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Oxytocin Synthesis and Oxytocin Receptor Expression by Cell Lines of Human Small Cell Carcinoma of the Lung Stimulate Tumor Growth through Autocrine/Paracrine Signaling¹

University of Liege, Institute of Pathology CHU-B23, +4, Center of Immunology & Laboratory of Neuroendocrinology [C. P., J-C. H., M-T. H., H. M., V. G., J-J. L.] and University of Liege, Institute of Pathology CHU-B23, Research Center on Experimental Cancerology & Laboratory of Molecular Oncology [R. W.], B-4000 Liege 1-Sart Tilman, Belgium, and University of Lille I, Endocrinology of Annelidae Laboratory, SN3, F-59655 Villeneuve d’Ascq, France [C. B.]

The objective of the present work was to investigate the existence of an oxytocin (OT)-mediated autocrine/paracrine signaling upon small cell carcinoma of the lung (SCCL) cell growth. In that view, OT receptor (OTR) expression, concomitant with OT synthesis and secretion, was evidenced on three different SCCL cell lines (DMS79, H146, and H345) and related to the vasopressin (VP) system. Specific OT, VP, OTR, V1a VP receptor (V1aR), and V1b/V3 VP receptor (V1bR/V3R) transcripts were identified by reverse transcription-PCR in all cell lines studied. Binding of ¹²⁵I-(d(CH₂)₅¹, Tyr(Me)²,Thr⁴,Orn⁸,Tyr⁹-NH₂)-vasotocin (OVTA) was observed on all SCCL cell lines, with a K_d (dissociation constant) ranging from 0.025–0.089 nM, depending on the cell line and the analytical method. Selectivity of ¹²⁵I-OVTA binding was confirmed by displacement curves obtained with various OTR and VP receptor agonists and antagonists (OT, OVTA, L-371,257, VP, F180). Immunocytochemistry identified cellular OT and VP, and peptide secretion was measured in supernatants of SCCL cultures. [³H]Thymidine incorporations, applied on H345 cells, demonstrated a dose-dependent mitogenic effect of exogenous OT (1 and 100 nM) that was abolished by the OTR antagonist OVTA. A decrease of proliferation was also observed with OVTA alone, showing a functional mitogenic effect of tumor-derived OT. Taken together, these observations demonstrate the existence of a functional OT-mediated autocrine/paracrine signaling actively implicated in growth and development of SCCL tumors. Furthermore, these findings point to the potential of OT antagonists for development as therapeutic agents for the treatment of SCCL.

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