of a novel prostate-specific antigen-activated peptide–doxorubicin conjugate in patients with prostate cancer.J. Clin. Oncol.20, 1874–1879 (2002).
McIntyre, J. O. & Matrisian, L. M. Molecular imaging of proteolytic activity in cancer.J. Cell Biochem.90, 1087–1097 (2003).
Sloane, B. F., Sameni, M., Podgorski, I., Cavallo-Medved, D. & Moin, K. Functional imaging of tumor proteolysis.Annu. Rev. Pharmacol. Toxicol.46, 301–315 (2006).
Acknowledgements
We thank all members of our laboratories for their helpful comments on the manuscript and apologize for omission of relevant works owing to space constraints. We especially thank J.P. Freije, X.S. Puente, G.R. Ordoñez and J. Quigley for helpful insights. C.L-O. is supported by grants from Ministerio de Educación y Ciencia, European Union, Fundación M. Botín, Fundación La Caixa and Fundación Lilly. L.M. is supported by grants from the National Cancer Institute, US National Institutes of Health, the US Department of Defense, and the American Cancer Society. The Instituto Universitario de Oncología is supported by Obra Social Cajastur-Asturias, Spain.
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Carlos López-Otín is at the Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, 33006 Oviedo, Spain.,
Carlos López-Otín
Lynn M. Matrisian is at the Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee 37232-6840, USA.,
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López-Otín, C., Matrisian, L. Emerging roles of proteases in tumour suppression.Nat Rev Cancer7, 800–808 (2007). https://doi.org/10.1038/nrc2228
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