Key Points
-
There are 11 human cysteine cathepsins, which primarily function as endopeptidases within endolysosomal compartments. Specific cysteine cathepsins have extracellular functions, for example, cathepsin K in bone remodelling by osteoclasts.
-
Multiple mechanisms increase cysteine cathepsin expression in tumours, including amplification of the cathepsin B gene and alternative splicing of cathepsin L and B transcripts. Increases in expression occur both in tumour cells and tumour-associated cells such as macrophages, endothelial cells and myoepithelial cells.
-
In tumours these enzymes can be secreted, bind to specific regions on the cell membrane and are localized in endolysosomal vesicles. Their substrates and functions differ depending on their location.
-
Causal roles for cysteine cathepsins in cancer have been demonstrated by pharmacological and genetic techniques. This includes functional downregulation of cysteine cathepsin activity by increasing expression of endogenous inhibitors and administration of small-molecule cysteine protease inhibitors.
-
Causal roles for cysteine cathepsins in cancer have also been identified in regard to intracellular matrix degradation following endocytosis of collagens by urokinase plasminogen activator receptor-associated protein (uPARAP).
-
Causal roles for specific cysteine cathepsins in cancer have been demonstrated by downregulating their expression or crossing mouse models of cancer with mice in which the cysteine cathepsin has been genetically ablated. These studies have identified roles for cysteine cathepsins in both tumour cells and tumour-associated cells such as endothelial cells and macrophages.
Abstract
Cysteine cathepsins are highly upregulated in a wide variety of cancers by mechanisms ranging from gene amplification to post-transcriptional modification. Their localization within intracellular lysosomes often changes during neoplastic progression, resulting in secretion of both inactive and active forms and association with binding partners on the tumour cell surface. Secreted, cell-surface and intracellular cysteine cathepsins function in proteolytic pathways that increase neoplastic progression. Direct proof for causal roles in tumour growth, migration, invasion, angiogenesis and metastasis has been shown by downregulating or ablating the expression of individual cysteine cathepsins in tumour cells and in transgenic mouse models of human cancer.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Rawlings, N. D., Morton, F. R. & Barrett, A. J. MEROPS: the peptidase database. Nucleic Acids Res. 34, D270–D272 (2006). This paper describes an excellent comprehensive database for proteases and protease inhibitors.
McCawley, L. J. & Matrisian, L. M. Matrix metalloproteinases: they're not just for matrix anymore! Curr. Opin. Cell Biol. 13, 534–540 (2001).
Egeblad, M. & Werb, Z. New functions for the matrix metalloproteinases in cancer progression. Nature Rev. Cancer 2, 161–174 (2002).
Lynch, C. C. & Matrisian, L. M. Matrix metalloproteinases in tumor–host cell communication. Differentiation 70, 561–573 (2002).
Mott, J. D. & Werb, Z. Regulation of matrix biology by matrix metalloproteinases. Curr. Opin. Cell Biol. 16, 558–564 (2004).
Balbin, M. et al. Loss of collagenase-2 confers increased skin tumor susceptibility to male mice. Nature Genet. 35, 252–257 (2003).
Harbeck, N. et al. Urokinase-type plasminogen activator and its inhibitor type 1 predict disease outcome and therapy response in primary breast cancer. Clin. Breast Cancer 5, 348–352 (2004).
Obiezu, C. V. & Diamandis, E. P. Human tissue kallikrein gene family: applications in cancer. Cancer Lett. 224, 1–22 (2005).
List, K. et al. Deregulated matriptase causes Ras-independent multistage carcinogenesis and promotes Ras-mediated malignant transformation. Genes Dev. 19, 1934–1950 (2005).
Sajid, M. & McKerrow, J. H. Cysteine proteases of parasitic organisms. Mol. Biochem. Parasitol. 120, 1–21 (2002).
McKerrow, J. H. Development of cysteine protease inhibitors as chemotherapy for parasitic diseases: insights on safety, target validation, and mechanism of action. Int. J. Parasitol. 29, 833–837 (1999).
Saftig, P. et al. Impaired osteoclastic bone resorption leads to osteopetrosis in cathepsin-K-deficient mice. Proc. Natl Acad. Sci. USA 95, 13453–13458 (1998).
Shi, G. P. et al. Cathepsin S required for normal MHC class II peptide loading and germinal center development. Immunity 10, 197–206 (1999).
Roth, W. et al. Cathepsin L deficiency as molecular defect of furless: hyperproliferation of keratinocytes and pertubation of hair follicle cycling. FASEB J. 14, 2075–2086 (2000).
Stypmann, J. et al. Dilated cardiomyopathy in mice deficient for the lysosomal cysteine peptidase cathepsin L. Proc. Natl Acad. Sci. USA 99, 6234–6239 (2002).
Reinheckel, T., Deussing, J., Roth, W. & Peters, C. Towards specific functions of lysosomal cysteine peptidases: phenotypes of mice deficient for cathepsin B or cathepsin L. Biol. Chem. 382, 735–741 (2001).
Driessen, C., Lennon-Dumenil, A. M. & Ploegh, H. L. Individual cathepsins degrade immune complexes internalized by antigen-presenting cells via Fcγ receptors. Eur. J. Immunol. 31, 1592–1601 (2001).
Felbor, U. et al. Neuronal loss and brain atrophy in mice lacking cathepsins B and L. Proc. Natl Acad. Sci. USA 99, 7883–7888 (2002).
Pham, C. T., Ivanovich, J. L., Raptis, S. Z., Zehnbauer, B. & Ley, T. J. Papillon–Lefevre syndrome: correlating the molecular, cellular, and clinical consequences of cathepsin C/dipeptidyl peptidase I deficiency in humans. J. Immunol. 173, 7277–7281 (2004).
Pham, C. T. & Ley, T. J. Dipeptidyl peptidase I is required for the processing and activation of granzymes A and B in vivo. Proc. Natl Acad. Sc.i USA 96, 8627–8632 (1999).
Caughey, G. H. New developments in the genetics and activation of mast cell proteases. Mol. Immunol. 38, 1353–1357 (2002).
Xia, L. et al. Localization of rat cathepsin K in osteoclasts and resorption pits: inhibition of bone resorption and cathepsin K-activity by peptidyl vinyl sulfones. Biol. Chem. 380, 679–687 (1999).
Friedrichs, B. et al. Thyroid functions of mouse cathepsins B, K, and L. J. Clin. Invest. 111, 1733–1745 (2003).
Hughes, S. J. et al. A novel amplicon at 8p22–23 results in overexpression of cathepsin B in esophageal adenocarcinoma. Proc. Natl Acad. Sci. USA 95, 12410–12415 (1998).
Lin, L. et al. A minimal critical region of the 8p22–23 amplicon in esophageal adenocarcinomas defined using sequence tagged site-amplification mapping and quantitative polymerase chain reaction includes the GATA-4 gene. Cancer Res. 60, 1341–1347 (2000).
Berquin, I. M., Cao, L., Fong, D. & Sloane, B. F. Identification of two new exons and multiple transcription start points in the 5′-untranslated region of the human cathepsin-B-encoding gene. Gene 159, 143–149 (1995).
Seth, P., Mahajan, V. S. & Chauhan, S. S. Transcription of human cathepsin L mRNA species hCATL B from a novel alternative promoter in the first intron of its gene. Gene 321, 83–91 (2003).
Arora, S. & Chauhan, S. S. Identification and characterization of a novel human cathepsin L splice variant. Gene 293, 123–131 (2002).
Yan, S. & Sloane, B. F. Molecular regulation of human cathepsin B: implication in pathologies. Biol. Chem. 384, 845–854 (2003).
Gong, Q., Chan, S. J., Bajkowski, A. S., Steiner, D. F. & Frankfater, A. Characterization of the cathepsin B gene and multiple mRNAs in human tissues: evidence for alternative splicing of cathepsin B pre-mRNA. DNA Cell Biol. 12, 299–309 (1993). References 24 and 26–30 describe the molecular mechanisms (amplification, alternative promoters and alternative splicing) that result in increased expression of the cysteine cathepsins B and L in cancer.
Zwicky, R., Muntener, K., Csucs, G., Goldring, M. B. & Baici, A. Exploring the role of 5′ alternative splicing and of the 3′-untranslated region of cathepsin B mRNA. Biol. Chem. 384, 1007–1018 (2003).
Hizel, C. et al. Evaluation of the 5′ spliced form of human cathepsin B mRNA in colorectal mucosa and tumors. Oncol. Rep. 5, 31–34 (1998).
Berquin, I. M., Ahram, M. & Sloane, B. F. Exon 2 of human cathepsin B derives from an Alu element. FEBS Lett. 419, 121–123 (1997).
Landry, J. R., Medstrand, P. & Mager, D. L. Repetitive elements in the 5′ untranslated region of a human zinc-finger gene modulate transcription and translation efficiency. Genomics 76, 110–116 (2001).
Baici, A., Montener, K., Willimann, A. & Zwicky, R. Regulation of human cathepsin B by alternative mRNA splicing: homeostasis, fatal errors and cell death. Biol. Chem. 387, 1017–1021 (2006).
Rao, J. S. Molecular mechanisms of glioma invasiveness: the role of proteases. Nature Rev. Cancer 3, 489–501 (2003).
Yan, S., Berquin, I. M., Troen, B. R. & Sloane, B. F. Transcription of human cathepsin B is mediated by Sp1 and Ets family factors in glioma. DNA Cell. Biol. 19, 79–91 (2000).
Konduri, S. et al. Elevated levels of cathepsin B in human glioblastoma cell lines. Int. J. Oncol. 19, 519–524 (2001).
Szpaderska, A. M., Silberman, S., Ahmed, Y. & Frankfater, A. Sp1 regulates cathepsin B transcription and invasiveness in murine B16 melanoma cells. Anticancer Res. 24, 3887–3891 (2004).
Jean, D., Guillaume, N. & Frade, R. Characterization of human cathepsin L promoter and identification of binding sites for NF-Y, Sp1 and Sp3 that are essential for its activity. Biochem J. 361, 173–184 (2002).
Jean, D., Rousselet, N. & Frade, R. Expression of cathepsin L in human tumor cells is under the control of distinct regulatory mechanisms. Oncogene 25, 1474–1784 (2006).
Deussing, J., von Olshausen, I. & Peters, C. Murine and human cathepsin Z: cDNA-cloning, characterization of the genes and chromosomal localization. Biochim. Biophys. Acta 1491, 93–106 (2000).
Shi, G. P. et al. Human cathepsin S: chromosomal localization, gene structure, and tissue distribution. J. Biol. Chem. 269, 11530–11536 (1994).
Rao, N. V., Rao, G. V. & Hoidal, J. R. Human dipeptidyl-peptidase I. Gene characterization, localization, and expression. J. Biol. Chem. 272, 10260–10265 (1997).
Dittmer, J. The biology of the Ets1 proto-oncogene. Mol. Cancer 2, 2–29 (2003).
Yoneda, T. & Hiraga, T. Crosstalk between cancer cells and bone microenvironment in bone metastasis. Biochem. Biophys. Res. Commun. 328, 679–687 (2005).
Condeelis, J. & Pollard, J. W. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 124, 263–266 (2006).
Matsumoto, M. et al. Essential role of p38 mitogen-activated protein kinase in cathepsin K gene expression during osteoclastogenesis through association of NFATc1 and PU.1. J. Biol. Chem. 279, 45969–45979 (2004).
Tamura, T., Thotakura, P., Tanaka, T. S., Ko, M. S. & Ozato, K. Identification of target genes and a unique cis element regulated by IRF-8 in developing macrophages. Blood 106, 1938–1947 (2005).
Berquin, I. M. et al. Differentiating agents regulate cathepsin B gene expression in HL-60 cells. J. Leukoc. Biol. 66, 609–616 (1999).
Campo, E. et al. Cathepsin B expression in colorectal carcinomas correlates with tumor progression and shortened patient survival. Am. J. Pathol. 145, 301–309 (1994).
Vasiljeva, O. et al. Tumor cell-derived and macrophage-derived cathepsin B promotes progression and lung metastasis of mammary cancer. Cancer Res. 66, 5242–5250 (2006). Shows that cathepsin B expressed by tumour cells and macrophages is functionally involved in malignant progression and metastasis of mammary cancers in MMTV-PyMT transgenic mice.
Paik, S. et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N. Engl. J. Med. 351, 2817–2826 (2004). Identifies cathepsin V (L2) as part of a two-gene invasion signature for predicting the recurrence of breast cancer.
Santamaria, I. et al. Cathepsin L2, a novel human cysteine proteinase produced by breast and colorectal carcinomas. Cancer Res. 58, 1624–1630 (1998).
Haider, A. S. et al. Genomic analysis defines a cancer-specific gene expression signature for human squamous cell carcinoma and distinguishes malignant hyperproliferation from benign hyperplasia. J. Invest. Dermatol. 126, 869–881 (2006).
Linnerth, N. M., Sirbovan, K. & Moorehead, R. A. Use of a transgenic mouse model to identify markers of human lung tumors. Int. J. Cancer 114, 977–982 (2005).
Fernandez, P. L. et al. Expression of cathepsins B and S in the progression of prostate carcinoma. Int. J. Cancer 95, 51–55 (2001).
Nagler, D. K. et al. Up-regulation of cathepsin X in prostate cancer and prostatic intraepithelial neoplasia. Prostate 60, 109–119 (2004).
Allinen, M. et al. Molecular characterization of the tumor microenvironment in breast cancer. Cancer Cell 6, 17–32 (2004).
Flannery, T. et al. The clinical significance of cathepsin S expression in human astrocytomas. Am. J. Pathol. 163, 175–182 (2003).
Mikkelsen, T. et al. Immunolocalization of cathepsin B in human glioma: implications for tumor invasion and angiogenesis. J. Neurosurg. 83, 285–290 (1995).
Buck, M. R., Karustis, D. G., Day, N. A., Honn, K. V. & Sloane, B. F. Degradation of extracellular-matrix proteins by human cathepsin B from normal and tumour tissues. Biochem J. 282, 273–278 (1992).
Ishidoh, K. & Kominami, E. Procathepsin L degrades extracellular matrix proteins in the presence of glycosaminoglycans in vitro. Biochem. Biophys. Res. Commun. 217, 624–631 (1995).
Mai, J., Sameni, M., Mikkelsen, T. & Sloane, B. F. Degradation of extracellular matrix protein tenascin-C by cathepsin B: an interaction involved in the progression of gliomas. Biol. Chem. 383, 1407–1413 (2002).
Gocheva, V. et al. Distinct roles for cysteine cathepsin genes in multistage tumorigenesis. Genes Dev. 20, 543–556 (2006). Shows that the cysteine cathepsins B, L and S, but not C, are functionally involved in invasion, angiogenesis, resistance to apoptosis and proliferation of pancreatic cancers in RIP1–Tag2 transgenic mice.
Kobayashi, H. et al. Effects of membrane-associated cathepsin B on the activation of receptor-bound prourokinase and subsequent invasion of reconstituted basement membranes. Biochim. Biophys. Acta 1178, 55–62 (1993).
Guo, M., Mathieu, P. A., Linebaugh, B., Sloane, B. F. & Reiners, J. J. Jr. Phorbol ester activation of a proteolytic cascade capable of activating latent transforming growth factor-βL a process initiated by the exocytosis of cathepsin B. J. Biol. Chem. 277, 14829–14837 (2002). References 66 and 67 provide evidence for the participation of secreted and membrane-associated cysteine cathepsin B in proteolytic networks on the tumour cell surface.
Behrendt, N. The urokinase receptor (uPAR) and the uPAR-associated protein (uPARAP/Endo180): membrane proteins engaged in matrix turnover during tissue remodeling. Biol. Chem. 385, 103–136 (2004).
Curino, A. C. et al. Intracellular collagen degradation mediated by uPARAP/Endo180 is a major pathway of extracellular matrix turnover during malignancy. J. Cell Biol. 169, 977–985 (2005). Shows that uPARAP expressed by tumour-associated fibroblasts is the functional link to collagen degradation by intracellular cysteine cathepsins in mammary cancer in MMTV-PyMT transgenic mice.
Cavallo-Medved, D. & Sloane, B. F. Cell-surface cathepsin B: understanding its functional significance. Curr. Top. Dev. Biol. 54, 313–341 (2003).
Podosomes — invadopodia — focal adhesions. Zellbiologie Aktuell [online], (2005).
Delaguillaumie, A. et al. Tetraspanin CD82 controls the association of cholesterol-dependent microdomains with the actin cytoskeleton in T lymphocytes: relevance to co-stimulation. J. Cell Sci. 117, 5269–5282 (2004).
Zilber, M. T. et al. MHC class II/CD38/CD9: a lipid-raft-dependent signaling complex in human monocytes. Blood 106, 3074–3081 (2005).
Cherukuri, A. et al. B cell signaling is regulated by induced palmitoylation of CD81. J. Biol. Chem. 279, 31973–31982 (2004).
Cavallo-Medved, D., Mai, J., Dosescu, J., Sameni, M. & Sloane, B. F. Caveolin-1 mediates the expression and localization of cathepsin B, pro-urokinase plasminogen activator and their cell-surface receptors in human colorectal carcinoma cells. J. Cell Sci. 118, 1493–1503 (2005).
Mai, J., Finley, R. L. Jr, Waisman, D. M. & Sloane, B. F. Human procathepsin B interacts with the annexin II tetramer on the surface of tumor cells. J. Biol. Chem. 275, 12806–12812 (2000). Identifies a tumour cell-surface binding partner for a cysteine cathepsin, cathepsin B.
Gerke, V. & Moss, S. E. Annexins: from structure to function. Physiol. Rev. 82, 331–371 (2002).
Mayran, N., Parton, R. G. & Gruenberg, J. Annexin II regulates multivesicular endosome biogenesis in the degradation pathway of animal cells. EMBO J. 22, 3242–3253 (2003).
Collette, J. et al. Biosynthesis and alternate targeting of the lysosomal cysteine protease cathepsin L. Int. Rev. Cytol. 241, 1–51 (2004).
Ulbricht, B. et al. Influence of 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE) on the localization of cathepsin B and cathepsin L in human lung tumor cells. Eur. J. Cell Biol. 74, 294–301 (1997).
Cougoule, C. et al. Activation of the lysosome-associated p61Hck isoform triggers the biogenesis of podosomes. Traffic 6, 682–694 (2005).
MacLeod, T. J., Kwon, M., Filipenko, N. R. & Waisman, D. M. Phospholipid-associated annexin A2–S100A10 heterotetramer and its subunits: characterization of the interaction with tissue plasminogen activator, plasminogen, and plasmin. J. Biol. Chem. 278, 25577–25584 (2003).
Uittenbogaard, A., Everson, W. V., Matveev, S. V. & Smart, E. J. Cholesteryl ester is transported from caveolae to internal membranes as part of a caveolin-annexin II lipid–protein complex. J. Biol. Chem. 277, 4925–4931 (2002).
Stahl, A. & Mueller, B. M. The urokinase-type plasminogen activator receptor, a GPI-linked protein, is localized in caveolae. J. Cell Biol. 129, 335–344 (1995).
Schwab, W. et al. Expression of the urokinase-type plasminogen activator receptor in human articular chondrocytes: association with caveolin and β1-integrin. Histochem. Cell Biol. 115, 317–323 (2001).
Bass, R. et al. Regulation of urokinase receptor proteolytic function by the tetraspanin CD82. J. Biol. Chem. 280, 14811–14818 (2006).
Sridhar, S. C. & Miranti, C. K. Tetraspanin KAI1/CD82 suppresses invasion by inhibiting integrin-dependent crosstalk with c-Met receptor and Src kinases. Oncogene 25, 2367–2378 (2006).
Hauck, C. R., Hsia, D. A., Puente, X. S., Cheresh, D. A. & Schlaepfer, D. D. FRNK blocks v-Src-stimulated invasion and experimental metastases without effects on cell motility or growth. EMBO J. 21, 6289–6302 (2002).
Roshy, S., Sloane, B. F. & Moin, K. Pericellular cathepsin B and malignant progression. Cancer Metastasis Rev. 22, 271–286 (2003).
Vollenweider, F., Kappeler, F., Itin, C. & Hauri, H. P. Mistargeting of the lectin ERGIC-53 to the endoplasmic reticulum of HeLa cells impairs the secretion of a lysosomal enzyme. J. Cell Biol. 142, 377–389 (1998).
Appenzeller, C., Andersson, H., Kappeler, F. & Hauri, H. P. The lectin ERGIC-53 is a cargo transport receptor for glycoproteins. Nature Cell Biol. 1, 330–334 (1999).
Podgorski, I. et al. Bone microenvironment modulates expression and activity of cathepsin B in prostate cancer. Neoplasia 7, 207–223 (2005).
Cavallo-Medved, D. et al. Mutant K-ras regulates cathepsin B localization on the surface of human colorectal carcinoma cells. Neoplasia 5, 507–519 (2003). Localizes the cysteine cathepsin B to caveolar membrane microdomains in colon cancer.
Waghray, A., Keppler, D., Sloane, B. F., Schuger, L. & Chen, Y. Q. Analysis of a truncated form of cathepsin H in human prostate tumor cells. J. Biol. Chem. 277, 11533–11538 (2002).
Reddy, V. Y., Zhang, Q. Y. & Weiss, S. J. Pericellular mobilization of the tissue-destructive cysteine proteinases, cathepsins B, L, and S, by human monocyte-derived macrophages. Proc. Natl Acad. Sci. USA 92, 3849–3853 (1995).
Punturieri, A. et al. Regulation of elastinolytic cysteine proteinase activity in normal and cathepsin K-deficient human macrophages. J. Exp. Med. 192, 789–799 (2000).
Rozhin, J., Sameni, M., Ziegler, G. & Sloane, B. F. Pericellular pH affects distribution and secretion of cathepsin B in malignant cells. Cancer Res. 54, 6517–6525 (1994).
Honn, K. V. et al. A lipoxygenase metabolite, 12-(S)-HETE, stimulates protein kinase C-mediated release of cathepsin B from malignant cells. Exp. Cell Res. 214, 120–130 (1994).
Schraufstatter, I. U. et al. IL-8-mediated cell migration in endothelial cells depends on cathepsin B activity and transactivation of the epidermal growth factor receptor. J. Immunol. 171, 6714–6722 (2003).
Gatenby, R. A., Gawlinski, E. T., Gmitro, A. F., Kaylor, B. & Gillies, R. J. Acid-mediated tumor invasion: a multidisciplinary study. Cancer Res. 66, 5216–5223 (2006).
Mueller, M. M. & Fusenig, N. E. Friends or foes- bipolar effects of the tumour stroma in cancer. Nature Rev. Cancer 4, 839–849 (2004).
Nishimura, Y., Itoh, K., Yoshioka, K., Uehata, M. & Himeno, M. Small guanosine triphosphatase Rho/Rho-associated kinase as a novel regulator of intracellular redistribution of lysosomes in invasive tumor cells. Cell Tissue Res. 301, 341–351 (2000).
Nishimura, Y., Itoh, K., Yoshioka, K., Tokuda, K. & Himeno, M. Overexpression of ROCK in human breast cancer cells: evidence that ROCK activity mediates intracellular membrane traffic of lysosomes. Pathol. Oncol. Res. 9, 83–95 (2003).
Nishimura, Y., Yoshioka, K., Bernard, O., Himeno, M. & Itoh, K. LIM kinase 1: evidence for a role in the regulation of intracellular vesicle trafficking of lysosomes and endosomes in human breast cancer cells. Eur. J. Cell Biol. 83, 369–380 (2004).
Alblas, J., Ulfman, L., Hordijk, P. & Koenderman, L. Activation of Rhoa and ROCK are essential for detachment of migrating leukocytes. Mol. Biol. Cell 12, 2137–2145 (2001).
Almeida, P. C. et al. Cathepsin B activity regulation. Heparin-like glycosaminogylcans protect human cathepsin B from alkaline pH-induced inactivation. J. Biol. Chem. 276, 944–951 (2001).
Nascimento, F. D. et al. Cathepsin X binds to cell surface heparan sulfate proteoglycans. Arch. Biochem. Biophys. 436, 323–332 (2005).
Sameni, M., Moin, K. & Sloane, B. F. Imaging proteolysis by living human breast cancer cells. Neoplasia 2, 496–504 (2000).
East, L. & Isacke, C. M. The mannose receptor family. Biochim. Biophys. Acta 1572, 364–386 (2002).
Sameni, M., Dosescu, J., Moin, K. & Sloane, B. F. Functional imaging of proteolysis: stromal and inflammatory cells increase tumor proteolysis. Mol. Imaging 2, 159–175 (2003).
Sokol, J. P. & Schiemann, W. P. Cystatin C antagonizes transforming growth factor beta signaling in normal and cancer cells. Mol. Cancer Res. 2, 183–195 (2004).
Kopitz, C., Anton, M., Gansbacher, B. & Kruger, A. Reduction of experimental human fibrosarcoma lung metastasis in mice by adenovirus-mediated cystatin C overexpression in the host. Cancer Res. 65, 8608–8612 (2005).
Zhang, J. et al. Cystatin M: a novel candidate tumor suppressor gene for breast cancer. Cancer Res. 64, 6957–6964 (2004).
Li, W. et al. Overexpression of stefin A in human esophageal squamous cell carcinoma cells inhibits tumor cell growth, angiogenesis, invasion, and metastasis. Clin. Cancer Res. 11, 8753–8762 (2005).
Vigneswaran, N. et al. Silencing of cystatin M in metastatic oral cancer cell line MDA-686Ln by siRNA increases cysteine proteinases and legumain activities, cell proliferation and in vitro invasion. Life Sci. 78, 898–907 (2006).
Wang, B. et al. Cathepsin S controls angiogenesis and tumor growth via matrix-derived angiogenic factors. J. Biol. Chem. (2005). Shows that cathepsin S expressed by tumour cells is functionally involved in the induction of angiogenesis associated with pancreatic cancer in RIP1–Tag2 transgenic mice.
Jedeszko, C. & Sloane, B. F. Cysteine cathepsins in human cancer. Biol. Chem. 385, 1017–1027 (2004).
Coussens, L. M., Fingleton, B. & Matrisian, L. M. Matrix metalloproteinase inhibitors and cancer: trials and tribulations. Science 295, 2387–2392 (2002).
Joyce, J. A. et al. Cathepsin cysteine proteases are effectors of invasive growth and angiogenesis during multistage tumorigenesis. Cancer Cell 5, 443–453 (2004). Shows that pharmacological knockdown of cysteine cathepsins reduces progression of pancreatic cancer in RIP1–Tag2 transgenic mice.
Bergers, G., Javaherian, K., Lo, K. M., Folkman, J. & Hanahan, D. Effects of angiogenesis inhibitors on multistage carcinogenesis in mice. Science 284, 808–812 (1999).
Krueger, S., Haeckel, C., Buehling, F. & Roessner, A. Inhibitory effects of antisense cathepsin B cDNA transfection on invasion and motility in a human osteosarcoma cell line. Cancer Res. 59, 6010–6014 (1999).
Mohanam, S. et al. Down-regulation of cathepsin B expression impairs the invasive and tumorigenic potential of human glioblastoma cells. Oncogene 20, 3665–3673 (2001).
Krueger, S., Kellner, U., Buehling, F. & Roessner, A. Cathepsin L antisense oligonucleotides in a human osteosarcoma cell line: effects on the invasive phenotype. Cancer Gene Ther. 8, 522–528 (2001).
Krueger, S. et al. Up-regulation of cathepsin X in Helicobacter pylori gastritis and gastric cancer. J. Pathol. 207, 32–42 (2005).
Sloane, B. F. et al. Cathepsin B and tumor proteolysis: contribution of the tumor microenvironment. Semin. Cancer Biol. 15, 149–157 (2005).
Kroemer, G. & Jaattela, M. Lysosomes and autophagy in cell death control. Nature Rev. Cancer 5, 886–897 (2005).
Yanamandra, N. et al. Blockade of cathepsin B expression in human glioblastoma cells is associated with suppression of angiogenesis. Oncogene 23, 2224–2230 (2004).
Coussens, L. M., Hanahan, D. & Arbeit, J. M. Genetic predisposition and parameters of malignant progression in K14-HPV16 transgenic mice. Am. J. Pathol. 149, 1899–1917 (1996).
Overall, C. M. & Kleifeld, O. Towards third generation matrix metalloproteinase inhibitors for cancer therapy. Br. J. Cancer 94, 941–946 (2006).
Urbich, C. et al. Cathepsin L is required for endothelial progenitor cell-induced neovascularization. Nature Med. 11, 206–213 (2005).
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).
Moin, K., Mclntyre, J. O., Matrisian, L. M. & Sloane, B. F. in In Vivo Imaging of Cancer Therapy (eds Shields, A. & Price, P.) (Humana Press, New Jersey, in the press).
Panchal, R. G., Cusack, E., Cheley, S. & Bayley, H. Tumor protease-activated, pore-forming toxins from a combinatorial library. Nature Biotechnol. 14, 852–856 (1996).
Potrich, C. et al. Cytotoxic activity of a tumor protease-activated pore-forming toxin. Bioconjug. Chem. 16, 369–376 (2005).
Bien, S. et al. Influence of doxorubicin on gene expression and protein pattern in HeLa cells. Int. J. Clin. Pharmacol. Ther. 42, 640–641 (2004).
Pan, C. et al. CD10 is a key enzyme involved in the activation of tumor-activated peptide prodrug CPI-0004Na and novel analogues: implications for the design of novel peptide prodrugs for the therapy of CD10+ tumors. Cancer Res. 63, 5526–5531 (2003).
Satchi-Fainaro, R. et al. Targeting angiogenesis with a conjugate of HPMA copolymer and TNP-470. Nature Med. 10, 255–261 (2004).
Vicent, M. J. & Duncan, R. Polymer conjugates: nanosized medicines for treating cancer. Trends Biotechnol. 24, 39–47 (2006).
Lakka, S. S. et al. Inhibition of cathepsin B and MMP-9 gene expression in glioblastoma cell line via RNA interference reduces tumor cell invasion, tumor growth and angiogenesis. Oncogene 23, 4681–4689 (2004).
Gondi, C. S. et al. RNAi-mediated inhibition of cathepsin B and uPAR leads to decreased cell invasion, angiogenesis and tumor growth in gliomas. Oncogene 23, 8486–8496 (2004).
Musil, D. et al. The refined 2.15 A X-ray crystal structure of human liver cathepsin B: the structural basis for its specificity. EMBO J. 10, 2321–2330 (1991).
Alvarez-Fernandez, M. et al. Inhibition of mammalian legumain by some cystatins is due to a novel second reactive site. J. Biol. Chem. 274, 19195–19203 (1999).
Zeeuwen, P. L. et al. Evidence that unrestricted legumain activity is involved in disturbed epidermal cornification in cystatin M/E deficient mice. Hum. Mol. Genet. 13, 1069–1079 (2004).
Langerholc, T. et al. Inhibitory properties of cystatin F and its localization in U937 promonocyte cells. FEBS J. 272, 1535–1545 (2005).
Abrahamson, M., Alvarez-Fernandez, M. & Nathanson, C. M. Cystatins. Biochem. Soc. Symp. 70, 179–199 (2003).
Acknowledgements
We acknowledge all the scientists who made contributions to the research reviewed here but who were not cited owing to space limitations. We acknowledge with special gratitude the contributions of M. Sameni and D. Cavallo-Medved, K. Moin, I. Podgorski, and D. R. Schwartz to this review. Microscopy was carried out in the Microscopy and Imaging Resources Laboratory of Wayne State University, supported in part by the US National Cancer Institute, National Institute of Environmental Health Sciences and National Technology Center for Networks and Pathways of the National Institutes of Health. The authors are supported by an Avon Foundation American Association for Cancer Research International Scholar Award in Breast Cancer Research (M.M.M.), the National Cancer Institute, the National Technology Center for Networks and Pathways of the National Institutes of Health, and a Department of Defense Breast Cancer Center of Excellence grant.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Related links
Related links
DATABASES
OMIM
FURTHER INFORMATION
Glossary
- Papillon–Lefevre syndrome
-
A rare genetic disorder that is due to mutation of cathepsin C, and is characterized by severe destructive periodontal inflammation and skin lesions.
- Pycnodysostosis
-
A rare genetic disorder that is due to mutation of cathepsin K, which is characterized by short stature and abnormally dense brittle bones.
- Alu element
-
A short interspersed repeated DNA element of ∼300 bp in length that comprises ∼5% of the human genome. It includes a site that is recognized by the restriction enzyme AluI.
- CpG island
-
A short stretch of DNA with a high frequency of phosphodiester-linked cytosine and guanine pairs. CpG islands are often located near and within promoters of frequently expressed genes, including housekeeping genes.
- Caveolae
-
A subset of lipid rafts, which are flask-shaped invaginations of plasma membrane containing the structural protein caveolin.
- Lipid raft
-
A cholesterol-rich region or domain in the plasma membrane.
- Tetraspanin
-
Conserved proteins with four transmembrane domains that associate laterally with one another and with partner proteins in dynamic multimolecular complexes in the plasma membrane, to form what is termed the tetraspanin web.
- Podosome
-
A dynamic actin-rich cell-adhesion structure that is associated with invasion and proteases, and is regulated by tyrosine kinases including Src.
- Invadopodia
-
Cell-surface protrusions that are associated with invasion, are sites of degradation of extracellular matrix, are rich in proteases and are regulated by tyrosine kinases.
- Annexin II
-
A member of a protein family that binds calcium and phospholipids. It exists as a monomer or heterotetramer with two molecules of S100A10 and is involved in plasminogen activation.
- Focal adhesions
-
Dynamic contacts that serve as a primary site of cell attachment to underlying matrices and bridging using transmembrane integrins to the actin cytoskeleton and signalling pathways.
- Angiogenic switch
-
A term designating the transition of an in situ tumour to an angiogenic phenotype accompanied by formation of new blood vessels and invasion of surrounding tissues.
Rights and permissions
About this article
Cite this article
Mohamed, M., Sloane, B. multifunctional enzymes in cancer. Nat Rev Cancer 6, 764–775 (2006). https://doi.org/10.1038/nrc1949
Issue Date:
DOI: https://doi.org/10.1038/nrc1949
