Emerging roles of proteases in tumour suppression

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

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support SIMILAR CONTENT BEING VIEWED BY OTHERS TMPRSS4, A TYPE II TRANSMEMBRANE SERINE PROTEASE, AS A POTENTIAL THERAPEUTIC TARGET IN CANCER Article Open access 03 April 2023 REMODELLING OF

THE TUMOUR MICROENVIRONMENT BY THE KALLIKREIN-RELATED PEPTIDASES Article 31 January 2022 MULTISCALE PROFILING OF PROTEASE ACTIVITY IN CANCER Article Open access 03 October 2022 REFERENCES *

Lopez-Otin, C. & Overall, C. M. Protease degradomics: a new challenge for proteomics. _Nature Rev. Mol. Cell Biol._ 3, 509–519 (2002). Article  CAS  Google Scholar  * Turk, B. Targeting

proteases: successes, failures and future prospects. _Nature Rev. Drug Discov._ 5, 785–799 (2006). Article  CAS  Google Scholar  * 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). Article  CAS  PubMed  Google Scholar  * Puente, X. S. & Lopez-Otin, C. A

genomic analysis of rat proteases and protease inhibitors. _Genome Res._ 14, 609–622 (2004). Article  CAS  PubMed  PubMed Central  Google Scholar  * Fisher, A. Mechanism of the proteolytic

activity of malignant tissue cells. _Nature_ 157, 442 (1946). Article  Google Scholar  * Egeblad, M. & Werb, Z. New functions for the matrix metalloproteinases in cancer progression.

_Nature Rev. Cancer_ 2, 161–174 (2002). Article  CAS  Google Scholar  * Mohamed, M. M. & Sloane, B. F. Cysteine cathepsins: multifunctional enzymes in cancer. _Nature Rev. Cancer_ 6,

764–775 (2006). Article  CAS  Google Scholar  * Borgono, C. A. & Diamandis, E. P. The emerging roles of human tissue kallikreins in cancer. _Nature Rev. Cancer_ 4, 876–890 (2004).

Article  CAS  Google Scholar  * Teitz, T. et al. Caspase 8 is deleted or silenced preferentially in childhood neuroblastomas with amplification of MYCN. _Nature Med._ 6, 529–535 (2000).

Article  CAS  PubMed  Google Scholar  * 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). Article  CAS  PubMed  Google Scholar  * Hoeller, D., Hecker, C. M. & Dikic, I. Ubiquitin and ubiquitin-like proteins in cancer pathogenesis. _Nature Rev. Cancer_ 6,

776–788 (2006). Article  CAS  Google Scholar  * Coussens, L. M., Fingleton, B. & Matrisian, L. M. Matrix metalloproteinase inhibitors and cancer: trials and tribulations. _Science_ 295,

2387–2392 (2002). Article  CAS  PubMed  Google Scholar  * Overall, C. M. & Lopez-Otin, C. Strategies for MMP inhibition in cancer: innovations for the post-trial era. _Nature Rev.

Cancer_ 2, 657–672 (2002). Article  CAS  Google Scholar  * Balbin, M. et al. Loss of collagenase-2 confers increased skin tumor susceptibility to male mice. _Nature Genet._ 35, 252–257

(2003). Article  CAS  PubMed  Google Scholar  * 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). Article  CAS  PubMed  Google Scholar  * Overall, C. M. & Kleifeld, O. Validating matrix metalloproteinases as drug targets

and anti-targets for cancer therapy. _Nature Rev. Cancer_ 6, 227–239 (2006). Article  CAS  Google Scholar  * 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). Article  CAS  PubMed  PubMed Central  Google Scholar  * Soung,

Y. H. et al. _CASPASE-8_ gene is inactivated by somatic mutations in gastric carcinomas. _Cancer Res._ 65, 815–821 (2005). CAS  PubMed  Google Scholar  * Harada, K. et al. Deregulation of

caspase 8 and 10 expression in pediatric tumors and cell lines. _Cancer Res._ 62, 5897–5901 (2002). CAS  PubMed  Google Scholar  * Stupack, D. G. et al. Potentiation of neuroblastoma

metastasis by loss of caspase-8. _Nature_ 439, 95–99 (2006). Article  CAS  PubMed  Google Scholar  * Shin, M. S. et al. Inactivating mutations of _CASP10_ gene in non-Hodgkin lymphomas.

_Blood_ 99, 4094–4099 (2002). Article  CAS  PubMed  Google Scholar  * Park, W. S. et al. Inactivating mutations of the _caspase-10_ gene in gastric cancer. _Oncogene_ 21, 2919–2925 (2002).

Article  CAS  PubMed  Google Scholar  * Soung, Y. H. et al. Somatic mutations of _CASP3_ gene in human cancers. _Hum. Genet._ 115, 112–115 (2004). Article  CAS  PubMed  Google Scholar  *

Offman, J. et al. Repeated sequences in _CASPASE-5_ and _FANCD2_ but not _NF1_ are targets for mutation in microsatellite-unstable acute leukemia/myelodysplastic syndrome. _Mol. Cancer Res._

3, 251–260 (2005). Article  CAS  PubMed  Google Scholar  * Lee, J. W. et al. Mutational analysis of the _CASP6_ gene in colorectal and gastric carcinomas. _APMIS_ 114, 646–650 (2006).

Article  CAS  PubMed  Google Scholar  * Soung, Y. H. et al. Inactivating mutations of _CASPASE-7_ gene in human cancers. _Oncogene_ 22, 8048–8052 (2003). Article  PubMed  CAS  Google Scholar

  * Bignell, G. R. et al. Identification of the familial cylindromatosis tumour-suppressor gene. _Nature Genet._ 25, 160–165 (2000). Article  CAS  PubMed  Google Scholar  * Hellerbrand, C.

et al. Reduced expression of CYLD in human colon and hepatocellular carcinomas. _Carcinogenesis_ 28, 21–27 (2007). Article  CAS  PubMed  Google Scholar  * Massoumi, R., Chmielarska, K.,

Hennecke, K., Pfeifer, A. & Fassler, R. Cyld inhibits tumor cell proliferation by blocking Bcl-3-dependent NF-κB signaling. _Cell_ 125, 665–677 (2006). Article  CAS  PubMed  Google

Scholar  * Li, M. et al. Deubiquitination of p53 by HAUSP is an important pathway for p53 stabilization. _Nature_ 416, 648–653 (2002). Article  CAS  PubMed  Google Scholar  * Masuya, D. et

al. The _HAUSP_ gene plays an important role in non-small cell lung carcinogenesis through p53-dependent pathways. _J. Pathol._ 208, 724–732 (2006). Article  CAS  PubMed  Google Scholar  *

Kim, J. H. et al. Roles of sumoylation of a reptin chromatin-remodelling complex in cancer metastasis. _Nature Cell Biol._ 8, 631–639 (2006). Article  CAS  PubMed  Google Scholar  * Levine,

B. Cell biology: autophagy and cancer. _Nature_ 446, 745–747 (2007). Article  CAS  PubMed  Google Scholar  * 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). Article  CAS  PubMed  Google Scholar  * Freije, J. M. et al. Matrix metalloproteinases and

tumor progression. _Adv. Exp. Med. Biol._ 532, 91–107 (2003). Article  CAS  PubMed  Google Scholar  * 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). Article  CAS  PubMed  Google Scholar  * 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). CAS  PubMed  Google Scholar

  * 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). Article  CAS  PubMed  Google Scholar  * Houghton, A. M. et al. Macrophage elastase (matrix metalloproteinase-12) suppresses growth of

lung metastases. _Cancer Res._ 66, 6149–6155 (2006). Article  CAS  PubMed  Google Scholar  * 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). Article  CAS  PubMed  PubMed Central  Google Scholar  * Yang, W. et al.

Human macrophage metalloelastase gene expression in colorectal carcinoma and its clinicopathologic significance. _Cancer_ 91, 1277–1283 (2001). Article  CAS  PubMed  Google Scholar  *

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). CAS  PubMed  Google Scholar  * 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). Article  CAS  PubMed  Google Scholar  * Dong, Z., Kumar, R., Yang, X. & Fidler, I. J. Macrophage-derived

metalloelastase is responsible for the generation of angiostatin in Lewis lung carcinoma. _Cell_ 88, 801–810 (1997). Article  CAS  PubMed  Google Scholar  * 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). CAS  PubMed  Google Scholar  * 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). Article  CAS  PubMed  Google Scholar  * Sternlicht, M. D. et al. The stromal proteinase MMP3/stromelysin-1 promotes mammary

carcinogenesis. _Cell_ 98, 137–146 (1999). Article  CAS  PubMed  PubMed Central  Google Scholar  * 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). CAS 

PubMed  Google Scholar  * Coussens, L. M., Tinkle, C. L., Hanahan, D. & Werb, Z. MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis. _Cell_ 103, 481–490

(2000). Article  CAS  PubMed  PubMed Central  Google Scholar  * Scorilas, A. et al. Overexpression of matrix-metalloproteinase-9 in human breast cancer: a potential favourable indicator in

node-negative patients. _Br. J. Cancer_ 84, 1488–1496 (2001). Article  CAS  PubMed  PubMed Central  Google Scholar  * 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).

Article  CAS  PubMed  PubMed Central  Google Scholar  * Pozzi, A., LeVine, W. F. & Gardner, H. A. Low plasma levels of matrix metalloproteinase 9 permit increased tumor angiogenesis.

_Oncogene_ 21, 272–281 (2002). Article  CAS  PubMed  Google Scholar  * 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 Cell_ 3, 589–601 (2003). Article  CAS  PubMed  PubMed Central  Google Scholar  * Andarawewa, K. L. et al. Dual stromelysin-3

function during natural mouse mammary tumor virus–ras tumor progression. _Cancer Res._ 63, 5844–5849 (2003). CAS  PubMed  Google Scholar  * 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). Article  CAS  PubMed  PubMed Central  Google Scholar  * Jost, M. et

al. Earlier onset of tumoral angiogenesis in matrix metalloproteinase-19-deficient mice. _Cancer Res._ 66, 5234–5241 (2006). Article  CAS  PubMed  Google Scholar  * Porter, S., Clark, I. M.,

Kevorkian, L. & Edwards, D. R. The ADAMTS metalloproteinases. _Biochem. J._ 386, 15–27 (2005). Article  CAS  PubMed  PubMed Central  Google Scholar  * Iruela-Arispe, M. L., Carpizo, D.

& Luque, A. ADAMTS1: a matrix metalloprotease with angioinhibitory properties. _Ann. NY Acad. Sci._ 995, 183–190 (2003). Article  CAS  PubMed  Google Scholar  * 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). Article  CAS  PubMed  Google Scholar  * Masui, T. et al. Expression of METH-1 and METH-2 in pancreatic cancer. _Clin. Cancer Res._ 7, 3437–3443 (2001).

CAS  PubMed  Google Scholar  * Liu, Y. J., Xu, Y. & Yu, Q. Full-length ADAMTS-1 and the ADAMTS-1 fragments display pro- and antimetastatic activity, respectively. _Oncogene_ 25,

2452–2467 (2006). Article  CAS  PubMed  PubMed Central  Google Scholar  * 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). Article  CAS  PubMed  Google Scholar  * Lee, N. V. et al. ADAMTS1 mediates the release of antiangiogenic

polypeptides from TSP1 and 2. _EMBO J._ 25, 5270–5283 (2006). Article  CAS  PubMed  PubMed Central  Google Scholar  * Porter, S. et al. Dysregulated expression of adamalysin-thrombospondin

genes in human breast carcinoma. _Clin. Cancer Res._ 10, 2429–2440 (2004). Article  CAS  PubMed  Google Scholar  * Rocks, N. et al. Expression of a disintegrin and metalloprotease (ADAM and

ADAMTS) enzymes in human non-small-cell lung carcinomas (NSCLC). _Br. J. Cancer_ 94, 724–730 (2006). Article  CAS  PubMed  PubMed Central  Google Scholar  * Lind, G. E. et al. _ADAMTS1_,

_CRABP1_, and _NR3C1_ identified as epigenetically deregulated genes in colorectal tumorigenesis. _Cell Oncol._ 28, 259–272 (2006). CAS  PubMed  PubMed Central  Google Scholar  * Dunn, J. R.

et al. METH-2 silencing and promoter hypermethylation in NSCLC. _Br. J. Cancer_ 91, 1149–1154 (2004). Article  CAS  PubMed  PubMed Central  Google Scholar  * Dunn, J. R. et al. Expression

of _ADAMTS-8_, a secreted protease with antiangiogenic properties, is downregulated in brain tumours. _Br. J. Cancer_ 94, 1186–1193 (2006). Article  CAS  PubMed  PubMed Central  Google

Scholar  * 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_. _Oncogene_ 26, 148–157 (2007). Article  CAS  PubMed  Google Scholar  * Sjoblom, T. et al. The consensus coding sequences of human breast and colorectal cancers. _Science_ 314,

268–274 (2006). Article  CAS  PubMed  Google Scholar  * Jin, H. et al. Epigenetic identification of _ADAMTS18_ 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. Acta_ 1751, 52–59 (2005). Article  CAS  PubMed  Google Scholar  * Goodman, O. B., Jr et al. Neprilysin inhibits angiogenesis via proteolysis of

fibroblast growth factor-2. _J. Biol. Chem._ 281, 33597–33605 (2006). Article  CAS  PubMed  Google Scholar  * Sumitomo, M. et al. Synergy in tumor suppression by direct interaction of

neutral endopeptidase with PTEN. _Cancer Cell_ 5, 67–78 (2004). Article  CAS  PubMed  Google Scholar  * Osman, I. et al. Loss of neutral endopeptidase and activation of protein kinase B

(Akt) is associated with prostate cancer progression. _Cancer_ 107, 2628–2636 (2006). Article  CAS  PubMed  Google Scholar  * 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). Article  CAS  PubMed  Google Scholar  * Zhang, P. et al. Identification of

_carboxypeptidase of glutamate like-B_ as a candidate suppressor in cell growth and metastasis in human hepatocellular carcinoma. _Clin. Cancer Res._ 12, 6617–6625 (2006). Article  CAS 

PubMed  Google Scholar  * Takada, H. et al. _ADAM23_, a possible tumor suppressor gene, is frequently silenced in gastric cancers by homozygous deletion or aberrant promoter

hypermethylation. _Oncogene_ 24, 8051–8060 (2005). Article  CAS  PubMed  Google Scholar  * Wahlstrom, A. M. et al. _Rce1_ deficiency accelerates the development of K-RAS-induced

myeloproliferative disease. _Blood_ 109, 763–768 (2007). Article  CAS  PubMed  PubMed Central  Google Scholar  * 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). Article  CAS  PubMed  Google Scholar  * 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). Article  CAS  PubMed  Google Scholar  * 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. Cancer_ 66, 743–746 (1996). Article  CAS  PubMed  Google Scholar  * Fortier, A. H. et al.

Recombinant prostate specific antigen inhibits angiogenesis _in vitro_ and _in vivo_. _Prostate_ 56, 212–219 (2003). Article  CAS  PubMed  Google Scholar  * 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). Article  CAS  PubMed 

Google Scholar  * Goyal, J. et al. The role for NES1 serine protease as a novel tumor suppressor. _Cancer Res._ 58, 4782–4786 (1998). CAS  PubMed  Google Scholar  * 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.

_Leukemia_ 18, 362–365 (2004). Article  CAS  PubMed  Google Scholar  * 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). Article  CAS  PubMed  Google Scholar  * 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). CAS  PubMed  Google Scholar  * Chen, L. M. et al. Down-regulation of prostasin serine protease: a

potential invasion suppressor in prostate cancer. _Prostate_ 48, 93–103 (2001). Article  CAS  PubMed  Google Scholar  * Chen, L. M. & Chai, K. X. Prostasin serine protease inhibits

breast cancer invasiveness and is transcriptionally regulated by promoter DNA methylation. _Int. J. Cancer_ 97, 323–329 (2002). Article  CAS  PubMed  Google Scholar  * 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. Cancer_ 92, 760–769 (2005). Article  CAS 

PubMed  PubMed Central  Google Scholar  * Tang, T. et al. Testisin, a glycosyl-phosphatidylinositol- linked serine protease, promotes malignant transformation _in vitro_ and _in vivo_.

_Cancer Res._ 65, 868–878 (2005). CAS  PubMed  Google Scholar  * Chen, M., Chen, L. M. & Chai, K. X. Androgen regulation of prostasin gene expression is mediated by sterol-regulatory

element-binding proteins and SLUG. _Prostate_ 66, 911–920 (2006). Article  CAS  PubMed  Google Scholar  * 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). Article  CAS  PubMed  PubMed Central  Google Scholar  * 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). CAS  PubMed  Google Scholar  * 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). Article  CAS  PubMed  Google Scholar  * 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). CAS  PubMed  Google Scholar  * Marsit, C. J., Okpukpara,

C., Danaee, H. & Kelsey, K. T. Epigenetic silencing of the _PRSS3_ putative tumor suppressor gene in non-small cell lung cancer. _Mol. Carcinog._ 44, 146–150 (2005). Article  CAS  PubMed

  Google Scholar  * Marsit, C. J. et al. Carcinogen exposure and gene promoter hypermethylation in bladder cancer. _Carcinogenesis_ 27, 112–116 (2006). Article  CAS  PubMed  Google Scholar 

* Ramirez-Montagut, T. et al. FAPα, a surface peptidase expressed during wound healing, is a tumor suppressor. _Oncogene_ 23, 5435–5446 (2004). Article  CAS  PubMed  Google Scholar  *

Klezovitch, O. et al. Hepsin promotes prostate cancer progression and metastasis. _Cancer Cell_ 6, 185–195 (2004). Article  CAS  PubMed  Google Scholar  * 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). CAS  PubMed  Google Scholar  * 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). Article  CAS  PubMed  Google Scholar  *

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). Article  CAS  PubMed  Google Scholar  * Varela, I. et al. Accelerated ageing in mice deficient in Zmpste24 protease is linked to p53 signalling activation.

_Nature_ 437, 564–568 (2005). Article  CAS  PubMed  Google Scholar  * Desnick, R. J. & Schuchman, E. H. Enzyme replacement and enhancement therapies: lessons from lysosomal disorders.

_Nature Rev. Genet._ 3, 954–966 (2002). Article  CAS  PubMed  Google Scholar  * 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). Article  CAS  PubMed  PubMed Central  Google Scholar  * Brummelkamp, T. R., Nijman, S. M.,

Dirac, A. M. & Bernards, R. Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-κB. _Nature_ 424, 797–801 (2003). Article  CAS  PubMed  Google Scholar  *

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).

Article  CAS  PubMed  Google Scholar  * McIntyre, J. O. & Matrisian, L. M. Molecular imaging of proteolytic activity in cancer. _J. Cell Biochem._ 90, 1087–1097 (2003). Article  CAS 

PubMed  Google Scholar  * 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). Article  CAS  PubMed  Google Scholar  Download references 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. AUTHOR

INFORMATION AUTHORS AND AFFILIATIONS * 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., Lynn M. Matrisian

Authors * Carlos López-Otín View author publications You can also search for this author inPubMed Google Scholar * Lynn M. Matrisian View author publications You can also search for this

author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Carlos López-Otín. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing financial interests. RELATED

LINKS RELATED LINKS DATABASES OMIM familial cylindromatosis FURTHER INFORMATION Carlos López-Otín's homepage Lynn M. Matrisian's homepage MEROPS — the peptidase database RIGHTS

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