Skip to main content
Top
Published in: Journal of Cancer Research and Clinical Oncology 10/2019

01-10-2019 | Ovarian Cancer | Original Article – Cancer Research

EP3 receptor is a prognostic factor in TA-MUC1-negative ovarian cancer

Authors: Bastian Czogalla, Christina Kuhn, Sabine Heublein, Elisa Schmöckel, Doris Mayr, Thomas Kolben, Fabian Trillsch, Alexander Burges, Sven Mahner, Udo Jeschke, Anna Hester

Published in: Journal of Cancer Research and Clinical Oncology | Issue 10/2019

Login to get access

Abstract

Purpose

Prostaglandin-mediated inflammatory reactions play a major role in different cancers. Recently, it has been observed that prostaglandin E2-receptor 3 (EP3) might be an independent prognostic factor for overall survival in cervical and endometrial cancer. The role of EP3 expression in ovarian cancer is currently unknown.

Methods

EP3 expression was analyzed by immunohistochemistry in 156 patient samples using the IR-scoring system. Expression levels were correlated with clinical and pathological parameters and with overall survival (OS) to assess for prognostic relevance. Data analysis was performed using Spearman’s correlations, Kruskal–Wallis test and Kaplan–Meier estimates.

Results

EP3 expression was significantly higher in clear-cell carcinoma (p < 0.001) compared to the other histological subtypes. No further correlations with clinical parameters could be found. EP3 expression correlated significantly with FSH-receptor expression (p < 0.001), galectin-1 expression in the tumor (p = 0.012) and with cytoplasmatic TA-MUC1 expression (p = 0.001). None of these parameters showed significant correlation with OS. In the TA-MUC1 negative subgroup, EP3 negative patients showed significantly longer OS (median OS: 102 months vs. 34 months in EP3 positive patients, p = 0.035), while EP3 did not appear to have prognostic relevance in the TA-MUC1-positive subgroup.

Conclusion

The potential prognostic relevance of EP3 expression for OS in TA-MUC1 negative patients might reflect an interplay between the COX and the MUC1 pathway, as it has been shown that MUC1 could induce COX2 expression. Our findings support the importance of the prostanoid signaling in TA-MUC1 negative ovarian cancer; however, future studies are necessary to characterize specific pathways and possible interactions.
Appendix
Available only for authorised users
Literature
go back to reference Aletti GD, Gostout BS, Podratz KC, Cliby WA (2006) Ovarian cancer surgical resectability: relative impact of disease, patient status, and surgeon. Gynecol Oncol 100(1):33–37CrossRefPubMed Aletti GD, Gostout BS, Podratz KC, Cliby WA (2006) Ovarian cancer surgical resectability: relative impact of disease, patient status, and surgeon. Gynecol Oncol 100(1):33–37CrossRefPubMed
go back to reference Ali-Fehmi R, Morris RT, Bandyopadhyay S, Che M, Schimp V, Malone JM Jr et al (2005) Expression of cyclooxygenase-2 in advanced stage ovarian serous carcinoma: correlation with tumor cell proliferation, apoptosis, angiogenesis, and survival. Am J Obstet Gynecol 192(3):819–825CrossRefPubMed Ali-Fehmi R, Morris RT, Bandyopadhyay S, Che M, Schimp V, Malone JM Jr et al (2005) Expression of cyclooxygenase-2 in advanced stage ovarian serous carcinoma: correlation with tumor cell proliferation, apoptosis, angiogenesis, and survival. Am J Obstet Gynecol 192(3):819–825CrossRefPubMed
go back to reference Baldwin LA, Huang B, Miller RW, Tucker T, Goodrich ST, Podzielinski I et al (2012) Ten-year relative survival for epithelial ovarian cancer. Obstet Gynecol 120(3):612–618CrossRefPubMed Baldwin LA, Huang B, Miller RW, Tucker T, Goodrich ST, Podzielinski I et al (2012) Ten-year relative survival for epithelial ovarian cancer. Obstet Gynecol 120(3):612–618CrossRefPubMed
go back to reference Bertagnolli MM, Eagle CJ, Zauber AG, Redston M, Solomon SD, Kim K et al (2006) Celecoxib for the prevention of sporadic colorectal adenomas. N Engl J Med 355(9):873–884CrossRefPubMed Bertagnolli MM, Eagle CJ, Zauber AG, Redston M, Solomon SD, Kim K et al (2006) Celecoxib for the prevention of sporadic colorectal adenomas. N Engl J Med 355(9):873–884CrossRefPubMed
go back to reference Chetry M, Thapa S, Hu X, Song Y, Zhang J, Zhu H et al (2018) The Role of galectins in tumor progression, treatment and prognosis of gynecological cancers. J Cancer 9(24):4742–4755CrossRefPubMedPubMedCentral Chetry M, Thapa S, Hu X, Song Y, Zhang J, Zhu H et al (2018) The Role of galectins in tumor progression, treatment and prognosis of gynecological cancers. J Cancer 9(24):4742–4755CrossRefPubMedPubMedCentral
go back to reference Dembo AJ, Davy M, Stenwig AE, Berle EJ, Bush RS, Kjorstad K (1990) Prognostic factors in patients with stage I epithelial ovarian cancer. Obstet Gynecol 75(2):263–273PubMed Dembo AJ, Davy M, Stenwig AE, Berle EJ, Bush RS, Kjorstad K (1990) Prognostic factors in patients with stage I epithelial ovarian cancer. Obstet Gynecol 75(2):263–273PubMed
go back to reference Dian D, Lenhard M, Mayr D, Heublein S, Karsten U, Goletz S et al (2013) Staining of MUC1 in ovarian cancer tissues with PankoMab-GEX detecting the tumour-associated epitope, TA-MUC1, as compared to antibodies HMFG-1 and 115D8. Histol Histopathol 28(2):239–244PubMed Dian D, Lenhard M, Mayr D, Heublein S, Karsten U, Goletz S et al (2013) Staining of MUC1 in ovarian cancer tissues with PankoMab-GEX detecting the tumour-associated epitope, TA-MUC1, as compared to antibodies HMFG-1 and 115D8. Histol Histopathol 28(2):239–244PubMed
go back to reference du Bois A, Reuss A, Pujade-Lauraine E, Harter P, Ray-Coquard I, Pfisterer J (2009) Role of surgical outcome as prognostic factor in advanced epithelial ovarian cancer: a combined exploratory analysis of 3 prospectively randomized phase 3 multicenter trials: by the Arbeitsgemeinschaft Gynaekologische Onkologie Studiengruppe Ovarialkarzinom (AGO-OVAR) and the Groupe d’Investigateurs Nationaux Pour les Etudes des Cancers de l’Ovaire (GINECO). Cancer 115(6):1234–1244CrossRefPubMed du Bois A, Reuss A, Pujade-Lauraine E, Harter P, Ray-Coquard I, Pfisterer J (2009) Role of surgical outcome as prognostic factor in advanced epithelial ovarian cancer: a combined exploratory analysis of 3 prospectively randomized phase 3 multicenter trials: by the Arbeitsgemeinschaft Gynaekologische Onkologie Studiengruppe Ovarialkarzinom (AGO-OVAR) and the Groupe d’Investigateurs Nationaux Pour les Etudes des Cancers de l’Ovaire (GINECO). Cancer 115(6):1234–1244CrossRefPubMed
go back to reference Emons G, Pahwa GS, Ortmann O, Knuppen R, Oberheuser F, Schulz KD (1990) LHRH-receptors and LHRH-agonist treatment in ovarian cancer: an overview. J Steroid Biochem Mol Biol 37(6):1003–1006CrossRefPubMed Emons G, Pahwa GS, Ortmann O, Knuppen R, Oberheuser F, Schulz KD (1990) LHRH-receptors and LHRH-agonist treatment in ovarian cancer: an overview. J Steroid Biochem Mol Biol 37(6):1003–1006CrossRefPubMed
go back to reference Harris RE (2009) Cyclooxygenase-2 (cox-2) blockade in the chemoprevention of cancers of the colon, breast, prostate, and lung. Inflammopharmacology 17(2):55–67CrossRefPubMed Harris RE (2009) Cyclooxygenase-2 (cox-2) blockade in the chemoprevention of cancers of the colon, breast, prostate, and lung. Inflammopharmacology 17(2):55–67CrossRefPubMed
go back to reference Hou R, Jiang L, Liu D, Lin B, Hu Z, Gao J et al (2017) Lewis(y) antigen promotes the progression of epithelial ovarian cancer by stimulating MUC1 expression. Int J Mol Med 40(2):293–302CrossRefPubMedPubMedCentral Hou R, Jiang L, Liu D, Lin B, Hu Z, Gao J et al (2017) Lewis(y) antigen promotes the progression of epithelial ovarian cancer by stimulating MUC1 expression. Int J Mol Med 40(2):293–302CrossRefPubMedPubMedCentral
go back to reference Kossai M, Leary A, Scoazec JY, Genestie C (2018) Ovarian cancer: a heterogeneous disease. Pathobiology 85(1–2):41–49CrossRefPubMed Kossai M, Leary A, Scoazec JY, Genestie C (2018) Ovarian cancer: a heterogeneous disease. Pathobiology 85(1–2):41–49CrossRefPubMed
go back to reference Ledermann J, Sehouli J, Zurawski B, Raspagliesi F, De Giorgi U, Banerjee S et al (2017) LBA41A double-blind, placebo-controlled, randomized, phase 2 study to evaluate the efficacy and safety of switch maintenance therapy with the anti-TA-MUC1 antibody PankoMab-GEX after chemotherapy in patients with recurrent epithelial ovarian carcinoma. Ann Oncol 28(suppl_8):viii46–viii50CrossRefPubMed Ledermann J, Sehouli J, Zurawski B, Raspagliesi F, De Giorgi U, Banerjee S et al (2017) LBA41A double-blind, placebo-controlled, randomized, phase 2 study to evaluate the efficacy and safety of switch maintenance therapy with the anti-TA-MUC1 antibody PankoMab-GEX after chemotherapy in patients with recurrent epithelial ovarian carcinoma. Ann Oncol 28(suppl_8):viii46–viii50CrossRefPubMed
go back to reference Matsumura N, Yamamoto M, Aruga A, Takasaki K, Nakano M (2002) Correlation between expression of MUC1 core protein and outcome after surgery in mass-forming intrahepatic cholangiocarcinoma. Cancer 94(6):1770–1776CrossRefPubMed Matsumura N, Yamamoto M, Aruga A, Takasaki K, Nakano M (2002) Correlation between expression of MUC1 core protein and outcome after surgery in mass-forming intrahepatic cholangiocarcinoma. Cancer 94(6):1770–1776CrossRefPubMed
go back to reference Mukherjee P, Basu GD, Tinder TL, Subramani DB, Bradley JM, Arefayene M et al (2009) Progression of pancreatic adenocarcinoma is significantly impeded with a combination of vaccine and COX-2 inhibition. J Immunol 182(1):216–224CrossRefPubMed Mukherjee P, Basu GD, Tinder TL, Subramani DB, Bradley JM, Arefayene M et al (2009) Progression of pancreatic adenocarcinoma is significantly impeded with a combination of vaccine and COX-2 inhibition. J Immunol 182(1):216–224CrossRefPubMed
go back to reference Niringiyumukiza JD, Cai H, Xiang W (2018) Prostaglandin E2 involvement in mammalian female fertility: ovulation, fertilization, embryo development and early implantation. Reprod Biol Endocrinol 16(1):43CrossRefPubMedPubMedCentral Niringiyumukiza JD, Cai H, Xiang W (2018) Prostaglandin E2 involvement in mammalian female fertility: ovulation, fertilization, embryo development and early implantation. Reprod Biol Endocrinol 16(1):43CrossRefPubMedPubMedCentral
go back to reference Obermajer N, Muthuswamy R, Odunsi K, Edwards RP, Kalinski P (2011) PGE(2)-induced CXCL12 production and CXCR38 expression controls the accumulation of human MDSCs in ovarian cancer environment. Can Res 71(24):7463–7470CrossRef Obermajer N, Muthuswamy R, Odunsi K, Edwards RP, Kalinski P (2011) PGE(2)-induced CXCL12 production and CXCR38 expression controls the accumulation of human MDSCs in ovarian cancer environment. Can Res 71(24):7463–7470CrossRef
go back to reference Perales-Puchalt A, Svoronos N, Rutkowski MR, Allegrezza MJ, Tesone AJ, Payne KK et al (2017) Follicle-stimulating hormone receptor is expressed by most ovarian cancer subtypes and is a safe and effective immunotherapeutic target. Clin Cancer Res 23(2):441–453CrossRefPubMed Perales-Puchalt A, Svoronos N, Rutkowski MR, Allegrezza MJ, Tesone AJ, Payne KK et al (2017) Follicle-stimulating hormone receptor is expressed by most ovarian cancer subtypes and is a safe and effective immunotherapeutic target. Clin Cancer Res 23(2):441–453CrossRefPubMed
go back to reference Rask K, Zhu Y, Wang W, Hedin L, Sundfeldt K (2006) Ovarian epithelial cancer: a role for PGE2-synthesis and signalling in malignant transformation and progression. Mol Cancer 5:62CrossRefPubMedPubMedCentral Rask K, Zhu Y, Wang W, Hedin L, Sundfeldt K (2006) Ovarian epithelial cancer: a role for PGE2-synthesis and signalling in malignant transformation and progression. Mol Cancer 5:62CrossRefPubMedPubMedCentral
go back to reference Rodriguez-Burford C, Barnes MN, Oelschlager DK, Myers RB, Talley LI, Partridge EE et al (2002) Effects of nonsteroidal anti-inflammatory agents (NSAIDs) on ovarian carcinoma cell lines: preclinical evaluation of NSAIDs as chemopreventive agents. Clin Cancer Res 8(1):202–209PubMed Rodriguez-Burford C, Barnes MN, Oelschlager DK, Myers RB, Talley LI, Partridge EE et al (2002) Effects of nonsteroidal anti-inflammatory agents (NSAIDs) on ovarian carcinoma cell lines: preclinical evaluation of NSAIDs as chemopreventive agents. Clin Cancer Res 8(1):202–209PubMed
go back to reference Semmlinger A, von Schoenfeldt V, Wolf V, Meuter A, Kolben TM, Kolben T et al (2018) EP3 (prostaglandin E2 receptor 3) expression is a prognostic factor for progression-free and overall survival in sporadic breast cancer. BMC Cancer 18(1):431CrossRefPubMedPubMedCentral Semmlinger A, von Schoenfeldt V, Wolf V, Meuter A, Kolben TM, Kolben T et al (2018) EP3 (prostaglandin E2 receptor 3) expression is a prognostic factor for progression-free and overall survival in sporadic breast cancer. BMC Cancer 18(1):431CrossRefPubMedPubMedCentral
go back to reference Tinder TL, Subramani DB, Basu GD, Bradley JM, Schettini J, Million A et al (2008) MUC1 enhances tumor progression and contributes toward immunosuppression in a mouse model of spontaneous pancreatic adenocarcinoma. J Immunol 181(5):3116–3125CrossRefPubMed Tinder TL, Subramani DB, Basu GD, Bradley JM, Schettini J, Million A et al (2008) MUC1 enhances tumor progression and contributes toward immunosuppression in a mouse model of spontaneous pancreatic adenocarcinoma. J Immunol 181(5):3116–3125CrossRefPubMed
go back to reference Tsujii M, Kawano S, DuBois RN (1997) Cyclooxygenase-2 expression in human colon cancer cells increases metastatic potential. Proc Natl Acad Sci USA 94(7):3336–3340CrossRefPubMedPubMedCentral Tsujii M, Kawano S, DuBois RN (1997) Cyclooxygenase-2 expression in human colon cancer cells increases metastatic potential. Proc Natl Acad Sci USA 94(7):3336–3340CrossRefPubMedPubMedCentral
go back to reference Vergote I, De Brabanter J, Fyles A, Bertelsen K, Einhorn N, Sevelda P et al (2001) Prognostic importance of degree of differentiation and cyst rupture in stage I invasive epithelial ovarian carcinoma. Lancet 357(9251):176–182CrossRefPubMed Vergote I, De Brabanter J, Fyles A, Bertelsen K, Einhorn N, Sevelda P et al (2001) Prognostic importance of degree of differentiation and cyst rupture in stage I invasive epithelial ovarian carcinoma. Lancet 357(9251):176–182CrossRefPubMed
go back to reference Williams CS, Mann M, DuBois RN (1999) The role of cyclooxygenases in inflammation, cancer, and development. Oncogene 18(55):7908–7916CrossRefPubMed Williams CS, Mann M, DuBois RN (1999) The role of cyclooxygenases in inflammation, cancer, and development. Oncogene 18(55):7908–7916CrossRefPubMed
go back to reference Ye Y, Vattai A, Ditsch N, Kuhn C, Rahmeh M, Mahner S et al (2018) Prostaglandin E2 receptor 3 signaling is induced in placentas with unexplained recurrent pregnancy losses. Endocr Connect 7(5):749–761CrossRefPubMedPubMedCentral Ye Y, Vattai A, Ditsch N, Kuhn C, Rahmeh M, Mahner S et al (2018) Prostaglandin E2 receptor 3 signaling is induced in placentas with unexplained recurrent pregnancy losses. Endocr Connect 7(5):749–761CrossRefPubMedPubMedCentral
go back to reference Zhu J, Trillsch F, Mayr D, Kuhn C, Rahmeh M, Hofmann S et al (2018) Prostaglandin receptor EP3 regulates cell proliferation and migration with impact on survival of endometrial cancer patients. Oncotarget 9(1):982–994PubMed Zhu J, Trillsch F, Mayr D, Kuhn C, Rahmeh M, Hofmann S et al (2018) Prostaglandin receptor EP3 regulates cell proliferation and migration with impact on survival of endometrial cancer patients. Oncotarget 9(1):982–994PubMed
go back to reference Zhuandi G, Tuanjie C, Luju L, Abdiryim A, Yingying D, Haoqin L et al (2018) FSH receptor binding inhibitor restrains follicular development and possibly attenuates carcinogenesis of ovarian cancer through down-regulating expression levels of FSHR and ERbeta in normal ovarian tissues. Gene 668:174–181CrossRefPubMed Zhuandi G, Tuanjie C, Luju L, Abdiryim A, Yingying D, Haoqin L et al (2018) FSH receptor binding inhibitor restrains follicular development and possibly attenuates carcinogenesis of ovarian cancer through down-regulating expression levels of FSHR and ERbeta in normal ovarian tissues. Gene 668:174–181CrossRefPubMed
Metadata
Title
EP3 receptor is a prognostic factor in TA-MUC1-negative ovarian cancer
Authors
Bastian Czogalla
Christina Kuhn
Sabine Heublein
Elisa Schmöckel
Doris Mayr
Thomas Kolben
Fabian Trillsch
Alexander Burges
Sven Mahner
Udo Jeschke
Anna Hester
Publication date
01-10-2019
Publisher
Springer Berlin Heidelberg
Published in
Journal of Cancer Research and Clinical Oncology / Issue 10/2019
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI
https://doi.org/10.1007/s00432-019-03017-8

Other articles of this Issue 10/2019

Journal of Cancer Research and Clinical Oncology 10/2019 Go to the issue