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

Abstract

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 FSH, and/or LH 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 tumorigenesis remains little explored. Using the LT2 mouse gonadotroph-cell line which produces FSH under Activin-stimulation, we first tested whether sub-cutaneous xenografts of LT2 cells resulted in tumour formation in Rag2KO mice. Histological analysis confirmed the presence of LT2-tumours with endothelial cells and macrophages in their microenvironment. FSH expression was found in a subset of clusters of LT2 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 LT2 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 LT2 cells with sActRIIB-Fc had no effect on cell proliferation or apoptosis, but Vegfa expression was inhibited, pointing to a likely paracrine effect of LT2 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.