Key Points
-
Human tissue kallikreins (hKs) comprise a subgroup of 15 homologous secreted trypsin or chymotrypsin-like serine proteases, encoded by a tightly clustered multigene family on chromosome 19q13.4.
-
KLK transcription is modulated by an assortment of stimulatory and inhibitory factors, among which steroid hormones are the best characterized. The proteolytic activity of hKs is regulated in several ways, including zymogen activation; complex formation with endogenous plasma and/or tissue inhibitors, such as α2-macroglobulin and serpins; inhibition by inorganic ions; and inactivation through internal (auto)fragmentation.
-
hKs are primarily expressed within the glandular epithelia of many organs and implicated in a range of normal physiological functions. New proteomic technologies could facilitate the identification of putative in vivo substrates and/or the substrate specificity for many of the newer, relatively uncharacterized hKs.
-
Kallikrein genes/proteins are aberrantly expressed in many cancer types and their expression is often associated with patient prognosis.
-
So far, experimental evidence indicates that hKs might promote or inhibit cancer-cell growth, angiogenesis, invasion and metastasis by proteolytic processing of growth-factor-binding proteins, activation of growth factors and other proteases, release of angiogenic or anti-angiogenic factors, and degradation of extracellular-matrix components. hKs are also implicated in the development of osteoblastic bone metastasis in prostate cancer.
-
The initial claim to fame of hKs is mainly attributed to the clinical impact of prostate-specific antigen as a biomarker for screening, diagnosis, staging and monitoring of prostate cancer. Recent reports indicate that many other kallikrein genes/proteins might prove to be promising tissue and/or serological cancer markers.
-
Exploitation and modulation of hK protease activity are attractive therapeutic approaches. hKs have been used in the activation of prodrugs and in the development of cancer vaccines, whereas hK promoters have been used for the specific delivery of toxic genes to tumour cells. Highly specific inhibitors of hK activity have also been developed and might represent promising agents for cancer treatment.
Abstract
Human tissue kallikreins (hKs), which are encoded by the largest contiguous cluster of protease genes in the human genome, are secreted serine proteases with diverse expression patterns and physiological roles. Although primarily known for their clinical applicability as cancer biomarkers, recent evidence implicates hKs in many cancer-related processes, including cell-growth regulation, angiogenesis, invasion and metastasis. They have been shown to promote or inhibit neoplastic progression, acting individually and/or in cascades with other hKs and proteases, and might represent attractive targets for therapeutic intervention.
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 Springer Link
- 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
Liotta, L. A. & Kohn, E. C. The microenvironment of the tumour–host interface. Nature 411, 375–379 (2001).
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). The first study to compare the protease repertoire (degradome) within human and mouse genomes and to report that the KLK locus is the largest cluster of contiguous protease genes within the human genome.
Werb, Z. ECM and cell surface proteolysis: regulating cellular ecology. Cell 91, 439–442 (1997).
Hara, M., Koyanagi, Y., Inoue, T. & Fukuyama, T. [Some physico-chemical characteristics of “-seminoprotein”, an antigenic component specific for human seminal plasma. Forensic immunological study of body fluids and secretion. VII.] Nippon Hoigaku Zasshi 25, 322–324 (1971).
Riegman, P. H. et al. The prostate-specific antigen gene and the human glandular kallikrein-1 gene are tandemly located on chromosome 19. FEBS Lett. 247, 123–126 (1989).
Diamandis, E. P. et al. New nomenclature for the human tissue kallikrein gene family. Clin. Chem. 46, 1855–1858 (2000). This paper describes the current official nomenclature used to denote human kallikrein genes and proteins and the rationale behind its use.
Yousef, G. M., Chang, A., Scorilas, A. & Diamandis, E. P. Genomic organization of the human kallikrein gene family on chromosome 19q13.3-q13.4. Biochem. Biophys. Res. Commun. 276, 125–133 (2000). The first report to describe the topology and organization of the extended human kallikrein locus on 19q13.4; later confirmed by others (reference 8).
Harvey, T. J. et al. Tissue-specific expression patterns and fine mapping of the human kallikrein (KLK) locus on proximal 19q13.4. J. Biol. Chem. 275, 37397–37406 (2000).
Cleutjens, K. B., van Eekelen, C. C., van der Korput, H. A., Brinkmann, A. O. & Trapman, J. Two androgen response regions cooperate in steroid hormone regulated activity of the prostate-specific antigen promoter. J. Biol. Chem. 271, 6379–6388 (1996).
Smith, M. S., Lechago, J., Wines, D. R., MacDonald, R. J. & Hammer, R. E. Tissue-specific expression of kallikrein family transgenes in mice and rats. DNA Cell Biol. 11, 345–358 (1992).
Mikolajczyk, S. D. et al. Ala217 is important for the catalytic function and autoactivation of prostate-specific human kallikrein 2. Eur. J. Biochem. 246, 440–446 (1997).
Magklara, A. et al. Characterization of the enzymatic activity of human kallikrein 6: autoactivation, substrate specificity, and regulation by inhibitors. Biochem. Biophys. Res. Commun. 307, 948–955 (2003).
Sotiropoulou, G. et al. Emerging interest in the kallikrein gene family for understanding and diagnosing cancer. Oncol. Res. 13, 381–391 (2003).
Lovgren, J., Rajakoski, K., Karp, M., Lundwall, A. & Lilja, H. Activation of the zymogen form of prostate-specific antigen by human glandular kallikrein 2. Biochem. Biophys. Res. Commun. 238, 549–555 (1997).
Takayama, T. K., McMullen, B. A., Nelson, P. S., Matsumura, M. & Fujikawa, K. Characterization of hK4 (prostase), a prostate-specific serine protease: activation of the precursor of prostate specific antigen (pro-PSA) and single-chain urokinase-type plasminogen activator and degradation of prostatic acid phosphatase. Biochemistry 40, 15341–15348 (2001).
Takayama, T. K., Carter, C. A. & Deng, T. Activation of prostate-specific antigen precursor (pro-PSA) by prostin, a novel human prostatic serine protease identified by degenerate PCR. Biochemistry 40, 1679–1687 (2001).
Caubet, C. et al. Degradation of corneodesmosome proteins by two serine proteases of the kallikrein family, SCTE/KLK5/hK5 and SCCE/KLK7/hK7. J. Invest Dermatol. 122, 1235–1244 (2004). The first report to demonstrate that an hK cascade might regulate skin desquamation.
Takayama, T. K., Fujikawa, K. & Davie, E. W. Characterization of the precursor of prostate-specific antigen. Activation by trypsin and by human glandular kallikrein. J. Biol. Chem. 272, 21582–21588 (1997).
Takada, Y., Skidgel, R. A. & Erdos, E. G. Purification of human urinary prokallikrein. Identification of the site of activation by the metalloproteinase thermolysin. Biochem. J. 232, 851–858 (1985).
Heeb, M. J. & Espana, F. α2-macroglobulin and C1-inactivator are plasma inhibitors of human glandular kallikrein. Blood Cells Mol. Dis. 24, 412–419 (1998).
Christensson, A., Laurell, C. B. & Lilja, H. Enzymatic activity of prostate-specific antigen and its reactions with extracellular serine proteinase inhibitors. Eur. J. Biochem. 194, 755–763 (1990).
Komatsu, N. et al. Expression and localization of tissue kallikrein mRNAs in human epidermis and appendages. J. Invest. Dermatol. 121, 542–549 (2003).
Rittenhouse, H. G., Finlay, J. A., Mikolajczyk, S. D. & Partin, A. W. Human Kallikrein 2 (hK2) and prostate-specific antigen (PSA): two closely related, but distinct, kallikreins in the prostate. Crit. Rev. Clin. Lab. Sci. 35, 275–368 (1998). An extensive review on hk2 and hK3/PSA that describes their discovery, isolation, biochemical characteristics and clinical applications.
Bayes, A. et al. Human kallikrein 6 activity is regulated via an autoproteolytic mechanism of activation/inactivation. Biol. Chem. 385, 517–524 (2004).
Hansson, L. et al. Cloning, expression, and characterization of stratum corneum chymotryptic enzyme. A skin-specific human serine proteinase. J. Biol. Chem. 269, 19420–19426 (1994).
Lovgren, J., Airas, K. & Lilja, H. Enzymatic action of human glandular kallikrein 2 (hK2). Substrate specificity and regulation by Zn2+ and extracellular protease inhibitors. Eur. J. Biochem. 262, 781–789 (1999).
Malm, J., Hellman, J., Hogg, P. & Lilja, H. Enzymatic action of prostate-specific antigen (PSA or hK3): substrate specificity and regulation by Zn2+, a tight-binding inhibitor. Prostate 45, 132–139 (2000).
Deperthes, D. Phage display substrate: a blind method for determining protease specificity. Biol. Chem. 383, 1107–1112 (2002). A comprehensive review describing the feasibility of using phage display for the identification of protease specificity and putative substrates.
Harris, J. L. et al. Rapid and general profiling of protease specificity by using combinatorial fluorogenic substrate libraries. Proc. Natl Acad. Sci. USA 97, 7754–7759 (2000). This paper describes the preparation and use of exhaustive fluorogenic tetrapeptide substrate libraries to identify the N-terminal substrate specificities of proteases.
Cloutier, S. M. et al. Substrate specificity of human kallikrein 2 (hK2) as determined by phage display technology. Eur. J. Biochem. 269, 2747–2754 (2002).
Coombs, G. S. et al. Substrate specificity of prostate-specific antigen (PSA). Chem. Biol. 5, 475–488 (1998).
Obiezu, C. V. et al. Higher human kallikrein gene 4 (klk4) expression indicates poor prognosis of ovarian cancer patients. Clin. Cancer Res. 7, 2380–2386 (2001).
Dong, Y. et al. Human kallikrein 4 (KLK4) is highly expressed in serous ovarian carcinomas. Clin. Cancer Res. 7, 2363–2371 (2001).
Kim, H. et al. Human kallikrein gene 5 (KLK5) expression is an indicator of poor prognosis in ovarian cancer. Br. J. Cancer 84, 643–650 (2001).
Yousef, G. M. et al. Human kallikrein 5: a potential novel serum biomarker for breast and ovarian cancer. Cancer Res. 63, 3958–3965 (2003).
Anisowicz, A., Sotiropoulou, G., Stenman, G., Mok, S. C. & Sager, R. A novel protease homolog differentially expressed in breast and ovarian cancer. Mol. Med. 2, 624–636 (1996).
Tanimoto, H., Underwood, L. J., Shigemasa, K., Parmley, T. H. & O'Brien, T. J. Increased expression of protease M in ovarian tumors. Tumour Biol. 22, 11–18 (2001).
Diamandis, E. P., Yousef, G. M., Soosaipillai, A. R. & Bunting, P. Human kallikrein 6 (zyme/protease M/neurosin): a new serum biomarker of ovarian carcinoma. Clin. Biochem. 33, 579–583 (2000). This study was among the first to show that a member of the extended kallikrein family might be a promising cancer biomarker.
Tanimoto, H. et al. The stratum corneum chymotryptic enzyme that mediates shedding and desquamation of skin cells is highly overexpressed in ovarian tumor cells. Cancer 86, 2074–2082 (1999).
Underwood, L. J. et al. Cloning of tumor-associated differentially expressed gene-14, a novel serine protease overexpressed by ovarian carcinoma. Cancer Res. 59, 4435–4439 (1999).
Magklara, A. et al. The human KLK8 (neuropsin/ovasin) gene: identification of two novel splice variants and its prognostic value in ovarian cancer. Clin. Cancer Res. 7, 806–811 (2001).
Kishi, T. et al. Human kallikrein 8, a novel biomarker for ovarian carcinoma. Cancer Res. 63, 2771–2774 (2003).
Luo, L. Y. et al. Prognostic value of human kallikrein 10 expression in epithelial ovarian carcinoma. Clin. Cancer Res. 7, 2372–2379 (2001).
Luo, L., Bunting, P., Scorilas, A. & Diamandis, E. P. Human kallikrein 10: a novel tumor marker for ovarian carcinoma? Clin. Chim. Acta 306, 111–118 (2001).
Luo, L. Y. et al. The serum concentration of human kallikrein 10 represents a novel biomarker for ovarian cancer diagnosis and prognosis. Cancer Res. 63, 807–811 (2003).
Diamandis, E. P. et al. Human kallikrein 11: a new biomarker of prostate and ovarian carcinoma. Cancer Res. 62, 295–300 (2002).
Kapadia, C. et al. Human kallikrein 13: production and purification of recombinant protein and monoclonal and polyclonal antibodies, and development of a sensitive and specific immunofluorometric assay. Clin. Chem. 49, 77–86 (2003).
Borgono, C. A. et al. Human kallikrein 14: a new potential biomarker for ovarian and breast cancer. Cancer Res. 63, 9032–9041 (2003).
Yousef, G. M. et al. Prognostic value of the human kallikrein gene 15 expression in ovarian cancer. J. Clin. Oncol. 21, 3119–3126 (2003).
Yousef, G. M. et al. Parallel overexpression of seven kallikrein genes in ovarian cancer. Cancer Res. 63, 2223–2227 (2003).
Welsh, J. B. et al. Large-scale delineation of secreted protein biomarkers overexpressed in cancer tissue and serum. Proc. Natl Acad. Sci. USA 100, 3410–3415 (2003).
Adib, T. R. et al. Predicting biomarkers for ovarian cancer using gene-expression microarrays. Br. J. Cancer 90, 686–692 (2004).
Yu, H. et al. Prostate specific antigen in breast cancer, benign breast disease and normal breast tissue. Breast Cancer Res. Treat. 40, 171–178 (1996).
Yu, H., Levesque, M. A., Clark, G. M. & Diamandis, E. P. Prognostic value of prostate-specific antigen for women with breast cancer: a large United States cohort study. Clin. Cancer Res. 4, 1489–1497 (1998).
Liu, X. L., Wazer, D. E., Watanabe, K. & Band, V. Identification of a novel serine protease-like gene, the expression of which is down-regulated during breast cancer progression. Cancer Res. 56, 3371–3379 (1996).
Goyal, J. et al. The role for NES1 serine protease as a novel tumor suppressor. Cancer Res. 58, 4782–4786 (1998).
Dhar, S. et al. Analysis of normal epithelial cell specific-1 (NES1)/Kallikrein 10 mRNA expression by in situ hybridization, a novel marker for breast cancer. Clin. Cancer Res. 7, 3393–3398 (2001).
Yousef, G. M., Magklara, A. & Diamandis, E. P. KLK12 is a novel serine protease and a new member of the human kallikrein gene family-differential expression in breast cancer. Genomics 69, 331–341 (2000).
Yousef, G. M., Chang, A. & Diamandis, E. P. Identification and characterization of KLK-L4, a new kallikrein-like gene that appears to be down-regulated in breast cancer tissues. J. Biol. Chem. 275, 11891–11898 (2000).
Yousef, G. M. et al. Cloning of a new member of the human kallikrein gene family, KLK14, which is down-regulated in different malignancies. Cancer Res. 61, 3425–3431 (2001).
Yousef, G. M. et al. Kallikrein gene downregulation in breast cancer. Br. J. Cancer 90, 167–172 (2004).
Magklara, A. et al. Decreased concentrations of prostate-specific antigen and human glandular kallikrein 2 in malignant versus nonmalignant prostatic tissue. Urology 56, 527–532 (2000).
Abrahamsson, P. A., Lilja, H., Falkmer, S. & Wadstrom, L. B. Immunohistochemical distribution of the three predominant secretory proteins in the parenchyma of hyperplastic and neoplastic prostate glands. Prostate 12, 39–46 (1988).
Pretlow, T. G. et al. Tissue concentrations of prostate-specific antigen in prostatic carcinoma and benign prostatic hyperplasia. Int. J. Cancer 49, 645–649 (1991).
Hakalahti, L. et al. Evaluation of PAP and PSA gene expression in prostatic hyperplasia and prostatic carcinoma using northern-blot analyses, in situ hybridization and immunohistochemical stainings with monoclonal and bispecific antibodies. Int. J. Cancer 55, 590–597 (1993).
Yousef, G. M. et al. Down-regulation of the human kallikrein gene 5 (KLK5) in prostate cancer tissues. Prostate 51, 126–132 (2002).
Luo, L. Y. & Diamandis, E. P. Down-regulation of the normal epithelial cell–specific 1 (NES1) gene is associated with unfavorable outcome of prostate cancer. Clin. Biochem. 33, 237 (2000).
Petraki, C. D. et al. Immunohistochemical localization of human kallikreins 6, 10 and 13 in benign and malignant prostatic tissues. Prostate Cancer Prostatic Dis. 6, 223–227 (2003).
Yousef, G. M. et al. Differential expression of Kallikrein gene 5 in cancerous and normal testicular tissues. Urology 60, 714–718 (2002).
Luo, L. Y., Rajpert-De Meyts, E. R., Jung, K. & Diamandis, E. P. Expression of the normal epithelial cell-specific 1 (NES1; KLK10) candidate tumour suppressor gene in normal and malignant testicular tissue. Br. J. Cancer 85, 220–224 (2001).
Bhattacharjee, A. et al. Classification of human lung carcinomas by mRNA expression profiling reveals distinct adenocarcinoma subclasses. Proc. Natl Acad. Sci. USA 98, 13790–13795 (2001).
Iacobuzio-Donahue, C. A. et al. Highly expressed genes in pancreatic ductal adenocarcinomas: a comprehensive characterization and comparison of the transcription profiles obtained from three major technologies. Cancer Res. 63, 8614–8622 (2003).
Yousef, G. M. et al. In-silico analysis of kallikrein gene expression in pancreatic and colon cancers. AntiCancer Res. 24, 43–51 (2004).
Chung, C. H. et al. Molecular classification of head and neck squamous cell carcinomas using patterns of gene expression. Cancer Cell 5, 489–500 (2004).
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).
Denmeade, S. R., Sokoll, L. J., Chan, D. W., Khan, S. R. & Isaacs, J. T. Concentration of enzymatically active prostate-specific antigen (PSA) in the extracellular fluid of primary human prostate cancers and human prostate cancer xenograft models. Prostate 48, 1–6 (2001).
Rajah, R., Valentinis, B. & Cohen, P. Insulin-like growth factor (IGF)-binding protein-3 induces apoptosis and mediates the effects of transforming growth factor-β1 on programmed cell death through a p53- and IGF-independent mechanism. J. Biol. Chem. 272, 12181–12188 (1997).
Cohen, P. et al. Prostate-specific antigen (PSA) is an insulin-like growth factor binding protein-3 protease found in seminal plasma. J. Clin. Endocrinol. Metab. 75, 1046–1053 (1992). One of the first reports to show that kallikreins might be involved in tumour progression by modulating tumour-cell growth in vitro and in vivo through growth factors.
Rehault, S. et al. Insulin-like growth factor binding proteins (IGFBPs) as potential physiological substrates for human kallikreins hK2 and hK3. Eur. J. Biochem. 268, 2960–2968 (2001).
Sutkowski, D. M. et al. Growth regulation of prostatic stromal cells by prostate-specific antigen. J. Natl Cancer Inst. 91, 1663–1669 (1999).
Sun, X. Y., Donald, S. P. & Phang, J. M. Testosterone and prostate specific antigen stimulate generation of reactive oxygen species in prostate cancer cells. Carcinogenesis 22, 1775–1780 (2001).
Frenette, G., Tremblay, R. R., Lazure, C. & Dube, J. Y. Prostatic kallikrein hK2, but not prostate-specific antigen (hK3), activates single-chain urokinase-type plasminogen activator. Int. J. Cancer 71, 897–899 (1997).
Mikolajczyk, S. D., Millar, L. S., Kumar, A. & Saedi, M. S. Prostatic human kallikrein 2 inactivates and complexes with plasminogen activator inhibitor-1. Int. J. Cancer 81, 438–442 (1999).
D'Andrea, M. R., Derian, C. K., Santulli, R. J. & Andrade-Gordon, P. Differential expression of protease-activated receptors-1 and-2 in stromal fibroblasts of normal, benign, and malignant human tissues. Am. J. Pathol. 158, 2031–2041 (2001).
Ohta, T. et al. Protease-activated receptor-2 expression and the role of trypsin in cell proliferation in human pancreatic cancers. Int. J. Oncol. 23, 61–66 (2003).
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).
Yu, H. et al. Prostate-specific antigen is a new favorable prognostic indicator for women with breast cancer. Cancer Res. 55, 2104–2110 (1995).
Derynck, R., Akhurst, R. J. & Balmain, A. TGF-β signaling in tumor suppression and cancer progression. Nature Genet. 29, 117–129 (2001).
Fortier, A. H., Nelson, B. J., Grella, D. K. & Holaday, J. W. Antiangiogenic activity of prostate-specific antigen. J. Natl Cancer Inst. 91, 1635–1640 (1999). The first paper to illustrate that a kallikrein family member might be involved in the regulation of angiogenesis in vivo.
Denmeade, S. R., Litvinov, I., Sokoll, L. J., Lilja, H. & Isaacs, J. T. Prostate-specific antigen (PSA) protein does not affect growth of prostate cancer cells in vitro or prostate cancer xenografts in vivo. Prostate 56, 45–53 (2003).
Hanahan, D. & Folkman, J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86, 353–364 (1996).
Deperthes, D. et al. Potential involvement of kallikrein hK2 in the hydrolysis of the human seminal vesicle proteins after ejaculation. J. Androl. 17, 659–665 (1996).
Lilja, H. A kallikrein-like serine protease in prostatic fluid cleaves the predominant seminal vesicle protein. J. Clin. Invest. 76, 1899–1903 (1985).
Watt, K. W., Lee, P. J., M'Timkulu, T., Chan, W. P. & Loor, R. Human prostate-specific antigen: structural and functional similarity with serine proteases. Proc. Natl Acad. Sci. USA 83, 3166–3170 (1986).
Webber, M. M., Waghray, A. & Bello, D. Prostate-specific antigen, a serine protease, facilitates human prostate cancer cell invasion. Clin. Cancer Res. 1, 1089–1094 (1995).
Bernett, M. J. et al. Crystal structure and biochemical characterization of human kallikrein 6 reveals that a trypsin-like kallikrein is expressed in the central nervous system. J. Biol. Chem. 277, 24562–24570 (2002). Together with references 147 and 148, this paper describes the three-dimensional trypsin-like fold of human kallikreins as determined by X-ray cystallography.
Barrett, A. D., Rawlings, N. D. & Woessner, J. F. (eds) Handbook of Proteolytic Enzymes. 1556–1558 (Elsevier Academic, London, 2004). A comprehensive textbook that categorizes and describes all known proteases.
Tschesche, H., Michaelis, J., Kohnert, U., Fedrowitz, J. & Oberhoff, R. Tissue kallikrein effectively activates latent matrix degrading metalloenzymes. Adv. Exp. Med. Biol. 247A, 545–548 (1989).
Desrivieres, S. et al. Activation of the 92 kDa type IV collagenase by tissue kallikrein. J. Cell Physiol. 157, 587–593 (1993).
Menashi, S. et al. Regulation of 92-kDa gelatinase B activity in the extracellular matrix by tissue kallikrein. Ann. NY Acad. Sci. 732, 466–468 (1994).
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).
Plendl, J. et al. Expression of tissue kallikrein and kinin receptors in angiogenic microvascular endothelial cells. Biol. Chem. 381, 1103–1115 (2000).
Emanueli, C. et al. Local delivery of human tissue kallikrein gene accelerates spontaneous angiogenesis in mouse model of hindlimb ischemia. Circulation 103, 125–132 (2001).
Jin, E. et al. Protease-activated receptor (PAR)-1 and PAR-2 participate in the cell growth of alveolar capillary endothelium in primary lung adenocarcinomas. Cancer 97, 703–713 (2003).
Heidtmann, H. H. et al. Generation of angiostatin-like fragments from plasminogen by prostate-specific antigen. Br. J. Cancer 81, 1269–1273 (1999).
Fortier, A. H. et al. Recombinant prostate specific antigen inhibits angiogenesis in vitro and in vivo. Prostate 56, 212–219 (2003).
Papadopoulos, I., Sivridis, E., Giatromanolaki, A. & Koukourakis, M. I. Tumor angiogenesis is associated with MUC1 overexpression and loss of prostate-specific antigen expression in prostate cancer. Clin. Cancer Res. 7, 1533–1538 (2001).
Hoffman, J. A. et al. Progressive vascular changes in a transgenic mouse model of squamous cell carcinoma. Cancer Cell 4, 383–391 (2003).
Wolf, W. C., Evans, D. M., Chao, L. & Chao, J. A synthetic tissue kallikrein inhibitor suppresses cancer cell invasiveness. Am. J. Pathol. 159, 1797–1805 (2001).
Ishii, K. et al. Evidence that the prostate-specific antigen (PSA)/Zn2+ axis may play a role in human prostate cancer cell invasion. Cancer Lett. 207, 79–87 (2004).
Henrikson, K. P., Salazar, S. L., Fenton, J. W. & Pentecost, B. T. Role of thrombin receptor in breast cancer invasiveness. Br. J. Cancer 79, 401–406 (1999).
Kamath, L., Meydani, A., Foss, F. & Kuliopulos, A. Signaling from protease-activated receptor-1 inhibits migration and invasion of breast cancer cells. Cancer Res. 61, 5933–5940 (2001).
Romanov, V. I., Whyard, T., Adler, H. L., Waltzer, W. C. & Zucker, S. Prostate cancer cell adhesion to bone marrow endothelium: the role of prostate-specific antigen. Cancer Res. 64, 2083–2089 (2004).
Yonou, H. et al. Prostate-specific antigen induces osteoplastic changes by an autonomous mechanism. Biochem. Biophys. Res. Commun. 289, 1082–1087 (2001).
Iwamura, M., Hellman, J., Cockett, A. T., Lilja, H. & Gershagen, S. Alteration of the hormonal bioactivity of parathyroid hormone-related protein (PTHrP) as a result of limited proteolysis by prostate-specific antigen. Urology 48, 317–325 (1996).
Cramer, S. D., Chen, Z. & Peehl, D. M. Prostate specific antigen cleaves parathyroid hormone-related protein in the PTH-like domain: inactivation of PTHrP-stimulated cAMP accumulation in mouse osteoblasts. J. Urol. 156, 526–531 (1996).
Ni, X. et al. Characterisation of human kallikrein 6/protease M expression in ovarian cancer. Br. J. Cancer 91, 725–731 (2004).
Majumdar, S. & Diamandis, E. P. The promoter and the enhancer region of the KLK 3 (prostate specific antigen) gene is frequently mutated in breast tumours and in breast carcinoma cell lines. Br. J. Cancer 79, 1594–1602 (1999).
Tsuyuki, D., Grass, L. & Diamandis, E. P. Frequent detection of mutations in the 5′ flanking region of the prostate-specific antigen gene in female breast cancer. Eur. J. Cancer 33, 1851–1854 (1997).
Bharaj, B. et al. Breast cancer prognostic significance of a single nucleotide polymorphism in the proximal androgen response element of the prostate specific antigen gene promoter. Breast Cancer Res. Treat. 61, 111–119 (2000).
Xue, W. et al. Susceptibility to prostate cancer: interaction between genotypes at the androgen receptor and prostate-specific antigen loci. Cancer Res. 60, 839–841 (2000).
Chiang, C. H., Chen, K. K., Chang, L. S. & Hong, C. J. The impact of polymorphism on prostate specific antigen gene on the risk, tumor volume and pathological stage of prostate cancer. J. Urol. 171, 1529–1532 (2004).
Wang, L. Z. et al. Polymorphisms in prostate-specific antigen (PSA) gene, risk of prostate cancer, and serum PSA levels in Japanese population. Cancer Lett. 202, 53–59 (2003).
Cramer, S. D. et al. Association between genetic polymorphisms in the prostate-specific antigen gene promoter and serum prostate-specific antigen levels. J. Natl. Cancer Inst. 95, 1044–1053 (2003).
Bharaj, B. B., Luo, L. Y., Jung, K., Stephan, C. & Diamandis, E. P. Identification of single nucleotide polymorphisms in the human kallikrein 10 (KLK10) gene and their association with prostate, breast, testicular, and ovarian cancers. Prostate 51, 35–41 (2002).
Li, B. et al. CpG methylation as a basis for breast tumor-specific loss of NES1/kallikrein 10 expression. Cancer Res. 61, 8014–8021 (2001). The first study to propose an epigenetic mechanism for dysregulated kallikrein expression during tumorigenesis.
Magklara, A., Brown, T. J. & Diamandis, E. P. Characterization of androgen receptor and nuclear receptor co-regulator expression in human breast cancer cell lines exhibiting differential regulation of kallikreins 2 and 3. Int. J. Cancer 100, 507–514 (2002).
Stamey, T. A. et al. Prostate-specific antigen as a serum marker for adenocarcinoma of the prostate. N. Engl. J. Med. 317, 909–916 (1987).
Stenman, U. H. New ultrasensitive assays facilitate studies on the role of human glandular kallikrein (hK2) as a marker for prostatic disease. Clin. Chem. 45, 753–754 (1999).
Nakamura, T. et al. The usefulness of serum human kallikrein 11 for discriminating between prostate cancer and benign prostatic hyperplasia. Cancer Res. 63, 6543–6546 (2003).
Diamandis, E. P. et al. Human kallikrein 6 (hK6): a new potential serum biomarker for diagnosis and prognosis of ovarian carcinoma. J. Clin. Oncol. 21, 1035–1043 (2003).
Cloutier, S. M. et al. Development of recombinant inhibitors specific to human kallikrein 2 using phage-display selected substrates. Eur. J. Biochem. 271, 607–613 (2004). This paper describes a novel approach for designing kallikrein-specific inhibitors, which might be useful in anticancer therapies.
Denmeade, S. R. et al. Specific and efficient peptide substrates for assaying the proteolytic activity of prostate-specific antigen. Cancer Res. 57, 4924–4930 (1997).
Denmeade, S. R. et al. Enzymatic activation of a doxorubicin-peptide prodrug by prostate-specific antigen. Cancer Res. 58, 2537–2540 (1998).
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).
DeFeo-Jones, D. et al. A prostate-specific antigen (PSA)-activated vinblastine prodrug selectively kills PSA-secreting cells in vivo. Mol. Cancer Ther. 1, 451–459 (2002).
Denmeade, S. R. et al. Prostate-specific antigen-activated thapsigargin prodrug as targeted therapy for prostate cancer. J. Natl. Cancer Inst. 95, 990–1000 (2003).
Latham, J. P., Searle, P. F., Mautner, V. & James, N. D. Prostate-specific antigen promoter/enhancer driven gene therapy for prostate cancer: construction and testing of a tissue-specific adenovirus vector. Cancer Res. 60, 334–341 (2000).
Suzuki, S. et al. Liposome-mediated gene therapy using HSV-TK/ganciclovir under the control of human PSA promoter in prostate cancer cells. Urol. Int. 67, 216–223 (2001).
Eder, J. P. et al. A phase I trial of a recombinant vaccinia virus expressing prostate-specific antigen in advanced prostate cancer. Clin. Cancer Res. 6, 1632–1638 (2000).
Heiser, A. et al. Human dendritic cells transfected with renal tumor RNA stimulate polyclonal T-cell responses against antigens expressed by primary and metastatic tumors. Cancer Res. 61, 3388–3393 (2001).
Barrou, B. et al. Vaccination of prostatectomized prostate cancer patients in biochemical relapse, with autologous dendritic cells pulsed with recombinant human PSA. Cancer Immunol. Immunother. 53, 453–460 (2004).
Diamandis, E. P., Yousef, G. M., Luo, L. Y., Magklara, A. & Obiezu, C. V. The new human kallikrein gene family: implications in carcinogenesis. Trends Endocrinol. Metab. 11, 54–60 (2000).
Yousef, G. M. & Diamandis, E. P. The new human tissue kallikrein gene family: structure, function, and association to disease. Endocr. Rev. 22, 184–204 (2001). A comprehensive review on the genomic characteristics and clinical usefulness of the extended human kallikrein family.
Clements, J. A., Willemsen, N. M., Myers, S. A. & Dong, Y. The tissue kallikrein family of serine proteases: functional roles in human disease and potential as clinical biomarkers. Crit. Rev. Clin. Lab. Sci. 41, 265–312 (2004).
Henttu, P. & Vihko, P. cDNA coding for the entire human prostate specific antigen shows high homologies to the human tissue kallikrein genes. Biochem. Biophys. Res. Commun. 160, 903–910 (1989).
Katz, B. A., Liu, B., Barnes, M. & Springman, E. B. Crystal structure of recombinant human tissue kallikrein at 2.0 A resolution. Protein Sci. 7, 875–885 (1998).
Gomis-Ruth, F. X. et al. The structure of human prokallikrein 6 reveals a novel activation mechanism for the kallikrein family. J. Biol. Chem. 277, 27273–27281 (2002).
Schechter, I. & Berger, A. On the size of the active site in proteases. I. Papain. Biochem. Biophys. Res. Commun. 27, 157–162 (1967).
Brillard-Bourdet, M., Moreau, T. & Gauthier, F. Substrate specificity of tissue kallikreins: importance of an extended interaction site. Biochim. Biophys. Acta 1246, 47–52 (1995).
Oka, T. et al. Role of loop structures of neuropsin in the activity of serine protease and regulated secretion. J. Biol. Chem. 277, 14724–14730 (2002).
Modrek, B. & Lee, C. A genomic view of alternative splicing. Nature Genet. 30, 13–19 (2002).
Johnson, J. M. et al. Genome-wide survey of human alternative pre-mRNA splicing with exon junction microarrays. Science 302, 2141–2144 (2003). One of the latest studies to investigate the frequency of alternative pre-mRNA splicing within the human genome.
Xi, Z. et al. Kallikrein 4 is a predominantly nuclear protein and is overexpressed in prostate cancer. Cancer Res. 64, 2365–2370 (2004).
Dong, Y., Kaushal, A., Brattsand, M., Nicklin, J. & Clements, J. A. Differential Splicing of KLK5 and KLK7 in epithelial ovarian cancer produces novel variants with potential as cancer biomarkers. Clin. Cancer Res. 9, 1710–1720 (2003).
Kurlender, L. et al. Differential expression of a human kallikrein 5 (KLK5) splice variant in ovarian and prostate cancer. Tumor Biol. 25, 149–156 (2004).
Yousef, G. M. et al. The kallikrein gene 5 (KLK5) splice variant 2 is a new biomarker for breast and ovarian cancer. Tumor Biol. (in the press).
Mitsui, S. et al. A novel isoform of a kallikrein-like protease, TLSP/hippostasin, (PRSS20), is expressed in the human brain and prostate. Biochem. Biophys. Res. Commun. 272, 205–211 (2000).
Nakamura, T. et al. Quantitative analysis of hippostasin/KLK11 gene expression in cancerous and noncancerous prostatic tissues. Urology 61, 1042–1046 (2003).
Chang, A., Yousef, G. M., Jung, K., Meyts, E. R. & Diamanids, E. P. Identification and molecular characterization of five novel kallikrein gene 13 (KLK13;KLK-L4) splice variants: differential expression in human testis and testicular cancer. AntiCancer Res. 21, 3147–3152 (2001).
Kumar, A., Mikolajczyk, S. D., Goel, A. S., Millar, L. S. & Saedi, M. S. Expression of pro form of prostate-specific antigen by mammalian cells and its conversion to mature, active form by human kallikrein 2. Cancer Res. 57, 3111–3114 (1997).
Rehbock, J., Buchinger, P., Hermann, A. & Figueroa, C. Identification of immunoreactive tissue kallikrein in human ductal breast carcinomas. J. Cancer Res. Clin. Oncol. 121, 64–68 (1995).
Hermann, A., Buchinger, P. & Rehbock, J. Visualization of tissue kallikrein in human breast carcinoma by two-dimensional western blotting and immunohistochemistry. Biol. Chem. Hoppe Seyler 376, 365–370 (1995).
Howarth, D. J., Aronson, I. B. & Diamandis, E. P. Immunohistochemical localization of prostate-specific antigen in benign and malignant breast tissues. Br. J. Cancer 75, 1646–1651 (1997).
Yu, H. & Diamandis, E. P. Measurement of serum prostate specific antigen levels in women and in prostatectomized men with an ultrasensitive immunoassay technique. J. Urol. 153, 1004–1008 (1995).
Foekens, J. A. et al. Expression of prostate-specific antigen (PSA) correlates with poor response to tamoxifen therapy in recurrent breast cancer. Br. J. Cancer 79, 888–894 (1999).
Yousef, G. M. et al. Human kallikrein gene 5 (KLK5) expression by quantitative PCR: an independent indicator of poor prognosis in breast cancer. Clin. Chem. 48, 1241–1250 (2002).
Talieri, M., Diamandis, E. P., Gourgiotis, D., Mathioudaki, K. & Scorilas, A. Expression analysis of the human kallikrein 7 (KLK7) in breast tumors: a new potential biomarker for prognosis of breast carcinoma. Thromb. Haemost. 91, 180–186 (2004).
Yousef, G. et al. The prognostic value of the human kallikrein gene 9 (KLK9) in breast cancer. Breast Cancer Res. Treat. 78, 149–158 (2003).
Luo, L. Y., Diamandis, E. P., Look, M. P., Soosaipillai, A. P. & Foekens, J. A. Higher expression of human kallikrein 10 in breast cancer tissue predicts tamoxifen resistance. Br. J. Cancer 86, 1790–1796 (2002).
Chang, A. et al. Human kallikrein gene 13 (KLK13) expression by quantitative RT-PCR: an independent indicator of favourable prognosis in breast cancer. Br. J. Cancer 86, 1457–1464 (2002).
Yousef, G. M. et al. Quantitative analysis of human kallikrein gene 14 expression in breast tumours indicates association with poor prognosis. Br. J. Cancer 87, 1287–1293 (2002).
Yousef, G. M. et al. The androgen-regulated gene human kallikrein 15 (KLK15) is an independent and favourable prognostic marker for breast cancer. Br. J. Cancer 87, 1294–1300 (2002).
Cane, S. et al. The novel serine protease tumor-associated differentially expressed gene-14 (KLK8/Neuropsin/Ovasin) is highly overexpressed in cervical cancer. Am. J. Obstet. Gynecol. 190, 60–66 (2004).
Hibbs, K. et al. Differential gene expression in ovarian carcinoma: identification of potential biomarkers. Am. J. Pathol. 165, 397–414 (2004).
Diamandis, E. P. et al. Immunofluorometric quantification of human kallikrein 5 expression in ovarian cancer cytosols and its association with unfavorable patient prognosis. Tumour. Biol. 24, 299–309 (2003).
Lu, K. H. et al. Selection of potential markers for epithelial ovarian cancer with gene expression arrays and recursive descent partition analysis. Clin. Cancer Res. 10, 3291–3300 (2004).
Hoffman, B. R. et al. Immunofluorometric quantitation and histochemical localisation of kallikrein 6 protein in ovarian cancer tissue: a new independent unfavourable prognostic biomarker. Br. J. Cancer 87, 763–771 (2002).
Kyriakopoulou, L. G. et al. Prognostic value of quantitatively assessed KLK7 expression in ovarian cancer. Clin. Biochem. 36, 135–143 (2003).
Shigemasa, K. et al. Human kallikrein 8 (hK8/TADG-14) expression is associated with an early clinical stage and favorable prognosis in ovarian cancer. Oncol. Rep. 11, 1153–1159 (2004).
Yousef, G. M. et al. Quantitative expression of the human kallikrein gene 9 (KLK9) in ovarian cancer: a new independent and favorable prognostic marker. Cancer Res. 61, 7811–7818 (2001).
Shigemasa, K., Gu, L., Tanimoto, H., O'Brien, T. J. & Ohama, K. Human kallikrein gene 11 (KLK11) mRNA overexpression is associated with poor prognosis in patients with epithelial ovarian cancer. Clin. Cancer Res. 10, 2766–2770 (2004).
Borgono, C. A. et al. Favorable prognostic value of tissue human kallikrein 11 (hK11) in patients with ovarian carcinoma. Int. J. Cancer 106, 605–610 (2003).
Scorilas, A. et al. Human kallikrein 13 protein in ovarian cancer cytosols: a new favorable prognostic marker. J. Clin. Oncol. 22, 678–685 (2004).
Yousef, G. M. et al. Steroid hormone regulation and prognostic value of the human kallikrein gene 14 in ovarian cancer. Am. J. Clin. Pathol. 119, 346–355 (2003).
Darson, M. F. et al. Human glandular kallikrein 2 (hK2) expression in prostatic intraepithelial neoplasia and adenocarcinoma: a novel prostate cancer marker. Urology 49, 857–862 (1997).
Nelson, P. S. et al. Molecular cloning and characterization of prostase, an androgen-regulated serine protease with prostate-restricted expression. Proc. Natl Acad. Sci. USA 96, 3114–3119 (1999). This is one of several papers to report the cloning of a novel kallikrein gene ( KLK4 ) in addition to KLK1, KLK2 and KLK3 , and one of the first indications of an extended human kallikrein gene family.
Day, C. H. et al. Characterization of KLK4 expression and detection of KLK4-specific antibody in prostate cancer patient sera. Oncogene 21, 7114–7120 (2002).
Obiezu, C. V. et al. Detection of human kallikrein 4 in healthy and cancerous prostatic tissues by immunofluorometry and immunohistochemistry. Clin. Chem. 48, 1232–1240 (2002).
Hooper, J. D. et al. Identification and characterization of klk14, a novel kallikrein serine protease gene located on human chromosome 19q13.4 and expressed in prostate and skeletal muscle. Genomics 73, 117–122 (2001).
Yousef, G. M. et al. Differential expression of the human kallikrein gene 14 (KLK14) in normal and cancerous prostatic tissues. Prostate 56, 287–292 (2003).
Yousef, G. M., Scorilas, A., Jung, K., Ashworth, L. K. & Diamandis, E. P. Molecular cloning of the human kallikrein 15 gene (KLK15). Up-regulation in prostate cancer. J. Biol. Chem. 276, 53–61 (2001).
Stephan, C. et al. Quantitative analysis of kallikrein 15 gene expression in prostate tissue. J. Urol. 169, 361–364 (2003).
Acknowledgements
The authors would like to thank past and present members of the Advanced Center for Detection of Cancer laboratory for their contributions to the kallikrein literature and for valuable discussions.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Related links
Related links
DATABASES
National Cancer Institute
Entrez Gene
FURTHER INFORMATION
Advanced Center for Detection of Cancer
Glossary
- SERINE PROTEASES
-
One of the four mechanistic classes of proteases — enzymes that catalyse the hydrolysis of peptide bonds. They are characterized by a catalytic mechanism by which the hydroxyl group of the active-site serine residue acts as the nucleophile that attacks the peptide bond.
- ORTHOLOGUE
-
Homologous genes in different species that are derived from a common ancestral gene following speciation. Orthologues usually retain the same function in the course of evolution.
- LOCUS CONTROL REGIONS
-
A class of cis-acting regulatory elements that regulate chromatin and the expression of linked genes over distances as long as 100 kb or more in a tissue- and copy-number-specific manner in a wide spectrum of mammalian gene families.
- SERPIN
-
A superfamily of serine-protease inhibitors. Most serpins are inhibitory and share a unique mechanism of inhibition in which they undergo a profound conformational change to trap their target protease in an irreversible complex, but differ in their specificity towards different serine proteases.
- ALTERNATIVE PRE-mRNA SPLICING
-
The process through which different combinations of exons within a single pre-mRNA are joined together to produce two or more distinct mature mRNAs. This is the most common mechanism for producing functionally diverse proteins from a single gene.
- ELISA
-
(Enzyme-linked immunosorbent assay.) A serological assay in which bound antigen is detected by antibodies linked to an enzyme, the activity of which can be assayed for the quantitative determination of the antigen–antibody interaction.
- GENETIC POLYMORPHISMS
-
Normal variant forms of a particular gene (that is, alleles) that are present in the population at a frequency of 1% or greater. Single-nucleotide polymorphisms are variations of a single base-pair position within a DNA sequence and are the most common form of genetic variation in human DNA.
- LINKAGE DISEQUILIBRIUM
-
When alleles at two or more different genetic loci occur in gametes more frequently in the population than expected given the known allele frequencies and recombination fraction between the two loci. This indicates that the loci are tightly linked; that is, sufficiently close together on the same chromosome to be co-inherited 50% of the time.
- CpG ISLANDS
-
Short stretches of DNA with an increased density of CpG dinucleotides relative to the bulk genome. Unmethylated CpG islands are positioned at the 5′ ends of many human genes. Aberrant methylation of CpG islands can cause gene silencing and contributes to carcinogenesis.
- SENSITIVITY
-
Represents the number of patients who are positive for a test result (true positives) divided by the total number of patients with the disease (true positive plus false negatives).
- SPECIFICITY
-
Represents the number of healthy individuals with a negative result (true negatives) divided by the total number of healthy individuals (true negative plus false positives).
Rights and permissions
About this article
Cite this article
Borgoño, C., Diamandis, E. The emerging roles of human tissue kallikreins in cancer. Nat Rev Cancer 4, 876–890 (2004). https://doi.org/10.1038/nrc1474
Issue Date:
DOI: https://doi.org/10.1038/nrc1474
This article is cited by
-
The identification of genes associated T-cell exhaustion and construction of prognostic signature to predict immunotherapy response in lung adenocarcinoma
Scientific Reports (2023)
-
p130Cas is required for androgen-dependent postnatal development regulation of submandibular glands
Scientific Reports (2023)
-
Unlocking the mystery associated with infertility and prostate cancer: an update
Medical Oncology (2023)
-
An insilico study of KLK-14 protein and its inhibition with curcumin and its derivatives
Chemical Papers (2022)
-
Biomarker implication of kallikrein-related peptidases as prognostic tissue substrates of poor survival in colorectal cancer
Cancer Cell International (2020)