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Thromb Haemost 2013; 110(03): 450-457
DOI: 10.1160/TH12-11-0791
Theme Issue Article
Schattauer GmbH

Kallikrein-related peptidases (KLKs) in gastrointestinal cancer: Mechanistic and clinical aspects

Christos K. Kontos
1   Department of Biochemistry and Molecular Biology, University of Athens, Athens, Greece
,
Konstantinos Mavridis
1   Department of Biochemistry and Molecular Biology, University of Athens, Athens, Greece
,
Maroulio Talieri
2   Department of Cellular Physiology, “George Papanicolaou” Research Center of Oncology, “Saint Savvas” Anticancer Hospital, Athens, Greece
,
Andreas Scorilas
1   Department of Biochemistry and Molecular Biology, University of Athens, Athens, Greece
› Author Affiliations
Further Information

Publication History

Received: 01 November 2012

Accepted after minor revision: 31 January 2013

Publication Date:
22 November 2017 (online)

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Summary

The human tissue kallikrein (KLK1) and kallikrein-related peptidases (KLKs) are secreted serine proteases with diverse expression patterns and physiological roles in different systems, including the digestive system. The aberrant expression of KLKs in gastrointestinal malignancies as well as their implication in carcinogenesis including cell growth regulation, angiogenesis, invasion, and metastasis, has prompted scientists to investigate their potential as cancer biomarkers. Expression of distinct KLKs is associated with various clinic-pathological parameters of patients with gastric, colorectal, pancreatic, hepatic, and esophageal cancer. Moreover, several KLKs possess significant favourable or unfavourable prognostic value in these human malignancies. Identification of novel diagnostic, prognostic and predictive biomarkers will contribute utmost to clinical decision-making, since early diagnosis of gastrointestinal cancer and early detection of recurrence following surgery are critical for the effective treatment of patients and for a positive clinical outcome. The current review provides a brief overview of the functional role of KLKs in gastric, colorectal, pancreatic, hepatic, and esophageal cancer, and describes the current status of KLKs as potential tumour biomarkers in these human malignancies.

Keywords

Gastric cancer - colorectal cancer - pancreatic carcinoma - molecular tumour markers - kallikrein splice variants
 

  • References

  • 1 Yousef GM, Kopolovic AD, Elliott MB. et al. Genomic overview of serine proteases. Biochem Biophys Res Commun 2003; 305: 28-36.
    CrossrefPubMedGoogle Scholar
  • 2 Diamandis EP, Yousef GM, Luo LY. et al. The new human kallikrein gene family: implications in carcinogenesis. Trends Endocrinol Metab 2000; 11: 54-60.
    CrossrefPubMedGoogle Scholar
  • 3 Yousef GM, Diamandis EP. The new human tissue kallikrein gene family: structure, function, and association to disease. Endocr Rev 2001; 22: 184-204.
    PubMedGoogle Scholar
  • 4 Clements JA, Willemsen NM, Myers SA. et al. The tissue kallikrein family of serine proteases: functional roles in human disease and potential as clinical biomarkers. Crit Rev Clin Lab Sci 2004; 41: 265-312.
    CrossrefPubMedGoogle Scholar
  • 5 Shaw JL, Diamandis EP. Distribution of 15 human kallikreins in tissues and biological fluids. Clin Chem 2007; 53: 1423-1432.
    CrossrefPubMedGoogle Scholar
  • 6 Borgono CA, Michael IP, Diamandis EP. Human tissue kallikreins: physiologic roles and applications in cancer. Mol Cancer Res 2004; 02: 257-280.
    CrossrefPubMedGoogle Scholar
  • 7 Borgono CA, Diamandis EP. The emerging roles of human tissue kallikreins in cancer. Nat Rev Cancer 2004; 04: 876-890.
    CrossrefPubMedGoogle Scholar
  • 8 Ferlay J, Shin HR, Bray F. et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010; 127: 2893-2917.
    CrossrefPubMedGoogle Scholar
  • 9 Avgeris M, Mavridis K, Scorilas A. Kallikrein-related peptidase genes as promising biomarkers for prognosis and monitoring of human malignancies. Biol Chem 2010; 391: 505-511.
    CrossrefPubMedGoogle Scholar
  • 10 Scorilas A, Mavridis K. Kallikrein-related peptidases (KLKs) as novel potential biomarkers in gastric cancer: An open yet challenging road lies ahead. J Surg Oncol 2012; 105: 223-224.
    CrossrefPubMedGoogle Scholar
  • 11 Bayani J, Diamandis EP. The physiology and pathobiology of human kallikrein-related peptidase 6 (KLK6). Clinical chemistry and laboratory medicine : CCLM / FESCC 2012; 50: 211-233.
    CrossrefPubMedGoogle Scholar
  • 12 Nagahara H, Mimori K, Utsunomiya T. et al. Clinicopathologic and biological significance of kallikrein 6 overexpression in human gastric cancer. Clin Cancer Res 2005; 11: 6800-6806.
    CrossrefPubMedGoogle Scholar
  • 13 Kim JJ, Kim JT, Yoon HR. et al. Upregulation and secretion of kallikrein-related peptidase 6 (KLK6) in gastric cancer. Tumour Biol 2012; 33: 731-738.
    CrossrefPubMedGoogle Scholar
  • 14 Nobili S, Bruno L, Landini I. et al. Genomic and genetic alterations influence the progression of gastric cancer. World J Gastroenterol 2011; 17: 290-299.
    CrossrefPubMedGoogle Scholar
  • 15 Sawant S, Snyman C, Bhoola K. Comparison of tissue kallikrein and kinin receptor expression in gastric ulcers and neoplasms. Int Immunopharmacol 2001; 01: 2063-2080.
    CrossrefPubMedGoogle Scholar
  • 16 Zhu B, Lu L, Cai W. et al. Kallikrein-binding protein inhibits growth of gastric carcinoma by reducing vascular endothelial growth factor production and angiogenesis. Mol Cancer Ther 2007; 06: 3297-3306.
    CrossrefPubMedGoogle Scholar
  • 17 Huang W, Zhong J, Wu LY. et al. Downregulation and CpG island hypermethylation of NES1/hK10 gene in the pathogenesis of human gastric cancer. Cancer Lett 2007; 251: 78-85.
    CrossrefPubMedGoogle Scholar
  • 18 Huang W, Tian XL, Wu YL. et al. Suppression of gastric cancer growth by baculovirus vector-mediated transfer of normal epithelial cell specific-1 gene. World J Gastroenterol 2008; 14: 5810-5815.
    CrossrefPubMedGoogle Scholar
  • 19 Feng B, Xu WB, Zheng MH. et al. Clinical significance of human kallikrein 10 gene expression in colorectal cancer and gastric cancer. J Gastroenterol Hepatol 2006; 21: 1596-1603.
    CrossrefPubMedGoogle Scholar
  • 20 Li M, Zhao ZW, Zhang Y. et al. Over-expression of Ephb4 is associated with carcinogenesis of gastric cancer. Dig Dis Sci 2011; 56: 698-706.
    CrossrefPubMedGoogle Scholar
  • 21 Yousef GM, White NM, Michael IP. et al. Identification of new splice variants and differential expression of the human kallikrein 10 gene, a candidate cancer biomarker. Tumour Biol 2005; 26: 227-235.
    CrossrefPubMedGoogle Scholar
  • 22 Zhao EH, Shen ZY, Liu H. et al. Clinical significance of human kallikrein 12 gene expression in gastric cancer. World J Gastroenterol 2012; 18: 6597-6604.
    CrossrefPubMedGoogle Scholar
  • 23 Avgeris M, Mavridis K, Scorilas A. Kallikrein-related peptidases in prostate, breast, and ovarian cancers: from pathobiology to clinical relevance. Biol Chem 2012; 393: 301-317.
    CrossrefPubMedGoogle Scholar
  • 24 Mavridis K, Scorilas A. Prognostic value and biological role of the kallikrein-related peptidases in human malignancies. Future Oncol 2010; 06: 269-285.
    CrossrefPubMedGoogle Scholar
  • 25 Yousef GM, Borgono CA, White NM. et al. In silico analysis of the human kallikrein gene 6. Tumour Biol 2004; 25: 282-289.
    CrossrefPubMedGoogle Scholar
  • 26 Shinmura K, Tao H, Yamada H. et al. Splice-site genetic polymorphism of the human kallikrein 12 (KLK12) gene correlates with no substantial expression of KLK12 protein having serine protease activity. Human mutation 2004; 24: 273-274.
    CrossrefPubMedGoogle Scholar
  • 27 Konstantoudakis G, Florou D, Mavridis K. et al. Kallikrein-related peptidase 13 (KLK13) gene expressional status contributes significantly in the prognosis of primary gastric carcinomas. Clin Biochem 2010; 43: 1205-1211.
    CrossrefPubMedGoogle Scholar
  • 28 Florou D, Mavridis K, Scorilas A. The kallikrein-related peptidase 13 (KLK13) gene is substantially up-regulated after exposure of gastric cancer cells to antineoplastic agents. Tumour Biol 2012; 33: 2069-2078.
    CrossrefPubMedGoogle Scholar
  • 29 Wen YG, Wang Q, Zhou CZ. et al. Identification and validation of Kallikrein-ralated peptidase 11 as a novel prognostic marker of gastric cancer based on immunohistochemistry. J Surg Oncol 2011; 104: 516-524.
    CrossrefPubMedGoogle Scholar
  • 30 Ramsay AJ, Reid JC, Adams MN. et al. Prostatic trypsin-like kallikrein-related peptidases (KLKs) and other prostate-expressed tryptic proteinases as regulators of signalling via proteinase-activated receptors (PARs). Biol Chem 2008; 389: 653-668.
    CrossrefPubMedGoogle Scholar
  • 31 Macfarlane SR, Seatter MJ, Kanke T. et al. Proteinase-activated receptors. Pharmacol Rev 2001; 53: 245-282.
    PubMedGoogle Scholar
  • 32 Nishibori M, Mori S, Takahashi HK. Physiology and pathophysiology of proteinase-activated receptors (PARs): PAR-2-mediated proliferation of colon cancer cell. J Pharmacol Sci 2005; 97: 25-30.
    CrossrefPubMedGoogle Scholar
  • 33 Caliendo G, Santagada V, Perissutti E. et al. Kallikrein protease activated receptor (PAR) axis: an attractive target for drug development. J Med Chem 2012; 55: 6669-6686.
    CrossrefPubMedGoogle Scholar
  • 34 Gratio V, Beaufort N, Seiz L. et al. Kallikrein-related peptidase 4: a new activator of the aberrantly expressed protease-activated receptor 1 in colon cancer cells. Am J Pathol 2010; 176: 1452-1461.
    CrossrefPubMedGoogle Scholar
  • 35 Gratio V, Loriot C, Virca GD. et al. Kallikrein-related peptidase 14 acts on proteinase-activated receptor 2 to induce signalling pathway in colon cancer cells. Am J Pathol 2011; 179: 2625-2636.
    CrossrefPubMedGoogle Scholar
  • 36 Kontos CK, Scorilas A. Kallikrein-related peptidases (KLKs): a gene family of novel cancer biomarkers. Clin Chem Lab Med 2012; 50: 1877-1891.
    CrossrefPubMedGoogle Scholar
  • 37 Talieri M, Li L, Zheng Y. et al. The use of kallikrein-related peptidases as adjuvant prognostic markers in colorectal cancer. Br J Cancer 2009; 100: 1659-1665.
    CrossrefPubMedGoogle Scholar
  • 38 Yu X, Tang HY, Li XR. et al. Over-expression of human kallikrein 11 is associated with poor prognosis in patients with low rectal carcinoma. Med Oncol 2010; 27: 40-44.
    CrossrefPubMedGoogle Scholar
  • 39 Devetzi M, Trangas T, Scorilas A. et al. Parallel overexpression and clinical significance of kallikrein-related peptidases 7 and 14 (KLK7 KLK14) in colon cancer. Thromb Haemost 2013; 109: 716-725.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 40 Talieri M, Alexopoulou DK, Scorilas A. et al. Expression analysis and clinical evaluation of kallikrein-related peptidase 10 (KLK10) in colorectal cancer. Tumour Biol 2011; 32: 737-744.
    CrossrefPubMedGoogle Scholar
  • 41 Ogawa K, Utsunomiya T, Mimori K. et al. Clinical significance of human kallikrein gene 6 messenger RNA expression in colorectal cancer. Clin Cancer Res 2005; 11: 2889-2893.
    CrossrefPubMedGoogle Scholar
  • 42 Kontos CK, Chantzis D, Papadopoulos IN. et al. Quantitative expression analysis and prognostic significance of KLK4 mRNA expression in colon cancer. In: Schmitt M, Fritz H, Sommerhoff CP, et al., editors. 3rd International Symposium on Kallikreins and Kallikrein-Related Peptidases 2009 August 30 - September 2, 2009. Munich, Germany: Hieronymus Druck und Verlag; 2009. p. 86
    Google Scholar
  • 43 Kontos CK, Chantzis D, Papadopoulos IN. et al. Kallikrein-related peptidase 4 (KLK4) mRNA predicts short-term relapse in colorectal adenocarcinoma patients. Cancer Lett 2013; 330: 106-112.
    CrossrefPubMedGoogle Scholar
  • 44 Talieri M, Mathioudaki K, Prezas P. et al. Clinical significance of kallikrein-related peptidase 7 (KLK7) in colorectal cancer. Thromb Haemost 2009; 101: 741-747.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 45 Liotta LA, Kohn EC. The microenvironment of the tumour-host interface. Nature 2001; 411: 375-379.
    CrossrefPubMedGoogle Scholar
  • 46 Johnson SK, Ramani VC, Hennings L. et al. Kallikrein 7 enhances pancreatic cancer cell invasion by shedding E-cadherin. Cancer 2007; 109: 1811-1820.
    CrossrefPubMedGoogle Scholar
  • 47 Ramani VC, Haun RS. The extracellular matrix protein fibronectin is a substrate for kallikrein 7. Biochem Biophys Res Commun 2008; 369: 1169-1173.
    CrossrefPubMedGoogle Scholar
  • 48 Lee CY, Marzan D, Lin G. et al. alpha2 Integrin-Dependent Suppression of Pancreatic Adenocarcinoma Cell Invasion Involves Ectodomain Regulation of Kallikrein-Related Peptidase-5. J Oncol 2011; 2011: 365651
    PubMedGoogle Scholar
  • 49 Ramani VC, Hennings L, Haun RS. Desmoglein 2 is a substrate of kallikrein 7 in pancreatic cancer. BMC Cancer 2008; 08: 373
    CrossrefPubMedGoogle Scholar
  • 50 Pignatelli M, Ansari TW, Gunter P. et al. Loss of membranous E-cadherin expression in pancreatic cancer: correlation with lymph node metastasis, high grade, and advanced stage. J Pathol 1994; 174: 243-248.
    CrossrefPubMedGoogle Scholar
  • 51 Chidgey M, Dawson C. Desmosomes: a role in cancer?. Br J Cancer 2007; 96: 1783-1787.
    CrossrefPubMedGoogle Scholar
  • 52 Werb Z. ECM and cell surface proteolysis: regulating cellular ecology. Cell 1997; 91: 439-442.
    CrossrefPubMedGoogle Scholar
  • 53 Iakovlev V, Siegel ER, Tsao MS. et al. Expression of kallikrein-related peptidase 7 predicts poor prognosis in patients with unresectable pancreatic ductal adenocarcinoma. Cancer Epidemiol Biomarkers Prev 2012; 21: 1135-1142.
    CrossrefPubMedGoogle Scholar
  • 54 Iacobuzio-Donahue CA, Ashfaq R, Maitra 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 2003; 63: 8614-8622.
    PubMedGoogle Scholar
  • 55 Hustinx SR, Cao D, Maitra A. et al. Differentially expressed genes in pancreatic ductal adenocarcinomas identified through serial analysis of gene expression. Cancer Biol Ther 2004; 03: 1254-1261.
    CrossrefPubMedGoogle Scholar
  • 56 Yousef GM, Borgono CA, Popalis C. et al. In-silico analysis of kallikrein gene expression in pancreatic and colon cancers. Anticancer Res 2004; 24: 43-51.
    PubMedGoogle Scholar
  • 57 Linardoutsos D, Avgeris M, Bramis J. et al. Expression analysis of kallikrein-related peptidase 4 gene (KLK4) in pancreatic cancer. In: Scorilas A, editor. 4th International Symposium on Kallikreins and Kallikrein-Related Peptidases; 2011. Rhodes, Greece: 2011
    Google Scholar
  • 58 Lavergne E, Petit-Courty A, Vallet A. et al. Expression pattern of the kallikrein-related peptidase (KLK) gene family in normal and pathological human liver. In: Scorilas A, editor. 4th International Symposium on Kallikreins and Kallikrein-Related Peptidases 2011. Rhodes, Greece: 2011
    Google Scholar
  • 59 Lu CY, Hsieh SY, Lu YJ. et al. Aberrant DNA methylation profile and frequent methylation of KLK10 and OXGR1 genes in hepatocellular carcinoma. Genes Chromosomes Cancer 2009; 48: 1057-1068.
    CrossrefPubMedGoogle Scholar
  • 60 Lu L, Yang Z, Zhu B. et al. Kallikrein-binding protein suppresses growth of hepatocellular carcinoma by anti-angiogenic activity. Cancer Lett 2007; 257: 97-106.
    CrossrefPubMedGoogle Scholar
  • 61 Dlamini Z, Bhoola KD. Upregulation of tissue kallikrein, kinin B1 receptor, and kinin B2 receptor in mast and giant cells infiltrating oesophageal squamous cell carcinoma. J Clin Pathol 2005; 58: 915-922.
    CrossrefPubMedGoogle Scholar
  • 62 Dlamini Z, Raidoo D, Bhoola K. Visualisation of tissue kallikrein and kinin receptors in oesophageal carcinoma. Immunopharmacology 1999; 43: 303-310.
    CrossrefPubMedGoogle Scholar