Inhibition of activin signalling reduces the growth of LβT2 gonadotroph pituitary tumours in mouse

in Endocrine-Related Cancer
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Audrey Ziverec Cancer Research Centre of Lyon (CRCL), INSERM U1052, CNRS UMR5286, Claude Bernard University, Lyon, France

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Marie Chanal Cancer Research Centre of Lyon (CRCL), INSERM U1052, CNRS UMR5286, Claude Bernard University, Lyon, France

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Perrine Raymond Cancer Research Centre of Lyon (CRCL), INSERM U1052, CNRS UMR5286, Claude Bernard University, Lyon, France

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Mirela Diana Ilie Cancer Research Centre of Lyon (CRCL), INSERM U1052, CNRS UMR5286, Claude Bernard University, Lyon, France
Endocrinology Department, “C.I. Parhon” National Institute of Endocrinology, Bucharest, Romania

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Dario De Alcubierre Cancer Research Centre of Lyon (CRCL), INSERM U1052, CNRS UMR5286, Claude Bernard University, Lyon, France

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Arja Pasternack Department of Physiology, Faculty of Medicine, University of Helsinki, Helsinki, Finland

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Olli Ritvos Department of Physiology, Faculty of Medicine, University of Helsinki, Helsinki, Finland

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Gerald Raverot Cancer Research Centre of Lyon (CRCL), INSERM U1052, CNRS UMR5286, Claude Bernard University, Lyon, France
Faculté de Médecine Lyon Est, Université Lyon 1, Lyon, France
Department of Endocrinology, Reference center for rare pituitary disease (HYPO), Groupement Hospitalier EST, Hospices Civils de Lyon, University of Lyon, Lyon, France

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https://orcid.org/0000-0002-9517-338X
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Philippe Bertolino Cancer Research Centre of Lyon (CRCL), INSERM U1052, CNRS UMR5286, Claude Bernard University, Lyon, France

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https://orcid.org/0000-0001-8064-8269

Correspondence should be addressed to P Bertolino: Philippe.Bertolino@inserm.fr
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Pituitary tumours are benign neoplasms that derive from hormone-producing cells of the pituitary gland. While medical treatments have emerged for most subtypes, gonadotroph tumours that express follicle-stimulating hormone (FSH) and/or luteinizing hormone still lack therapeutic options apart from surgery and radiotherapy. Activin ligands are physiological regulators of production and secretion of FSH by gonadotroph cells, but their role in gonadotroph tumourigenesis remains little explored. Using the LβT2 mouse gonadotroph cell line which produces FSH under activin stimulation, we first tested whether subcutaneous xenografts of LβT2 cells resulted in tumour formation in Rag2KO mice. Histological analysis confirmed the presence of LβT2 tumours with endothelial cells and macrophages in their microenvironment. FSH expression was found in a subset of clusters of LβT2 cells in the tumours. We subsequently addressed the consequences of targeting activin signalling via injection of a soluble activin decoy receptor (sActRIIB-Fc). sActRIIB-Fc treatment resulted in significantly decreased LβT2 tumour volume. Reduced Smad2 phosphorylation as well as inhibition of tumour-induced FSH production confirmed the efficient targeting of activin-downstream signalling in treated tumours. More interestingly, treated tumours showed significantly fewer endothelial cells associated with reduced Vegfa expression. In vitro treatment of LβT2 cells with sActRIIB-Fc had no effect on cell proliferation or apoptosis, but Vegfa expression was inhibited, pointing to a likely paracrine effect of LβT2 cells on endothelial cells through activin-mediated Vegfa regulation. Further in vitro and in vivo studies are now needed to pinpoint the exact roles of activin signalling in these processes prior to translating these observations to the clinic.

 

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