Abstract
Objective
Equilibrative and concentrative nucleoside transporters (ENTs and CNTs) mediate the cellular uptake of anticancer nucleosides and sensitivity to such compounds. We studied the expression of ENTs and CNTs in ovarian carcinoma effusions.
Methods
ENT1, ENT2, ENT4 and CNT3 expression was analyzed in 66 ovarian carcinoma effusions (61 peritoneal, 5 pleural) from 64 ovarian carcinoma patients by flow cytometry. The majority of patients received platinum-based chemotherapy. Results were analyzed for association with clinicopathologic parameters and survival.
Results
With the exception of one ENT2-negative effusion, ENT1, ENT2, ENT4 and CNT3 protein was detected on carcinoma cells in all effusions, with expression observed in 1–95% of tumor cells. Nucleoside transporter expression was comparable between peritoneal and pleural effusions and was unrelated to age, tumor grade, International Federation of Gynecology and Obstetrics (FIGO) stage, residual tumor volume after surgery, previous exposure to chemotherapy and response to chemotherapy at diagnosis (P > 0.05). No correlation was found between ENT or CNT expression and overall survival or progression-free survival, although higher ENT2 expression was associated with a trend for longer overall (45 vs. 23 months; P = 0.055) and progression-free (17 vs. 5 months; P = 0.087) survival.
Conclusion
Nucleoside transporters are frequently expressed in ovarian carcinoma effusions, but their expression generally appears to be unrelated to chemoresponse in this cancer in a cohort of patients treated by platinum-based chemotherapy. The role of ENT2 as a prognostic marker in this disease, as well as the role of these molecules in determining chemoresponse in patients treated by nucleoside analogs, merits further research.
Similar content being viewed by others
References
Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ (2009) Cancer statistics, 2009. CA Cancer J Clin 59:225–249
Davidson B (2001) Ovarian carcinoma and serous effusions. Changing views regarding tumor progression and review of current literature. Anal Cell Pathol 23:107–128
Baldwin SA, Beal PR, Yao SYM, King AE, Cass CE, Young JD (2004) The equilibrative nucleoside transporter family, SLC29. Pflügers Arch 447:735–743
Damaraju VL, Damaraju S, Young JD, Baldwin SA, Mackey J, Sawyer MB, Cass CE (2003) Nucleoside anticancer drugs: the role of nucleoside transporters in resistance to cancer chemotherapy. Oncogene 22:7524–7536
Galmarini CM, Mackey JR, Dumontet C (2002) Nucleoside analogues and nucleobases in cancer treatment. Lancet Oncol 3:415–424
Farré X, Guillén-Gómez E, Sánchez L, Hardisson D, Plaza Y, Lloberas J, Casado FJ, Palacios J, Pastor-Anglada M (2004) Expression of the nucleoside-derived drug transporters hCNT1, hENT1 and hENT2 in gynecologic tumors. Int J Cancer 112:959–966
Ferrandina G, Mey V, Nannizzi S, Ricciardi S, Petrillo M, Ferlini C, Danesi R, Scambia G, Del Tacca M (2010) Expression of nucleoside transporters, deoxycitidine kinase, ribonucleotide reductase regulatory subunits, and gemcitabine catabolic enzymes in primary ovarian cancer. Cancer Chemother Pharmacol 65:679–686
Dong HP, Holth A, Berner A, Davidson B, Risberg B (2007) Flow cytometric immunphenotyping of epithelial cancer cells in effusions–technical considerations and pitfalls. Cytometry B Clin Cytom 72:332–343
Davidson B, Nielsen S, Christensen J, Asschenfeldt P, Berner A, Risberg B, Johansen P (2001) The role of desmin and N-cadherin in effusion cytology: a comparative study using established markers of mesothelial and epithelial cells. Am J Surg Pathol 25:1405–1412
Dong HP, Kleinberg L, Davidson B, Risberg B (2008) Methods for simultaneous measurement of apoptosis and cell surface phenotype of epithelial cells in effusions by flow cytometry. Nat Protoc 3:955–964
Dong HP, Holth A, Kleinberg L, Ruud MG, Elstrand MB, Tropé CG, Davidson B, Risberg B (2009) Evaluation of cell surface expression of phosphatidylserine in ovarian carcinoma effusions using the annexin-V/7-AAD assay: clinical relevance and comparison with other apoptosis parameters. Am J Clin Pathol 132:756–762
Miller AB, Hoogstraten B, Staquet M, Winkler A (1981) Reporting results of cancer treatment. Cancer 47:207–214
Cannistra SA (2004) Cancer of the ovary. N Engl J Med 351:2519–2529
Yap TA, Carden CP, Kaye SB (2009) Beyond chemotherapy: targeted therapies in ovarian cancer. Nat Rev Cancer 9:167–181
Lund B, Hansen OP, Theilade K, Hansen M, Neijt JP (1994) Phase II study of gemcitabine (2’, 2’-difluorodeoxycytidine) in previously treated ovarian cancer patients. J Natl Cancer Inst 86:1530–1533
Lorusso D, Di Stefano A, Fanfani F, Scambia G (2006) Role of gemcitabine in ovarian cancer treatment. Ann Oncol 17(Suppl 5):v188–v194
Pfisterer J, Plante M, Vergote I, du Bois A, Hirte H, Lacave AJ, Wagner U, Stähle A, Stuart G, Kimmig R, Olbricht S, Le T, Emerich J, Kuhn W, Bentley J, Jackisch C, Lück H, Rochon J, Zimmermann AH, Eisenhauer E (2006) Gemcitabine plus carboplatin compared with carboplatin in patients with platinum-sensitive recurrent ovarian cancer: an intergroup trial of the AGO-OVAR, the NCIC CTG, and the EORTC GCG. J Clin Oncol 24:4699–4707
Davidson B, Dong HP, Berner A, Christensen J, Nielsen S, Johansen P, Bryne M, Asschenfeldt P, Risberg B (2002) Detection of malignant epithelial cells in effusions using flow cytometric immunophenotyping: an analysis of 92 cases. A J Clin Pathol 118:85–92
Pennycooke M, Chaudary N, Shuralyova I, Zhang Y, Coe IR (2001) Differential expression of human nucleoside transporters in normal and tumor tissue. Biochem Biophys Res Commun 280:951–959
Spratlin J, Sangha R, Glubrecht D, Dabbagh L, Young JD, Dumontet C, Cass C, Lai R, Mackey JR (2004) The absence of human equilibrative nucleoside transporter 1 is associated with reduced survival in patients with gemcitabine-treated pancreas adenocarcinoma. Clin Cancer Res 10:6956–6961
Maréchal R, Mackey JR, Lai R, Demetter P, Peeters M, Polus M, Cass CE, Young J, Salmon I, Devière J, van Laethem J (2009) Human equilibrative nucleoside transporter 1 and human concentrative nucleoside transporter 3 predict survival after adjuvant gemcitabine therapy in resected pancreatic adenocarcinoma. Clin Cancer Res 15:2913–2919
Acknowledgments
This study was supported by a grant from the Norwegian Cancer Society, by the Research Foundation of the Norwegian Radium Hospital and by the Inger and John Fredriksen Foundation for Ovarian Cancer Research. Annika J. Bock is the receiver of a MD/PhD student scholarship from the Faculty of Medicine, University of Oslo.
Conflict of interest
None.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Bock, A.J., Dong, H.P., Tropé, C.G. et al. Nucleoside transporters are widely expressed in ovarian carcinoma effusions. Cancer Chemother Pharmacol 69, 467–475 (2012). https://doi.org/10.1007/s00280-011-1716-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00280-011-1716-7