Abstract
In epithelial ovarian cancer, the high mortality rate is usually ascribed to late diagnosis, since these tumors commonly lack early-warning symptoms, but tumor-associated biomarkers useful for prognosis or therapy response prediction are in short supply. However, members of the tissue kallikrein serine protease family, the serine protease uPA and its inhibitor PAI-1, are associated with tumor progression of ovarian cancer. Therefore, we used ELISA to determine uPA, PAI-1, and tissue kallikreins hK5–8, 10, 11, and 13 in extracts of 142 primary tumor tissue specimens from ovarian cancer patients and studied the strength of association between protein expression levels of these tumor tissue-associated factors. uPA, PAI-1, hk5, and hk8 were related to FIGO stage; hK5 expression was higher in FIGO III/IV than in FIGO I/II patient tissues. PAI-1 and hk5 differed significantly according to nuclear grading; expression of hK5 was higher in G3 than in G1/2 tumors. Associations between uPA, PAI-1, and the tissue kallikreins were weak. There were strong pairwise correlations within the cluster of tissue kallikreins hK5, 6, 7, 8, 10, and 11, but their bivariate distributions depended on nuclear grading. These results support the notion that several tissue kallikreins are co-expressed in ovarian cancer patients, substantiating the existence of a steroid hormone-driven tissue kallikrein cascade in this disease.
References
Bast, R.C. Jr., Lilja, H., Urban, N., Rimm, D.L., Fritsche, H., Gray, J., Veltri, R., Klee, G., Allen, A., Kim, N., Gutman, S., Rubin, M.A., and Hruszkewycz, A. (2005). Translational crossroads for biomarkers. Clin. Cancer Res.11, 6103–6108.10.1158/1078-0432.CCR-04-2213Search in Google Scholar
Borgfeldt, C., Hansson, S.R., Gustavsson, B., Masback, A., and Casslen, B. (2001). Dedifferentiation of serous ovarian cancer from cystic to solid tumors is associated with increased expression of mRNA for urokinase plasminogen activator (uPA), its receptor (uPAR) and its inhibitor (PAI-1). Int. J. Cancer92, 497–502.10.1002/ijc.1215Search in Google Scholar
Borgono, C.A. and Diamandis, E.P. (2004). The emerging roles of human tissue kallikreins in cancer. Nat. Rev. Cancer4, 876–890.10.1038/nrc1474Search in Google Scholar
Borgono, C.A., Grass, L., Soosaipillai, A., Yousef, G.M., Petraki, C.D., Howarth, D.H., Fracchioli, S., Katsaros, D., Diamandis, E.P. (2001). Human kallikrein 14: a new potential biomarker for ovarian and breast cancer. Cancer Res.63, 9032–9041.Search in Google Scholar
Borgono, C.A., Fracchioli, S., Yousef, G.M., Rigault de la Longrais, I.A., Luo, L.Y., Soosaipillai, A., Puopolo, M., Grass, L., Scorilas, A., Diamandis, E.P., and Katsaros, D. (2003). Favorable prognostic value of tissue human kallikrein 11 (hK11) in patients with ovarian carcinoma. Int. J. Cancer106, 605–610.10.1002/ijc.11296Search in Google Scholar
Borgono, C.A., Michael, I.P., and Diamandis, E.P. (2004). Human tissue kallikreins: physiologic roles and applications in cancer. Mol. Cancer Res.2, 257–280.10.1158/1541-7786.257.2.5Search in Google Scholar
Burke, H.B., Goodman, P.H., Rosen, D.B., Henson, D.E., Weinstein, J.N., Harrell, F.E. Jr., Marks, J.R., Winchester, D.P., and Bostwick, D.G. (1997). Artificial neural networks improve the accuracy of cancer survival prediction. Cancer79, 857–862.10.1002/(SICI)1097-0142(19970215)79:4<857::AID-CNCR24>3.0.CO;2-YSearch in Google Scholar
Cannistra, S.A. (2004). Cancer of the ovary. N. Engl. J. Med.351, 2519–2529.10.1056/NEJMra041842Search in Google Scholar
Castellino, F.J. and Ploplis, V.A. (2005). Structure and function of the plasminogen/plasmin system. Thromb. Haemost.93, 647–654.Search in Google Scholar
Clements, J.A., Willemsen, N.M., Myers, S.A., and Dong, Y. (2004). The tissue kallikrein family of serine proteases: functional roles in human disease and potential as clinical biomarkers. Crit. Rev. Clin. Lab. Sci.41, 265–312.10.1080/10408360490471931Search in Google Scholar
De Laurentiis, M., de Placido, S., Bianco, A.R., Clark, G.M., and Ravdin, P.M. (1999). A prognostic model that makes quantitative estimates of probability of relapse for breast cancer patients. Clin. Cancer Res.5, 4133–4139.Search in Google Scholar
Diamandis, E.P., Yousef, G.M., Soosaipillai, A.R., and Bunting, P. (2000). Human kallikrein 6 (zyme/protease M/neurosin): a new serum biomarker of ovarian carcinoma. Clin. Biochem.33, 579–583.10.1016/S0009-9120(00)00182-XSearch in Google Scholar
Diamandis, E.P., Scorilas, A., Fracchioli, S., Van Gramberen, M., De Bruijn, H., Henrik, A., Soosaipillai, A., Grass, L., Yousef, G.M., Stenman, U.H., et al. (2003). Human kallikrein 6 (hK6): a new potential serum biomarker for diagnosis and prognosis of ovarian carcinoma. J. Clin. Oncol.21, 1035–1043.10.1200/JCO.2003.02.022Search in Google Scholar
Durand, M.K., Bodker, J.S., Christensen, A., Dupont, D.M., Hansen, M., Jensen, J.K., Kjelgaard, S., Mathiasen, L., Pedersen, K.E., Skeldal, S., et al. (2004). Plasminogen activator inhibitor-I and tumour growth, invasion, and metastasis. Thromb. Haemost.91, 438–449.10.1160/TH03-12-0784Search in Google Scholar
Frederick, R., Pochet, L., Charlier, C., and Masereel, B. (2005). Modulators of the coagulation cascade: focus and recent advances in inhibitors of tissue factor, factor VIIa and their complex. Curr. Med. Chem.12, 397–417.10.2174/0929867053363108Search in Google Scholar
Frenette, G., Tremblay, R.R., Lazure, C., and Dube, J.Y. (1997). Prostatic kallikrein hK2, but not prostate-specific antigen (hK3), activates single-chain urokinase-type plasminogen activator. Int. J. Cancer71, 897–899.10.1002/(SICI)1097-0215(19970529)71:5<897::AID-IJC31>3.0.CO;2-2Search in Google Scholar
Garner, E.I. (2005). Advances in the early detection of ovarian carcinoma. J. Reprod. Med.50, 447–453.Search in Google Scholar
Gleeson, N.C., Hill, B.J., Moscinski, L.C., Mark, J.E., Roberts, W.S., Hoffman, M-S., Fiorica, J-V., and Cavanagh, D. (1996). Urokinase plasminogen activator in ovarian cancer. Eur. J. Gynaecol. Oncol.17, 110–113.Search in Google Scholar
Harbeck, N., Kates, R., Ulm, K., Graeff, H., and Schmitt, M. (2000). Neural network analysis of follow-up data in primary breast cancer. Int. J. Biol. Markers15, 116–122.10.1177/172460080001500123Search in Google Scholar
Jerez-Aragones, J.M., Gomez-Ruiz, J.A., Ramos-Jimenez, G., Munoz-Perez, J., and Alba-Corlejo, E. (2003). A combined neural network and decision trees model for prognosis of breast cancer relapse. Artif. Intell. Med.27, 45–63.10.1016/S0933-3657(02)00086-6Search in Google Scholar
Johann, D.J. Jr., McGuigan, M.D., Patel, A.R., Tomov, S., Ross, S., Conrads, T.P., Veenstra, T.D., Fishman, D.A., Whiteley, G.R., Petricoin, E.F. III, and Liotta, L.A. (2004). Clinical proteomics and biomarker discovery. Ann. NY Acad. Sci.1022, 295–305.10.1196/annals.1318.045Search in Google Scholar
Kates, R., Schmitt M., and Harbeck N. (2003) Advanced statistical methods for the definition of new staging models. Recent Results Cancer Res.62, 101–113.10.1007/978-3-642-59349-9_9Search in Google Scholar
Kishi, T., Grass, L., Soosaipillai, A., Scorilas, A., Harbeck, N., Schmalfeldt, B., Dorn, J., Mysliwiec, M., Schmitt, M., and Diamandis, E.P. (2003). Human kallikrein 8: a novel biomarker for ovarian carcinoma. Cancer Res.63, 2771–2774.Search in Google Scholar
Konecny, G., Untch, M., Pihan, A., Kimmig, R., Gropp, M., Stieber, P., Hepp, H., Slamon, D., and Pegram, M. (2001). Association of urokinase-type plasminogen activator and its inhibitor with disease progression and prognosis in ovarian cancer. Clin. Cancer Res.7, 1743–1749.Search in Google Scholar
Kuhn, W., Pache, L., Schmalfeldt, B., Dettmar, P., Schmitt, M., Jänicke, F., and Graeff, H. (1994). Urokinase (uPA) and PAI-1 predict survival in advanced ovarian cancer patients (FIGO III) after radical surgery and platinum-based chemotherapy. Gynecol. Oncol.55, 401–409.10.1006/gyno.1994.1313Search in Google Scholar
Kuhn, W., Schmalfeldt, B., Reuning, U., Pache, L., Berger, U., Ulm, K., Harbeck, N., Späthe, K., Dettmar, P., Höfler, H., et al. (1999). Prognostic significance of urokinase (uPA) and its inhibitor PAI-1 for survival in advanced ovarian carcinoma stage FIGO IIIc. Br. J. Cancer79, 1746–1751.10.1038/sj.bjc.6690278Search in Google Scholar
List, K., Jensen, O.N., Bugge, T.H., Lund, L.R., Ploug, M., Danø, K., and Behrendt, N. (2000). Plasminogen-independent initiation of the pro-urokinase activation cascade in vivo. Activation of pro-urokinase by glandular kallikrein (mGK-6) in plasminogen-deficient mice. Biochemistry39, 508–515.Search in Google Scholar
Luo, L.Y., Bunting, P., Scorilas, A., and Diamandis, E.P. (2001). Human kallikrein 10: a novel tumor marker for ovarian carcinoma? Clin. Chim. Acta306, 111–118.10.1016/S0009-8981(01)00401-6Search in Google Scholar
Luo, L.Y., Katsaros, D., Scorilas, A., Fracchioli, S., Bellino, R., van Gramberen, M., de Bruijn, H., Henrik, A., Stenman, UH., Massobrio, M., et al. (2003). The serum concentration of human kallikrein 10 represents a novel biomarker for ovarian cancer diagnosis and prognosis. Cancer Res.63, 807–811.Search in Google Scholar
Magklara, A., Scorilas, A., Katsaros, D., Massobrio, M., Yousef, G.M., Fracchioli, S., Danese, S., and Diamandis, E.P. (2001). 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.Search in Google Scholar
Myohanen, H. and Vaheri, A. (2004). Regulation and interactions in the activation of cell-associated plasminogen. Cell. Mol. Life Sci.61, 2840–2858.10.1007/s00018-004-4230-9Search in Google Scholar PubMed
Obiezu, C.V. and Diamandis, E.P. (2005). Human tissue kallikrein gene family: applications in cancer. Cancer Lett.224, 1–22.10.1016/j.canlet.2004.09.024Search in Google Scholar PubMed
Paliouras, M. and Diamandis, E.P. (2006). The kallikrein world: an update on the human tissue kallikreins. Biol. Chem.387, 643–652.10.1515/BC.2006.083Search in Google Scholar PubMed
Reuning, U., Magdolen, V., Wilhelm, O., Fischer, K., Lutz, V., Graeff, H., and Schmitt, M. (1998). Multifunctional potential of the plasminogen activation system in tumor invasion and metastasis. Int. J. Oncol.13, 893–906.10.3892/ijo.13.5.893Search in Google Scholar PubMed
Reuning, U., Magdolen, V., Hapke, S., and Schmitt, M. (2003). Molecular and functional interdependence of the urokinase-type plasminogen activator system with integrins. Biol. Chem.384, 1119–1131.10.1515/BC.2003.125Search in Google Scholar PubMed
Rosen, D.G., Wang, L., Atkinson, J.N., Yu, Y., Lu, K.H., Diamandis, E.P, Hellstrom, I., Mok, S.C., Liu, J., and Bast R.C. Jr. (2005). Potential markers that complement expression of CA125 in epithelial ovarian cancer. Gynecol. Oncol.99, 267–277.10.1016/j.ygyno.2005.06.040Search in Google Scholar PubMed
Schenone, M., Furie, B.C., and Furie, B. (2004). The blood coagulation cascade. Curr. Opin. Hematol.11, 272–277.10.1097/01.moh.0000130308.37353.d4Search in Google Scholar PubMed
Schmalfeldt, B., Kuhn, W., Reuning, U., Pache, L., Dettmar, P., Schmitt, M., Jänicke, F., Höfler, H., and Graeff, H. (1995). Primary tumor and metastasis in ovarian cancer differ in their content of urokinase-type plasminogen activator, its receptor, and inhibitors types 1 and 2. Cancer Res.55, 3958–3963.Search in Google Scholar
Schmitt, M., Harbeck, N., Thomssen, C., Wilhelm, O., Magdolen, V., Reuning, U., Ulm, K., Höfler, H., Jänicke, F., and Graeff, H. (1997). Clinical impact of the plasminogen activation system in tumor invasion and metastasis: prognostic relevance and target for therapy. Thromb. Haemost.78, 285–296.10.1055/s-0038-1657541Search in Google Scholar
Scorilas, A., Borgono, C.A., Harbeck, N., Dorn, J., Schmalfeldt, B., Schmitt, M., and Diamandis, E.P. (2004). Human kallikrein 13 protein in ovarian cancer cytosols: a new favourable prognostic marker. J. Clin. Oncol.22, 678–685.10.1200/JCO.2004.05.144Search in Google Scholar PubMed
Shi, Y. (2004). Caspase activation, inhibition, and reactivation: a mechanistic view. Protein Sci.13, 1979–1987.10.1110/ps.04789804Search in Google Scholar PubMed PubMed Central
Skrzydlewska, E., Sulkowska, M., Koda, M., and Sulkowski, S. (2005). Proteolytic-antiproteolytic balance and its regulation in carcinogenesis. World J. Gastroenterol.11, 1251–1266.10.3748/wjg.v11.i9.1251Search in Google Scholar
Takayama, T.K., McMullen, B.A., Nelson, P.S., Matsumura, M., and Fujikawa, K. (2001). 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. Biochemistry40, 15341–15348.10.1021/bi015775eSearch in Google Scholar
van der Burg, M.E., Henzen-Logmans, S.C., Berns, E.M., van Putten, W.L., Klijn, J.G., and Foekens, J.A. (1996). Expression of urokinase-type plasminogen activator (uPA) and its inhibitor PAI-1 in benign, borderline, malignant primary and metastatic ovarian tumors. Int. J. Cancer69, 475–479.10.1002/(SICI)1097-0215(19961220)69:6<475::AID-IJC10>3.0.CO;2-0Search in Google Scholar
Whitehouse, C. and Solomon, E. (2003). Current status of the molecular characterization of the ovarian cancer antigen CA125 and implications for its use in clinical screening. Gynecol. Oncol.88, 152–157.10.1006/gyno.2002.6708Search in Google Scholar
Yousef, G.M. and Diamandis, E.P. (2002). Human tissue kallikreins: a new enzymatic cascade pathway? Biol. Chem.383, 1045–1057.10.1515/BC.2002.113Search in Google Scholar
Yousef, G.M., Kyriakopoulou, L.G., Scorilas, A., Fracchioli, S., Ghiringhello, B., Zarghooni, M., Chang, A., Diamandis, M., Giardina, G., Hartwick, W.J., et al. (2001). Quantitative expression of the human kallikrein gene 9 (KLK9) in ovarian cancer: a new independent and favorable prognostic marker. Cancer Res.61, 7811–7618.Search in Google Scholar
Yousef, G.M., Polymeris, M.E., Yacoub, G.M., Scorilas, A., Soosaipillai, A., Popalis, S., Fracchioli, S., Katsaros, D., and Diamandis, E.P. (2003). Parallel overexpression of seven kallikrein genes in ovarian cancer. Cancer Res.63, 2223–2227.Search in Google Scholar
Yousef, G.M., Obiezu, C.V., Luo, L.Y., Magklara, A., Borgono, C.A., Kishi, T., Memari, N., Michael, I.P., Sidiropoulos, M., Kurlender, L., et al. (2005). Human tissue kallikreins: from gene structure to function and clinical applications. Adv. Clin. Chem.39, 11–79.10.1016/S0065-2423(04)39002-5Search in Google Scholar
Zhang, Z., Barnhill, S.D., Zhang, H., Xu, F., Yu, Y., Jacobs, I., Woolas, R.P., Berchuck, A., Madyastha, K.R., and Bast R.C. Jr. (1999). Combination of multiple serum markers using an artificial neural network to improve specificity in discriminating malignant from benign pelvic masses. Gynecol. Oncol.73, 56–61.10.1006/gyno.1999.5320Search in Google Scholar
©2006 by Walter de Gruyter Berlin New York
