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The emerging roles of human tissue kallikreins in cancer

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.

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Figure 1: Kallikrein locus, gene and protein characteristics.
Figure 2: Putative roles of human tissue kallikreins in tumour development.

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References

  1. Liotta, L. A. & Kohn, E. C. The microenvironment of the tumour–host interface. Nature 411, 375–379 (2001).

    Article  CAS  PubMed  Google Scholar 

  2. 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.

    Article  CAS  PubMed  Google Scholar 

  3. Werb, Z. ECM and cell surface proteolysis: regulating cellular ecology. Cell 91, 439–442 (1997).

    Article  CAS  PubMed  Google Scholar 

  4. 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).

    CAS  PubMed  Google Scholar 

  5. 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).

    Article  CAS  PubMed  Google Scholar 

  6. 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.

    Article  CAS  PubMed  Google Scholar 

  7. 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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  9. 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).

    Article  CAS  PubMed  Google Scholar 

  10. 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).

    Article  CAS  PubMed  Google Scholar 

  11. 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).

    Article  CAS  PubMed  Google Scholar 

  12. 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).

    Article  CAS  PubMed  Google Scholar 

  13. Sotiropoulou, G. et al. Emerging interest in the kallikrein gene family for understanding and diagnosing cancer. Oncol. Res. 13, 381–391 (2003).

    Article  PubMed  Google Scholar 

  14. 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).

    Article  CAS  PubMed  Google Scholar 

  15. 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).

    Article  CAS  PubMed  Google Scholar 

  16. 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).

    Article  CAS  PubMed  Google Scholar 

  17. 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.

    Article  CAS  PubMed  Google Scholar 

  18. 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).

    Article  CAS  PubMed  Google Scholar 

  19. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 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).

    Article  CAS  PubMed  Google Scholar 

  21. 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).

    Article  CAS  PubMed  Google Scholar 

  22. Komatsu, N. et al. Expression and localization of tissue kallikrein mRNAs in human epidermis and appendages. J. Invest. Dermatol. 121, 542–549 (2003).

    Article  CAS  PubMed  Google Scholar 

  23. 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.

    Article  CAS  PubMed  Google Scholar 

  24. Bayes, A. et al. Human kallikrein 6 activity is regulated via an autoproteolytic mechanism of activation/inactivation. Biol. Chem. 385, 517–524 (2004).

    Article  CAS  PubMed  Google Scholar 

  25. 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).

    Article  CAS  PubMed  Google Scholar 

  26. 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).

    Article  CAS  PubMed  Google Scholar 

  27. 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).

    Article  CAS  PubMed  Google Scholar 

  28. 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.

    Article  CAS  PubMed  Google Scholar 

  29. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. 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).

    Article  CAS  PubMed  Google Scholar 

  31. Coombs, G. S. et al. Substrate specificity of prostate-specific antigen (PSA). Chem. Biol. 5, 475–488 (1998).

    Article  CAS  PubMed  Google Scholar 

  32. 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).

    CAS  PubMed  Google Scholar 

  33. Dong, Y. et al. Human kallikrein 4 (KLK4) is highly expressed in serous ovarian carcinomas. Clin. Cancer Res. 7, 2363–2371 (2001).

    CAS  PubMed  Google Scholar 

  34. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Yousef, G. M. et al. Human kallikrein 5: a potential novel serum biomarker for breast and ovarian cancer. Cancer Res. 63, 3958–3965 (2003).

    CAS  PubMed  Google Scholar 

  36. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. 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).

    Article  CAS  PubMed  Google Scholar 

  38. 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.

    Article  CAS  PubMed  Google Scholar 

  39. 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).

    Article  CAS  PubMed  Google Scholar 

  40. 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).

    CAS  PubMed  Google Scholar 

  41. 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).

    CAS  PubMed  Google Scholar 

  42. Kishi, T. et al. Human kallikrein 8, a novel biomarker for ovarian carcinoma. Cancer Res. 63, 2771–2774 (2003).

    CAS  PubMed  Google Scholar 

  43. Luo, L. Y. et al. Prognostic value of human kallikrein 10 expression in epithelial ovarian carcinoma. Clin. Cancer Res. 7, 2372–2379 (2001).

    CAS  PubMed  Google Scholar 

  44. 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).

    Article  CAS  PubMed  Google Scholar 

  45. 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).

    CAS  PubMed  Google Scholar 

  46. Diamandis, E. P. et al. Human kallikrein 11: a new biomarker of prostate and ovarian carcinoma. Cancer Res. 62, 295–300 (2002).

    CAS  PubMed  Google Scholar 

  47. 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).

    Article  CAS  PubMed  Google Scholar 

  48. Borgono, C. A. et al. Human kallikrein 14: a new potential biomarker for ovarian and breast cancer. Cancer Res. 63, 9032–9041 (2003).

    CAS  PubMed  Google Scholar 

  49. Yousef, G. M. et al. Prognostic value of the human kallikrein gene 15 expression in ovarian cancer. J. Clin. Oncol. 21, 3119–3126 (2003).

    Article  CAS  PubMed  Google Scholar 

  50. Yousef, G. M. et al. Parallel overexpression of seven kallikrein genes in ovarian cancer. Cancer Res. 63, 2223–2227 (2003).

    CAS  PubMed  Google Scholar 

  51. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Adib, T. R. et al. Predicting biomarkers for ovarian cancer using gene-expression microarrays. Br. J. Cancer 90, 686–692 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. 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).

    Article  CAS  PubMed  Google Scholar 

  54. 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).

    CAS  PubMed  Google Scholar 

  55. 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).

    CAS  PubMed  Google Scholar 

  56. 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 

  57. 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).

    CAS  PubMed  Google Scholar 

  58. 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).

    Article  CAS  PubMed  Google Scholar 

  59. 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).

    Article  CAS  PubMed  Google Scholar 

  60. 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).

    CAS  PubMed  Google Scholar 

  61. Yousef, G. M. et al. Kallikrein gene downregulation in breast cancer. Br. J. Cancer 90, 167–172 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. 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).

    Article  CAS  PubMed  Google Scholar 

  63. 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).

    Article  CAS  PubMed  Google Scholar 

  64. 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).

    Article  CAS  PubMed  Google Scholar 

  65. 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).

    Article  CAS  PubMed  Google Scholar 

  66. Yousef, G. M. et al. Down-regulation of the human kallikrein gene 5 (KLK5) in prostate cancer tissues. Prostate 51, 126–132 (2002).

    Article  CAS  PubMed  Google Scholar 

  67. 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).

    Article  Google Scholar 

  68. 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).

    Article  CAS  PubMed  Google Scholar 

  69. Yousef, G. M. et al. Differential expression of Kallikrein gene 5 in cancerous and normal testicular tissues. Urology 60, 714–718 (2002).

    Article  PubMed  Google Scholar 

  70. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. 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).

    CAS  PubMed  Google Scholar 

  73. Yousef, G. M. et al. In-silico analysis of kallikrein gene expression in pancreatic and colon cancers. AntiCancer Res. 24, 43–51 (2004).

    CAS  PubMed  Google Scholar 

  74. 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).

    Article  CAS  PubMed  Google Scholar 

  75. 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 

  76. 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).

    Article  CAS  PubMed  Google Scholar 

  77. 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).

    Article  CAS  PubMed  Google Scholar 

  78. 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.

    CAS  PubMed  Google Scholar 

  79. 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).

    Article  CAS  PubMed  Google Scholar 

  80. Sutkowski, D. M. et al. Growth regulation of prostatic stromal cells by prostate-specific antigen. J. Natl Cancer Inst. 91, 1663–1669 (1999).

    Article  CAS  PubMed  Google Scholar 

  81. 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).

    Article  CAS  PubMed  Google Scholar 

  82. 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).

    Article  CAS  PubMed  Google Scholar 

  83. 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).

    Article  CAS  PubMed  Google Scholar 

  84. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. 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).

    CAS  PubMed  Google Scholar 

  86. 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 

  87. Yu, H. et al. Prostate-specific antigen is a new favorable prognostic indicator for women with breast cancer. Cancer Res. 55, 2104–2110 (1995).

    CAS  PubMed  Google Scholar 

  88. Derynck, R., Akhurst, R. J. & Balmain, A. TGF-β signaling in tumor suppression and cancer progression. Nature Genet. 29, 117–129 (2001).

    Article  CAS  PubMed  Google Scholar 

  89. 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.

    Article  CAS  PubMed  Google Scholar 

  90. 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).

    Article  CAS  PubMed  Google Scholar 

  91. Hanahan, D. & Folkman, J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86, 353–364 (1996).

    Article  CAS  PubMed  Google Scholar 

  92. 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).

    CAS  PubMed  Google Scholar 

  93. Lilja, H. A kallikrein-like serine protease in prostatic fluid cleaves the predominant seminal vesicle protein. J. Clin. Invest. 76, 1899–1903 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. 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).

    CAS  PubMed  Google Scholar 

  96. 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.

    Article  CAS  PubMed  Google Scholar 

  97. 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.

    Google Scholar 

  98. 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).

    Article  CAS  PubMed  Google Scholar 

  99. Desrivieres, S. et al. Activation of the 92 kDa type IV collagenase by tissue kallikrein. J. Cell Physiol. 157, 587–593 (1993).

    Article  CAS  PubMed  Google Scholar 

  100. 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).

    Article  CAS  PubMed  Google Scholar 

  101. 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 

  102. Plendl, J. et al. Expression of tissue kallikrein and kinin receptors in angiogenic microvascular endothelial cells. Biol. Chem. 381, 1103–1115 (2000).

    Article  CAS  PubMed  Google Scholar 

  103. 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).

    Article  CAS  PubMed  Google Scholar 

  104. 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).

    Article  CAS  PubMed  Google Scholar 

  105. Heidtmann, H. H. et al. Generation of angiostatin-like fragments from plasminogen by prostate-specific antigen. Br. J. Cancer 81, 1269–1273 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. 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 

  107. 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).

    CAS  PubMed  Google Scholar 

  108. Hoffman, J. A. et al. Progressive vascular changes in a transgenic mouse model of squamous cell carcinoma. Cancer Cell 4, 383–391 (2003).

    Article  CAS  PubMed  Google Scholar 

  109. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. 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).

    Article  CAS  PubMed  Google Scholar 

  111. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. 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).

    CAS  PubMed  Google Scholar 

  113. 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).

    Article  CAS  PubMed  Google Scholar 

  114. Yonou, H. et al. Prostate-specific antigen induces osteoplastic changes by an autonomous mechanism. Biochem. Biophys. Res. Commun. 289, 1082–1087 (2001).

    Article  CAS  PubMed  Google Scholar 

  115. 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).

    Article  CAS  PubMed  Google Scholar 

  116. 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).

    Article  CAS  PubMed  Google Scholar 

  117. Ni, X. et al. Characterisation of human kallikrein 6/protease M expression in ovarian cancer. Br. J. Cancer 91, 725–731 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. 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).

    Article  CAS  PubMed  Google Scholar 

  120. 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).

    Article  CAS  PubMed  Google Scholar 

  121. 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).

    CAS  PubMed  Google Scholar 

  122. 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).

    Article  CAS  PubMed  Google Scholar 

  123. 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).

    Article  CAS  PubMed  Google Scholar 

  124. 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).

    Article  CAS  PubMed  Google Scholar 

  125. 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).

    Article  CAS  PubMed  Google Scholar 

  126. 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.

    CAS  PubMed  Google Scholar 

  127. 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).

    Article  CAS  PubMed  Google Scholar 

  128. 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).

    Article  CAS  PubMed  Google Scholar 

  129. 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).

    Article  CAS  PubMed  Google Scholar 

  130. 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).

    CAS  PubMed  Google Scholar 

  131. 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).

    Article  CAS  PubMed  Google Scholar 

  132. 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.

    Article  CAS  PubMed  Google Scholar 

  133. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Denmeade, S. R. et al. Enzymatic activation of a doxorubicin-peptide prodrug by prostate-specific antigen. Cancer Res. 58, 2537–2540 (1998).

    CAS  PubMed  Google Scholar 

  135. 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 

  136. 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).

    CAS  PubMed  Google Scholar 

  137. 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).

    Article  CAS  PubMed  Google Scholar 

  138. 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).

    CAS  PubMed  Google Scholar 

  139. 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).

    Article  CAS  PubMed  Google Scholar 

  140. 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).

    CAS  PubMed  Google Scholar 

  141. 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).

    CAS  PubMed  Google Scholar 

  142. 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).

    Article  PubMed  Google Scholar 

  143. 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).

    Article  CAS  PubMed  Google Scholar 

  144. 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.

    CAS  PubMed  Google Scholar 

  145. 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).

    Article  CAS  PubMed  Google Scholar 

  146. 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).

    Article  CAS  PubMed  Google Scholar 

  147. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. 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).

    Article  CAS  PubMed  Google Scholar 

  149. Schechter, I. & Berger, A. On the size of the active site in proteases. I. Papain. Biochem. Biophys. Res. Commun. 27, 157–162 (1967).

    Article  CAS  PubMed  Google Scholar 

  150. 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).

    Article  PubMed  Google Scholar 

  151. 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).

    Article  CAS  PubMed  Google Scholar 

  152. Modrek, B. & Lee, C. A genomic view of alternative splicing. Nature Genet. 30, 13–19 (2002).

    Article  CAS  PubMed  Google Scholar 

  153. 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.

    Article  CAS  PubMed  Google Scholar 

  154. Xi, Z. et al. Kallikrein 4 is a predominantly nuclear protein and is overexpressed in prostate cancer. Cancer Res. 64, 2365–2370 (2004).

    Article  CAS  PubMed  Google Scholar 

  155. 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).

    CAS  PubMed  Google Scholar 

  156. 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).

    Article  CAS  Google Scholar 

  157. 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).

  158. 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).

    Article  CAS  PubMed  Google Scholar 

  159. Nakamura, T. et al. Quantitative analysis of hippostasin/KLK11 gene expression in cancerous and noncancerous prostatic tissues. Urology 61, 1042–1046 (2003).

    Article  PubMed  Google Scholar 

  160. 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).

    CAS  PubMed  Google Scholar 

  161. 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).

    CAS  PubMed  Google Scholar 

  162. 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).

    Article  CAS  PubMed  Google Scholar 

  163. 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).

    Article  CAS  PubMed  Google Scholar 

  164. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. 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).

    Article  CAS  PubMed  Google Scholar 

  166. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. 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).

    Article  CAS  PubMed  Google Scholar 

  168. 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).

    Article  CAS  PubMed  Google Scholar 

  169. 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).

    Article  CAS  PubMed  Google Scholar 

  170. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. 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).

    Article  CAS  PubMed  Google Scholar 

  175. Hibbs, K. et al. Differential gene expression in ovarian carcinoma: identification of potential biomarkers. Am. J. Pathol. 165, 397–414 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. 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).

    Article  CAS  PubMed  Google Scholar 

  177. 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).

    Article  CAS  PubMed  Google Scholar 

  178. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Kyriakopoulou, L. G. et al. Prognostic value of quantitatively assessed KLK7 expression in ovarian cancer. Clin. Biochem. 36, 135–143 (2003).

    Article  CAS  PubMed  Google Scholar 

  180. 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).

    CAS  PubMed  Google Scholar 

  181. 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).

    CAS  PubMed  Google Scholar 

  182. 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).

    Article  CAS  PubMed  Google Scholar 

  183. 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).

    Article  CAS  PubMed  Google Scholar 

  184. Scorilas, A. et al. Human kallikrein 13 protein in ovarian cancer cytosols: a new favorable prognostic marker. J. Clin. Oncol. 22, 678–685 (2004).

    Article  CAS  PubMed  Google Scholar 

  185. 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).

    Article  CAS  PubMed  Google Scholar 

  186. 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).

    Article  CAS  PubMed  Google Scholar 

  187. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. 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).

    Article  CAS  PubMed  Google Scholar 

  189. 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).

    Article  CAS  PubMed  Google Scholar 

  190. 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).

    Article  CAS  PubMed  Google Scholar 

  191. 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).

    Article  CAS  PubMed  Google Scholar 

  192. 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).

    Article  CAS  PubMed  Google Scholar 

  193. Stephan, C. et al. Quantitative analysis of kallikrein 15 gene expression in prostate tissue. J. Urol. 169, 361–364 (2003).

    Article  CAS  PubMed  Google Scholar 

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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.

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Correspondence to Eleftherios P. Diamandis.

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DATABASES

National Cancer Institute

acute lymphoblastic leukaemia

breast cancer

head and neck cancer

lung cancer

ovarian cancer

pancreatic cancer

prostate cancer

testicular cancer

Entrez Gene

hK3

hK4

hK7

hK13

hK15

IGF1

IGF1R

IGF2

IGFBP2

IGFBP3

IGFBP4

IGFBP5

KLK1

KLK2

KLK5

KLK6

KLK8

KLK10

KLK11

KLK14

plasminogen

SRC1

uPA

uPAR

FURTHER INFORMATION

Advanced Center for Detection of Cancer

Cancer Degradome Project

Human Gene Nomenclature Committee

MEROPS peptidase database

Serine protease home page

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).

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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

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