title: CD73 is associated with poor prognosis in high-grade serous ovarian cancer.
abstract: The cell surface nucleotidase CD73 is an immunosuppressive enzyme involved in tumor progression and metastasis. Although preclinical studies suggest that CD73 can be targeted for cancer treatment, the clinical impact of CD73 in ovarian cancer remains unclear. In this study, we investigated the prognostic value of CD73 in high-grade serous (HGS) ovarian cancer using gene and protein expression analyses. Our results demonstrate that high levels of CD73 are significantly associated with shorter disease-free survival and overall survival in patients with HGS ovarian cancer. Furthermore, high levels of CD73 expression in ovarian tumor cells abolished the good prognosis associated with intraepithelial CD8(+) cells. Notably, CD73 gene expression was highest in the C1/stromal molecular subtype of HGS ovarian cancer and positively correlated with an epithelial-to-mesenchymal transition gene signature. Moreover, in vitro studies revealed that CD73 and extracellular adenosine enhance ovarian tumor cell growth as well as expression of antiapoptotic BCL-2 family members. Finally, in vivo coinjection of ID8 mouse ovarian tumor cells with mouse embryonic fibroblasts showed that CD73 expression in fibroblasts promotes tumor immune escape and thereby tumor growth. In conclusion, our study highlights a role for CD73 as a prognostic marker of patient survival and also as a candidate therapeutic target in HGS ovarian cancers.
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Québec, Canada. Institut du Cancer de Montréal, Montréal, Québec, Canada. Faculté de Pharmacie, Université de Montréal, Québec, Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: Turcotte
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Québec, Canada. Institut du Cancer de Montréal, Montréal, Québec, Canada.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Spring
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Québec, Canada. Institut du Cancer de Montréal, Montréal, Québec, Canada.
authors.forename: Sandra
authors.initials: S
authors.lastname: Pommey
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Québec, Canada. Institut du Cancer de Montréal, Montréal, Québec, Canada.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Chouinard
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Québec, Canada. Institut du Cancer de Montréal, Montréal, Québec, Canada.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Cousineau
authors.affiliation: Computational Sciences and Statistical Analysis, Jackson Laboratory for Genomic Medicine, Farmington, Connecticut.
authors.forename: Joshy
authors.initials: J
authors.lastname: George
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Chen
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Deena M A
authors.initials: DM
authors.lastname: Gendoo
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Haibe-Kains
authors.affiliation: Department of Obstetrics and Gynecology, University Hospital Frankfurt, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Karn
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Québec, Canada. Department of Medicine, Université de Montréal, Quebec, Canada. Department of Pathology, Centre hospitalier de l'Université de Montréal (CHUM), Quebec, Canada.
authors.forename: Kurosh
authors.initials: K
authors.lastname: Rahimi
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Québec, Canada. Institut du Cancer de Montréal, Montréal, Québec, Canada.
authors.forename: Cécile
authors.initials: C
authors.lastname: Le Page
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Québec, Canada. Institut du Cancer de Montréal, Montréal, Québec, Canada. Department of Pathology, Centre hospitalier de l'Université de Montréal (CHUM), Quebec, Canada. Division of Gynecologic-Oncology, Department of Obstectrics and Gynecology, Université de Montréal, Montreal, Canada.
authors.forename: Diane
authors.initials: D
authors.lastname: Provencher
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Québec, Canada. Institut du Cancer de Montréal, Montréal, Québec, Canada. Department of Pathology, Centre hospitalier de l'Université de Montréal (CHUM), Quebec, Canada. Division of Gynecologic-Oncology, Department of Obstectrics and Gynecology, Université de Montréal, Montreal, Canada.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Mes-Masson
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Québec, Canada. Institut du Cancer de Montréal, Montréal, Québec, Canada. Faculté de Pharmacie, Université de Montréal, Québec, Canada. john.stagg@umontreal.ca.
authors.forename: John
authors.initials: J
authors.lastname: Stagg
mesh_terms: D015720:5'-Nucleotidase / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001081:Apyrase / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D018572:Disease-Free Survival; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009375:Neoplasms, Glandular and Epithelial / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D019139:Tumor Escape / Q000276:immunology
chemical_list: D015703:Antigens, CD; D014408:Biomarkers, Tumor; D058851:GPI-Linked Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D015720:5'-Nucleotidase; C548241:NT5E protein, human; D001081:Apyrase; C067869:CD39 antigen