Clinical utility of kallikrein-related peptidases (KLK) in urogenital malignancies

Summary

Kallikrein-related peptidases (KLK), which represent a major tissue-associated proteolytic system, stand for a rich source of biomarkers that may allow molecular classification, early diagnosis and prognosis of human malignancies as well as prediction of response or failure to cancer-directed drugs. International research points to an important role of certain KLKs in female and male urogenital tract malignancies, in addition to cancers of the lung, brain, skin, head and neck, and the gastrointestinal tract. Regarding the female/male urogenital tract, remarkably, all of the KLKs are expressed in the normal prostate, testis, and kidney whereas the uterus, the ovary, and the urinary bladder are expressing a limited number of KLKs only. Most of the information regarding KLK expression in tumour-affected organs is available for ovarian cancer; all of the 12 KLKs tested so far were found to be elevated in the malignant state, depicting them as valuable biomarkers to distinguish between the normal and the cancerous phenotype. In contrast, for kidney cancer, a series of KLKs was found to be downregulated, while other KLKs were not expressed. Evidently, depending on the type of cancer or cancer stage, individual KLKs may show characteristics of a Janus-faced behaviour, by either expanding or inhibiting cancer progression and metastasis.

Keywords

Cancer - proteases - endometrium - ovary - prostate

• References

• 1 Siegel R. et al. Cancer treatment and survivorship statistics, 2012. CA Cancer J Clin 2012; 62: 220-241.
• 2 Siegel R. et al. Cancer statistics, 2012. CA Cancer J Clin 2012; 62: 10-29.
• 3 GLOBOCAN 2008. Estimated cancer incidence, mortality, prevalence and disability-adjusted life years (DALYs) worldwide in 2008. Available at http://globocan.iarc.fr/
• 4 FIGO, International Federation of gynaecology and Obstetrics. Available at http://www.figo.org
• 5 National Cancer Institute. Available at http://www.cancer.gov/dictionary/?CdrID=45618
• 6 Schmitt M, Magdolen V. Using kallikrein-related peptidases (KLK) as novel cancer biomarkers. Thromb Haemost 2009; 101: 222-224.
• 7 Avgeris M. et al. Kallikrein-related peptidase genes as promising biomarkers for prognosis and monitoring of human malignancies. Biol Chem 2010; 391: 505-511.
• 8 Shaw JL, Diamandis EP. Distribution of 15 human kallikreins in tissues and biological fluids. Clin Chem 2007; 53: 1423-1432.
• 9 Shaw JL. et al. Role of tissue kallikrein-related peptidases in cervical mucus remodeling and host defense. Biol Chem 2008; 389: 1513-1522.
• 10 Jin H. et al. Expression of tumour-associated differentially expressed Gene-14 (TADG-14/KLK8) and its protein hK8 in uterine endometria and endometrial carcinomas. Tumour Biol 2006; 27: 274-282.
• 11 Borgoño CA. et al. Human kallikrein 14: a new potential biomarker for ovarian and breast cancer. Cancer Res 2003; 24: 9032-9041.
• 12 Petraki CD. et al. The spectrum of human kallikrein 6 (zyme/protease M/neurosin) expression in human tissues, as assessed by immunohistochemistry. J Histochem Cytochem 2001; 49: 1431-1441.
• 13 Petraki CD. et al. Human kallikrein 10 expression in normal tissues by immunohistochemistry. J Histochem Cytochem 2002; 50: 1247-1261.
• 14 Petraki CD. et al. Human kallikrein 13 expression in normal tissues. An immunohistochemical study. J Histochem. Cytochem 2003; 51: 493-501.
• 15 Avgeris M. et al. Kallikrein-related peptidases in prostate, breast, and ovarian cancers: from pathobiology to clinical relevance. Biol Chem 2012; 393: 301-317.
• 16 Petraki CD. et al. Cellular distribution of human tissue kallikreins: immunohistochemical localisation. Biol Chem 2006; 387: 653-663.
• 17 Xi Z. et al. Kallikrein 4 is a predominantly nuclear protein and is overexpressed in prostate cancer. Cancer Res 2004; 64: 2365-2370.
• 18 Gabril M. et al. Immunohistochemical analysis of kallikrein-related peptidases in the normal kidney and renal tumours: potential clinical implications. Biol Chem 2010; 391: 403-409.
• 19 Emami N, Diamandis EP. Utility of kallikrein-related peptidases (KLKs) as cancer biomarkers. Clin Chem 2008; 54: 1600-1607.
• 20 Bittoni MA. et al. Assessment of the effects of severe obesity and lifestyle risk factors on stage of endometrial cancer. Cancer Epidemiol Biomarkers Prev 2013; 01: 76-81.
• 21 Folkins AK, Longare TA. Hereditary gynaecological malignancies: advances in screening and treatment. Histopathology 2013; 01: 2-30.
• 22 Bovicelli A. et al. Conservative treatment of early endometrial cancer. J Cell Physiology 2013; 228: 1154-1159.
• 23 Sood AK. et al. Value of preoperative CA 125 level in the management of uterine cancer and prediction of clinical outcome. Obstet Gynaecol 1997; 03: 441-447.
• 24 Myers SA, Clements JA. Kallikrein 4 (KLK4), a new member of the human kallikrein gene family is up-regulated by estrogen and progesterone in the human endometrial cancer cell line, KLE. J Clin Endocrinol Metab 2001; 05: 2323-2326.
• 25 Zhang SQ. et al. Kallikrein 4 overexpression in endometrial carcinoma and upregulation by estrogen via mitogen-activated protein kinase signal pathway. Int J Gynaecol Cancer 2009; 08: 1377-1383.
• 26 Santin AD. et al. Overexpression of kallikrein 10 (hK10) in uterine serous papillary carcinomas. Am J Obstet Gynaecol 2006; 05: 1296-1302.
• 27 Santin AD. et al. Human kallikrein 6: a new potential serum biomarker for uterine serous papillary cancer. Clin Cancer Res 2005; 09: 3320-3325.
• 28 zur Hausen H. Papillomaviruses - to vaccination and beyond. Biochemistry 2008; 05: 498-503.
• 29 Rose PG. et al. Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med 1999; 15: 1144-1153.
• 30 Micke O. et al. The impact of squamous cell carcinoma (SCC) antigen in patients with advanced cancer of uterine cervix treated with (chemo)-radiotherapy. Anticancer Res 2005; 3A: 1663-1666.
• 31 Santin AD. et al. The serine protease stratum corneum chymotryptic enzyme (kallikrein 7) is highly overexpressed in squamous cervical cancer cells. Gynaecol Oncol 2004; 02: 283-288.
• 32 Termini L. et al. Analysis of human kallikrein 7 expression as a potential biomarker in cervical neoplasia. Int J Cancer 2010; 02: 485-490.
• 33 Tian X. et al. Expression of human kallikrein 7 (hK7/SCCE) and its inhibitor antileukoprotease (ALP/SLPI) in uterine endocervical glands and in cervical adenocarcinomas. Oncol Rep 2004; 05: 1001-1006.
• 34 Cane S. et al. The novel serine protease tumour-associated differentially expressed gene-14 (KLK8/Neuropsin/Ovasin) is highly overexpressed in cervical cancer. Am J Obstet Gynaecol 2004; 01: 60-66.
• 35 Lengyel E. Ovarian cancer development and metastasis. Am J Pathol 2010; 03: 1053-1064.
• 36 Yip P. et al. Comprehensive serum profiling for the discovery of epithelial ovarian cancer biomarkers. PLoS One 2011; 12: e29533.
• 37 Rosen DG. et al. Potential markers that complement expression of CA125 in epithelial ovarian cancer. Gynaecol Oncol 2005; 02: 267-277.
• 38 Dorn J. et al. Primary tumour levels of human tissue kallikreins affect surgical success and survival in ovarian cancer patients. Clin Cancer Res 2007; 06: 1742-1748.
• 39 Yousef GM, Diamandis EP. The human kallikrein gene family: new biomarkers for ovarian cancer. Cancer Treat Res 2009; 149: 165-187.
• 40 White N. et al. Human kallikrein related peptidases 6 and 13 in combination with CA125 is a more sensitive test for ovarian cancer than CA125 alone. Cancer Biomark 2009; 06: 279-287.
• 41 Yousef GM, Diamandis EP. The new human tissue kallikrein gene family: structure function and association to disease. Endocr Rev 2001; 22: 184-204.
• 42 Bignotti E. et al. Differential gene expression profiles between tumour biopsies and short-term primary cultures of ovarian serous carcinomas: identification of novel molecular biomarkers for early diagnosis and therapy. gynaecol Oncol 2006; 02: 405-416.
• 43 Dong Y. et al. Human kallikrein 4 (KLK4) is highly expressed in serous ovarian carcinomas. Clin Cancer Res 2001; 08: 2363-2371.
• 44 Yousef GM. et al. Parallel overexpression of seven kallikrein genes in ovarian cancer. Cancer Res 2003; 09: 2223-2227.
• 45 Adib TR. et al. Predicting biomarkers for ovarian cancer using gene-expression microarrays. Br J Cancer 2004; 03: 686-692.
• 46 Tanimoto H. et al. Increased expression of protease M in ovarian tumours. Tumour Biol 2001; 01: 11-18.
• 47 Tanimoto H. et al. The stratum corneum chymotryptic enzyme that mediates shedding and desquamation of skin cells is highly overexpressed in ovarian tumour cells. Cancer 1999; 10: 2047-2082.
• 48 Dong Y. et al. Differential splicing of KLK5 and KLK7 in epithelial ovarian cancer produces novel variants with potential as cancer biomarkers. Clin Cancer Res 2003; 05: 1710-1720.
• 49 Shvartsman HS. et al. Overexpression of kallikrein 10 in epithelial ovarian carcinomas. Gynaecol Oncol 2003; 01: 44-50.
• 50 Gilks CB. et al. Distinction between serous tumours of low malignant potential and serous carcinomas based on global mRNA expression profiling. Gynaecol Oncol 2005; 03: 684-694.
• 51 Yousef GM. et al. Steroid hormone regulation and prognostic value of the human kallikrein gene 14 in ovarian cancer. Am J Clin Pathol 2003; 03: 346-355.
• 52 Yousef GM. et al. Prognostic value of the human kallikrein gene 15 expression in ovarian cancer. J Clin Oncol 2003; 16: 3119-3126.
• 53 Shan SJ. et al. Unfavourable prognostic value of human kallikrein 7 quantified by ELISA in ovarian cancer cytosols. Clin Chem 2006; 10: 1879-1886.
• 54 Dorn J. et al. Disease processes may be Reflected by correlations among tissue kallikrein proteases but not with proteolytic factors uPA and PAI-1 in primary ovarian carcinoma. Biol Chem 2006; 08: 1121-1128.
• 55 Zheng Y. et al. A multiparametric panel for ovarian cancer diagnosis, prognosis, and response to chemotherapy. Clin Cancer Res 2007; 23: 6984-6992.
• 56 Dorn J. et al. Clinical relevance of kallikrein-related peptidases in ovarian cancer. In: Kallikrein-related peptidases. Volume 2 - Novel cancer-related biomarkers. deGruyter, Berlin: 2012. pp. 145-166.
• 57 O’Mara TA. et al. Kallikrein-related peptidase 3 KLK3/PSA single nucleotide polymorphisms and ovarian cancer survival. Twin Res Hum Genet 2011; 14: 323-327.
• 58 Obiezu CV. et al. Higher human kallikrein gene 4 (KLK4) expression indicates poor prognosis of ovarian cancer patients. Clin Cancer Res 2001; 08: 2380-2386.
• 59 Diamandis EP. et al. Immunofluorometric quantification of human kallikrein 5 expression in ovarian cancer cytosols and its association with unfavourable patient prognosis. Tumour Biol 2003; 06: 299-309.
• 60 Kim H. et al. Human kallikrein gene 5 (KLK5) expression is an indicator of poor prognosis in ovarian cancer. Br J Cancer 2001; 05: 643-650.
• 61 Hoffman BR. et al. Immunofluorometric quantitation and histochemical localisation of kallikrein 6 protein in ovarian cancer tissue: a new independent unfavourable prognostic biomarker. Br J Cancer 2002; 07: 763-771.
• 62 Seiz L. et al. Stromal cell-associated expression of kallikrein-related peptidase 6 (KLK6) indicates poor prognosis of ovarian cancer patients. Biol Chem 2012; 391: 391-401.
• 63 Kyriakopoulou LG. et al. Prognostic value of quantitatively assessed KLK7 expression in ovarian cancer. Clin Biochem 2003; 36: 135-143.
• 64 Yousef GM. et al. Quantitative expression of the human kallikrein gene 9 (KLK9) in ovarian cancer: a new independent and favourable prognostic marker. Cancer Res 2001; 21: 7811-7818.
• 65 Borgoño CA. et al. Human kallikrein 8 protein is a favourable prognostic marker in ovarian cancer. Clin Cancer Res 2006; 05: 1487-1493.
• 66 Kishi T. et al. Human kallikrein 8 a novel biomarker for ovarian carcinoma. Cancer Res 2003; 63: 2771-2774.
• 67 Shigemasa K. et al. Human kallikrein 8 (hK8/TADG-14) expression is associated with an early clinical stage and favourable prognosis in ovarian cancer. Oncol Rep 2004; 11: 1153-1159.
• 68 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 2001; 07: 806-811.
• 69 Kountourakis P. et al. Expression and prognostic significance of kallikrein-related peptidase 8 protein levels in advanced ovarian cancer by using automated quantitative analysis. Thromb Haemost 2009; 101: 541-546.
• 70 Luo LY. et al. Prognostic value of human kallikrein 10 expression in epithelial ovarian carcinoma. Clin Cancer Res 2001; 08: 2372-2379.
• 71 Borgoño CA. et al. Favourable prognostic value of tissue human kallikrein 11 (hK11) in patients with ovarian carcinoma. Int J Cancer 2003; 04: 605-610.
• 72 Diamandis EP. et al. Human kallikrein 11: an indicator of favourable prognosis in ovarian cancer patients. Clin Biochem 2004; 09: 823-829.
• 73 Scorilas A. et al. Human kallikrein 13 protein in ovarian cancer cytosols: a new favourable prognostic marker. J Clin Oncol 2004; 04: 768-785.
• 74 Shigemasa K. et al. Human kallikrein gene 11 (KLK11) mRNA overexpression is associated with poor prognosis in patients with epithelial ovarian cancer. Clin Cancer Res 2004; 08: 2766-2770.
• 75 White NM. et al. KLK6 and KLK13 predict tumour recurrence in epithelial ovarian carcinoma. Br J Cancer 2009; 101: 1107-1113.
• 76 Dorn J. et al. Circulating biomarker tissue kallikrein-related peptidase KLK5 impacts ovarian cancer patients’ survival. Ann Oncol 2011; 08: 1783-1790.
• 77 Bandiera E. et al. Human kallikrein 5: an interesting novel biomarker in ovarian cancer patients that elicits humoral response. Int J Gynaecol Cancer 2009; 06: 1015-1021.
• 78 Diamandis EP. et al. Human kallikrein 6 (hK6): a new potential serum biomarker for diagnosis and prognosis of ovarian carcinoma. J Clin Oncol 2003; 06: 1035-1043.
• 79 Koh SC. et al. The association with age, human tissue kallikreins 6 and 10 and hemostatic markers for survival outcome from epithelial ovarian cancer. Arch Gynaecol Obstet 2011; 01: 183-190.
• 80 Luo LY. et al. The serum concentration of human kallikrein 10 represents a novel biomarker for ovarian cancer diagnosis and prognosis. Cancer Res 2003; 04: 807-811.
• 81 Oikonomopoulou K. et al. Prediction of ovarian cancer prognosis and response to chemotherapy by a serum-based multiparametric biomarker panel. Br J Cancer 2008; 07: 1103-1113.
• 82 El Sherbini MA. et al. Diagnostic value of serum kallikrein-related peptidases 6 and 10 versus CA125 in ovarian cancer. Int J Gynaecol Cancer 2011; 04: 625-632.
• 83 Koh SC. et al. Combined panel of serum human tissue kallikreins and CA-125 for the detection of epithelial ovarian cancer. J gynaecol Oncol 2012; 23: 175-181.
• 84 Shih IeM. et al. Ovarian cancer specific kallikrein profile in effusions. Gynaecol Oncol 2007; 105: 501-507.
• 85 Xi Z. et al. Kallikrein 4 is associated with paclitaxel resistance in ovarian cancer. Gynaecol Oncol 2004; 01: 80-85.
• 86 Dong Y. et al. Kallikrein-related peptidase 7 promotes multicellular aggregation via the alpha(5)beta(1) integrin pathway and paclitaxel chemoresistance in serous epithelial ovarian carcinoma. Cancer Res 2010; 70: 2624-2633.
• 87 Cheng L. et al. Analysis of chemotherapy response programs in ovarian cancers by the next-generation sequencing technologies. Gynaecol Oncol 2010; 117: 159-169.
• 88 Xin L. Cells of origin for cancer: an updated view from prostate cancer. Oncogene. 2012. Epub ahead of print
• 89 Epstein JI. et al. Update on the Gleason grading system for prostate cancer: results of an international consensus conference of urologic pathologists. Adv Anat Pathol 2006; 13: 57-59.
• 90 Barbieri CE. et al. Exome sequencing identifies recurrent SPOP FOXA1 and MED12 mutations in prostate cancer. Nat Genet 2012; 44: 685-689.
• 91 Berger MF. et al. The genomic complexity of primary human prostate cancer. Nature 2011; 470: 214-220.
• 92 Beroukhim R. et al. The landscape of somatic copy-number alteration across human cancers. Nature 2010; 463: 899-905.
• 93 Grasso CS. et al. The mutational landscape of lethal castration-resistant prostate cancer. Nature 2012; 487: 239-243.
• 94 Taylor BS. et al. Integrative genomic profiling of human prostate cancer. Cancer Cell 2010; 18: 11-22.
• 95 Fendler A. et al. miRNAs can predict prostate cancer biochemical relapse and are involved in tumour progression. Int J Oncol 2011; 39: 1183-1192.
• 96 Becker C. et al. The role of molecular forms of prostate-specific antigen (PSA or hK3) and of human glandular kallikrein 2 (hK2) in the diagnosis and monitoring of prostate cancer and in extra-prostatic disease. Crit Rev Clin Lab Sci 2001; 38: 357-399.
• 97 Kuriyama M. et al. Quantitation of prostate-specific antigen in serum by a sensitive enzyme immunoassay. Cancer Res 1980; 40: 4658-4662.
• 98 Lilja H. et al. Prostate-specific antigen and prostate cancer: prediction detection and monitoring. Nat Rev Cancer 2008; 08: 268-278.
• 99 Stamey TA. et al. Prostate-specific antigen as a serum marker for adenocarcinoma of the prostate. N Engl J Med 1987; 317: 909-916.
• 100 Ulmert D. et al. Prostate kallikrein markers in diagnosis risk stratification and prognosis. Nat Rev Urol 2009; 06: 384-391.
• 101 Fillon M. Urology meeting highlights prostate, bladder cancers. J Natl Cancer Inst 2012; 104: 1348-1349.
• 102 Nam RK. et al. Serum human glandular kallikrein-2 protease levels predict the presence of prostate cancer among men with elevated prostate-specific antigen. J Clin Oncol 2000; 18: 1036-1042.
• 103 Mavridis K. et al. Expression analysis and study of the KLK15 mRNA splice variants in prostate cancer and benign prostatic hyperplasia. Cancer Sci 2010; 101: 693-699.
• 104 Lawrence MG. et al. Kallikreins on steroids: structure unction and hormonal regulation of prostate-specific antigen and the extended allikrein locus. Endocr Rev 2010; 31: 407-446.
• 105 Lai J. et al. Direct progesterone receptor and indirect androgen receptor interactions with the kallikrein-related peptidase 4 gene promoter in breast and prostate cancer. Mol Cancer Res 2009; 07: 129-141.
• 106 Olkhov-Mitsel E. et al. Quantitative DNA methylation analysis of genes coding for kallikrein-related peptidases 6 and 10 as biomarkers for prostate cancer. Epigenetics 2012; 07: 1037-1045.
• 107 Pampalakis G. et al. The epigenetic basis for the aberrant expression of kallikreins in human cancers. Biol Chem 2006; 387: 795-799.
• 108 Pasic MD. et al. Epigenetic regulation of kallikrein-related peptidases: there is a whole new world out there. Biol Chem 2012; 393: 319-330.
• 109 Sidiropoulos M. et al. Downregulation of human kallikrein 10 (KLK10/NES1) by CpG island hypermethylation in breast ovarian and prostate cancers. Tumour Biol 2005; 26: 324-336.
• 110 White NM. et al. The miRNA-kallikrein axis of interaction: a new dimension in the pathogenesis of prostate cancer. Biol Chem 2012; 393: 379-389.
• 111 Shariat SF. et al. Tumour markers in prostate cancer I: blood-based markers. Acta Oncol 2011; 50 (Suppl. 01) 61-75.
• 112 Viatori M. Testicular cancer. Semin Oncol Nurs 2012; 28: 180-189.
• 113 Okamoto K. Epigenetics: a way to understand the origin and biology of testicular germ cell tumours. Int J Urol 2012; 19: 504-511.
• 114 Barlow LJ. et al. Serum tumour markers in the evaluation of male germ cell tumours. Nat Rev Urol 2010; 07: 610-617.
• 115 Salem M, Gilligan T. Serum tumour markers and their utilisation in the management of germ-cell tumours in adult males. Expert Rev Anticancer Ther 2011; 11: 1-4.
• 116 Emerson RE, Ulbright TM. Intratubular germ cell neoplasia of the testis and its associated cancers: the use of novel biomarkers. Pathology 2010; 42: 344-355.
• 117 Favilla V. et al. New advances in clinical biomarkers in testis cancer. Front Biosci 2010; 02: 456-477.
• 118 Chieffi P. New prognostic markers and potential therapeutic targets in human testicular germ cell tumours. Curr Med Chem 2011; 18: 5033-5040.
• 119 Luo LY. et al. Human tissue kallikreins and testicular cancer. APMIS 2003; 111: 225-232.
• 120 Yousef GM. et al. Differential expression of Kallikrein gene 5 in cancerous and normal testicular tissues. Urology 2002; 60: 714-718.
• 121 Luo LY. et al. Expression of the normal epithelial cell-specific 1 (NES1; KLK10) candidate tumour suppressor gene in normal and malignant testicular tissue. Br J Cancer 2001; 85: 220-224.
• 122 Chang A. et al. Identification and molecular characterisation of five novel kallikrein gene 13 (KLK13; KLK-L4) splice variants: differential expression in the human testis and testicular cancer. Anticancer Res 2001; 21: 3147-3152.
• 123 Yousef GM. et al. Cloning of a new member of the human kallikrein gene family, KLK14, which is down-regulated in different malignancies. Cancer Res 2001; 61: 3425-3431.
• 124 Arsanious A. et al. From bench to bedside: current and future applications of molecular profiling in renal cell carcinoma. Mol Cancer 2009; 08: 20
• 125 McLaughlin JK. et al. Epidemiologic aspects of renal cell carcinoma. Semin Oncol 2006; 33: 527-533.
• 126 Fuhrman SA. et al. Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol 1982; 06: 655-663.
• 127 Latif F. et al. Identification of the von Hippel-Lindau disease tumour suppressor gene. Science 1993; 260: 1317-1320.
• 128 Moore LE. et al. von Hippel-Lindau (VHL) inactivation in sporadic clear cell renal cancer: associations with germline VHL polymorphisms and etiologic risk factors. PLoS Genet 2011; 07: e1002312
• 129 White NM. et al. Dysregulation of kallikrein-related peptidases in renal cell carcinoma: potential targets of miRNAs. Biol Chem 2010; 391: 411-423.
• 130 Girgis AH. et al. Multilevel whole-genome analysis reveals candidate biomarkers in clear cell renal cell carcinoma. Cancer Res 2012; 72: 5273-5284.
• 131 White NM, Yousef GM. Translating molecular signatures of renal cell carcinoma into clinical practice. J Urol 2011; 186: 9-11.
• 132 Beleut M. et al. Integrative genome-wide expression profiling identifies three distinct molecular subgroups of renal cell carcinoma with different patient outcome. BMC Cancer 2012; 12: 310
• 133 Youssef YM. et al. Accurate molecular classification of kidney cancer subtypes using microRNA signature. Eur Urol 2011; 59: 721-730.
• 134 Petraki CD. et al. Prognostic implications of the immunohistochemical expression of human kallikreins 5, 6, 10 and 11 in renal cell carcinoma. Tumour Biol 2006; 27: 1-7.
• 135 Borgono CA, Diamandis EP. The emerging roles of human tissue kallikreins in cancer. Nat Rev Cancer 2004; 04: 876-890.
• 136 Donat SM. Evaluation and follow-up strategies for superficial bladder cancer. Urol Clin North Am 2003; 30: 765-776.
• 137 von der Maase H. et al. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin with methotrexate vinblastine doxorubicin plus cisplatin in patients with bladder cancer. J Clin Oncol 2005; 23: 4602-4608.
• 138 Shinoda Y. et al. Association of KLK5 overexpression with invasiveness of urinary bladder carcinoma cells. Cancer Sci 2007; 98: 1078-1086.
• 139 Chen JC. et al. Immunohistochemical detection of prostate-specific antigen expression in primary urothelial carcinoma of the urinary bladder. Anticancer Res 2008; 28: 4149-4154.
• 140 Kunju LP. et al. Prostate-specific antigen high-molecular-weight cytokeratin (clone 34betaE12) and/or p63: an optimal immunohistochemical panel to distinguish poorly differentiated prostate adenocarcinoma from urothelial carcinoma. Am J Clin Pathol 2006; 125: 675-681.
• 141 Lane Z. et al. Immunohistochemical expression of prostatic antigens in adenocarcinoma and villous adenoma of the urinary bladder. Am J Surg Pathol 2008; 32: 1322-1326.
• 142 Clements J, Mukhtar A. Tissue kallikrein and the bradykinin B2 receptor are expressed in endometrial and prostate cancers. Immunopharmacology 1997; 36: 217-220.
• 143 Clements J. et al. Glandular kallikrein gene expression in the human uterus. Braz J Med Biol Res 1994; 27: 1855-1863.
• 144 Clements J, Mukhtar A. Glandular kallikreins and prostate-specific antigen are expressed in the human endometrium. J Clin Endocrinol Metab 1994; 78: 1536-1539.
• 145 Santin AD. et al. Gene expression fingerprint of uterine serous papillary carcinoma: identification of novel molecular markers for uterine serous cancer diagnosis and therapy. Br J Cancer 2005; 92: 1561-1573.
• 146 Seliger E. et al. Determination of prostate-specific antigen (PSA) in cytosol of breast tumours and human endometrium--new diagnostic approaches. Zentralbl Gynakol 1998; 120: 172-175.
• 147 Kucera E. et al. Prostate specific antigen PSA in breast and ovarian cancer. Anticancer Res 1997; 17: 4735-4737.
• 148 Yu H. et al. Expression of the prostate-specific antigen gene by a primary ovarian carcinoma. Cancer Res 1995; 55: 1603-1606.
• 149 Davidson B. et al. Kallikrein 4 expression is up-regulated in epithelial ovarian carcinoma cells in effusions. Am J Clin Pathol 2005; 123: 360-368.
• 150 Hibbs K. et al. Differential gene expression in ovarian carcinoma: identification of potential biomarkers. Am J Pathol 2004; 165: 397-414.
• 151 Yousef GM. et al. Human kallikrein gene 5 KLK5 expression by quantitative PCR: an independent indicator of poor prognosis in breast cancer. Clin Chem 2002; 48: 1241-1250.
• 152 Anisowicz A. et al. Novel protease homolog differentially expressed in breast and ovarian cancer. Mol Med 1996; 02: 624-626.
• 153 Gyorffy B. et al. Implementing an online tool for genome-wide validation of survival-associated biomarkers in ovarian-cancer using microarray data from 1287 patients. Endocr Relat Cancer 2012; 19: 197
• 154 Hu CJ. et al. Correlation of hK6 expression with clinicopathological features and prognosis in epithelial ovarian cancer. Zhonghua Zhong Liu Za Zhi 2009; 31: 520-523.
• 155 Lu KH. et al. Selection of potential markers for epithelial ovarian cancer with gene expression arrays and recursive descent partition analysis. Clin Cancer Res 2004; 10: 3291-3300.
• 156 Ni X. et al. Characterisation of human kallikrein 6/protease M expression in ovarian cancer. Br J Cancer 2004; 91: 725-731.
• 157 Shan SJ. et al. Transcriptional upregulation of human tissue kallikrein 6 in ovarian cancer: clinical and mechanistic aspects. Br J Cancer 2007; 96: 362-372.
• 158 Welsh JB. et al. Large-scale delineation of secreted protein biomarkers overexpressed in cancer tissue and serum. Proc Natl Acad Sci USA 2003; 100: 3410-3415.
• 159 Yousef GM. et al. In silico analysis of the human kallikrein gene 6. Tumour Biol 2004; 25: 282-289.
• 160 Psyrri A. et al. Human tissue kallikrein 7 a novel biomarker for advanced ovarian carcinoma using a novel in situ quantitative method of protein expression. Ann Oncol 2008; 19: 1271-1277.
• 161 Yousef GM. et al. Steroid hormone regulation and prognostic value of the human kallikrein gene 14 in ovarian cancer. Am J Clin Pathol 2003; 119: 346-355.
• 162 Batra J. et al. A kallikrein 15 KLK15 single nucleotide polymorphism located close to a novel exon shows evidence of association with poor ovarian cancer survival. BMC Cancer 2011; 11: 119
• 163 Dong Y. et al. Tissue-specific promoter utilisation of the kallikrein-related peptidase genes KLK5 and KLK7 and cellular localisation of the encoded proteins suggest roles in exocrine pancreatic function. Biol Chem 2008; 389: 99-109.
• 164 Harvey TJ. et al. Tissue-specific expression patterns and fine mapping of the human kallikrein (KLK) locus on proximal 19q13.4. J Biol Chem 2000; 275: 37397-37406.
• 165 Hooper JD. et al. Identification and characterisation of KLK14 a novel kallikrein serine protease gene located on human chromosome 19q13.4 and expressed in prostate and skeletal muscle. Genomics 2001; 73: 117-122.
• 166 Kishi T. et al. Development of an immunofluorometric assay and quantification of human kallikrein 7 in tissue extracts and biological fluids. Clin Chem 2004; 50: 709-716.
• 167 Obiezu CV. et al. Human kallikrein 4: quantitative study in tissues and evidence for its secretion into biological fluids. Clin Chem 2005; 51: 1432-1442.
• 168 Yousef GM. et al. Genomic organisation of the human kallikrein gene family on chromosome 19q13.3-q13.4. Biochem Biophys Res Commun 2000; 276: 125-133.
• 169 Yousef GM. et al. Prostase/KLK-L1 is a new member of the human kallikrein gene family expressed in prostate and breast tissues and is hormonally regulated. Cancer Res 1999; 59: 4252-4256.
• 170 Becker C. et al. The role of molecular forms of prostate-specific antigen (PSA or hK3) and of human glandular kallikrein 2 (hK2) in the diagnosis and monitoring of prostate cancer and in extra-prostatic disease. Crit Rev Clin Lab Sci 2001; 38: 357-399.
• 171 Kwiatkowski MK. et al. In prostatism patients the ratio of human glandular kallikrein to free PSA improves the discrimination between prostate cancer and benign hyperplasia within the diagnostic "gray zone" of total PSA 4 to 10 ng/mL. Urology 1998; 52: 360-365.
• 172 Magklara A. et al. The combination of human glandular kallikrein and free prostate-specific antigen (PSA) enhances discrimination between prostate cancer and benign prostatic hyperplasia in patients with moderately increased total PSA. Clin Chem 1999; 45: 1960-1966.
• 173 Ylikoski A. et al. Simultaneous quantification of prostate-specific antigen and human glandular kallikrein 2 mRNA in blood samples from patients with prostate cancer and benign disease. Clin Chem 2002; 48: 1265-1271.
• 174 Stephan C. et al. PSA and other tissue kallikreins for prostate cancer detection. Eur J Cancer 2007; 43: 1918-1926.
• 175 Steuber T. et al. Free PSA isoforms and intact and cleaved forms of urokinase plasminogen activator receptor in serum improve selection of patients for prostate cancer biopsy. Int J Cancer 2007; 120: 1499-1504.
• 176 Steuber T. et al. Comparison of free and total forms of serum human kallikrein 2 and prostate-specific antigen for prediction of locally advanced and recurrent prostate cancer. Clin Chem 2007; 53: 233-240.
• 177 Avgeris M. et al. Kallikrein-related peptidase 4 gene (KLK4) in prostate tumours: quantitative expression analysis and evaluation of its clinical significance. Prostate 2011; 71: 1780-1789.
• 178 Dong Y. et al. Compartmentalized expression of kallikrein 4 (KLK4/hK4) isoforms in prostate cancer: nuclear cytoplasmic and secreted forms. Endocr Relat Cancer 2005; 12: 875-889.
• 179 Klokk TI. et al. Kallikrein 4 is a proliferative factor that is overexpressed in prostate cancer. Cancer Res 2007; 67: 5221-52230.
• 180 Petraki CD. et al. Immunohistochemical localisation of human kallikreins 6 10 and 13 in benign and malignant prostatic tissues. Prostate Cancer Prostatic Dis 2003; 06: 223-227.
• 181 Petraki CD. et al. Immunohistochemical localisation of human kallikreins 6 and 10 in pancreatic islets. Histochem J 2002; 34: 313-322.
• 182 Ramsay AJ. et al. Kallikrein-related peptidase 4 (KLK4) initiates intracellular signaling via protease-activated receptors (PARs; KLK4 and PAR-2 are co-expressed during prostate cancer progression. J Biol Chem 2008; 283: 12293-12304.
• 183 Seiz L. et al. Polyclonal antibodies against kallikrein-related peptidase 4 (KLK4): immunohistochemical assessment of KLK4 expression in healthy tissues and prostate cancer. Biol Chem 2010; 391: 391-401.
• 184 Stephenson SA. et al. Localisation of a new prostate-specific antigen-related serine protease gene KLK4 is evidence for an expanded human kallikrein gene family cluster on chromosome 19q13.3-13.4. J Biol Chem 1999; 274: 23210-23214.
• 185 Korbakis D. et al. Quantitative analysis of human kallikrein 5 (KLK5) expression in prostate needle biopsies: an independent cancer biomarker. Clin Chem 2009; 55: 904-913.
• 186 Yousef GM. et al. Down-regulation of the human kallikrein gene 5 (KLK5) in prostate cancer tissues. Prostate 2002; 51: 126-132.
• 187 Jamaspishvili T. et al. Immunohistochemical localisation and analysis of kallikrein-related peptidase 7 and 11 expression in paired cancer and benign foci in prostate cancer patients. Neoplasma 2011; 58: 298-303.
• 188 Xuan Q. et al. Expression of the serine protease kallikrein 7 and its inhibitor antileukoprotease is decreased in prostate cancer. Arch Pathol Lab Med 2008; 132: 1796-1801.
• 189 Yousef GM. et al. The KLK7 (PRSS6) gene encoding for the stratum corneum chymotryptic enzyme is a new member of the human kallikrein gene family - genomic characterisation mapping tissue expression and hormonal regulation. Gene 2000; 254: 119-128.
• 190 Kishi T. et al. Human kallikrein 8: immunoassay development and identification in tissue extracts and biological fluids. Clin Chem 2003; 49: 87-96.
• 191 Bi X. et al. Association of TMPRSS2 and KLK11 gene expression levels with clinical progression of human prostate cancer. Med Oncol 2010; 27: 145-151.
• 192 Diamandis EP. et al. Human kallikrein 11: a new biomarker of prostate and ovarian carcinoma. Cancer Res 2002; 62: 295-300.
• 193 Luo LY. et al. Purification and characterisation of human kallikrein 11 a candidate prostate and ovarian cancer biomarker from seminal plasma. Clin Cancer Res 2006; 12: 742-750.
• 194 Scorilas A, Gregorakis AK. mRNA expression analysis of human kallikrein 11 (KLK11) may be useful in the discrimination of benign prostatic hyperplasia from prostate cancer after needle prostate biopsy. Biol Chem 2006; 387: 789-793.
• 195 Stavropoulou P. et al. Expression analysis and prognostic significance of human kallikrein 11 in prostate cancer. Clin Chim Acta 2005; 357: 190-195.
• 196 Memari N. et al. Human kallikrein-related peptidase 12: antibody generation and immunohistochemical localisation in prostatic tissues. Prostate 2007; 67: 1465-1474.
• 197 Nakamura T. et al. The usefulness of serum human kallikrein 11 for discriminating between prostate cancer and benign prostatic hyperplasia. Cancer Res 2003; 63: 6543-6546.
• 198 Nakamura T. et al. Quantitative analysis of hippostasin/KLK11 gene expression in cancerous and noncancerous prostatic tissues. Urology 2003; 61: 1042-1046.
• 199 Rabien A. et al. High expression of KLK14 in prostatic adenocarcinoma is associated with elevated risk of prostate-specific antigen relapse. Tumour Biol 2008; 29: 1-8.
• 200 Yousef GM. et al. Differential expression of the human kallikrein gene 14 (KLK14) in normal and cancerous prostatic tissues. Prostate 2003; 56: 287-292.
• 201 Cumming AD. et al. Expression of tissue kallikrein in human kidney. Clin Sci (Lond) 1994; 87: 5-11.
• 202 Rae F. et al. The human tissue kallikreins (KLKs 1-3) and a novel KLK1 mRNA transcript are expressed in a renal cell carcinoma cDNA library. Immunopharmacology 1999; 45: 83-88.
• 203 Kishi T. et al. Activation and enzymatic characterisation of recombinant human kallikrein 8. Biol Chem 2006; 387: 723-731.
• 204 Kontos CK, Scorilas A. Kallikrein-related peptidases (KLKs): a gene family of novel cancer biomarkers. Clin Chem Lab Med 2012; 50: 1877-1891.
• 205 Sotiropoulou G, Pampalakis G. Targeting the kallikrein-related peptidases for drug development. Trends Pharmacol Sci 2012; 33: 623-634.
• 206 Beaufort N. et al. Interdependence of kallikrein-related peptidases in proteolytic networks. Biol Chem 2010; 391: 581-587.
• 207 Debela M. et al. Structures and specificity of the human kallikrein-related peptidases KLK 4, 5, 6, and 7. Biol Chem 2008; 389: 623-632.