Pituitary folliculo-stellate cells modulate tumor vasculature and extracellular matrix composition in experimental lactosomatotropinomas

Abstract

Folliculo-stellate cells (FSCs) constitute 5–10 % of the adenohypophysis and have been proposed as paracrine regulators of pituitary cells. However, their participation in pituitary tumor development remains unclear. We generated a lacto-somatotropic tumor model by subcutaneous injection of GH3 (lacto-somatotrophs) and the FSCs TtT/GF, isolated or combined, in immunodeficient mice, to study the role of the FSCs on tumor formation, hormone secretion, vascularization and extra-cellular matrix involvement. The co-culture of both cell lines let us gain insight into the proliferative and secretory action of FSC in pituitary tumor modulation. Our results showed that initially GH3:TtT/GF tumors had an earlier onset, but lately, TtT/GF cells restrained GH3:TtT/GF tumor growth and their Prl synthesis, although no differences were observed in the proliferative potential of tumor cells in vivo. Instead, TtT/GF cells exerted a direct mitogenic action on GH3 cells in vitro. Moreover, GH3 tumors had fewer irrigating vessels, lower vascular area and a higher VEGF/bFGF ratio that correlated with Hif1a expression, consistent with the tissue hypoxia and hemorrhage. These features were downregulated in their co-injected counterparts, which interestingly showed an increased deposition of collagens, glycoproteins and mucopolysaccharides extra-cellular matrix (EMC) components. Isolated TtT/GF injected cells did not generate tumors, but they developed fibrous masses characterized by collagen and high bFGF production. In conclusion, our results demonstrate that FSCs are dual regulators of pituitary tumor growth, with a mitogenic action on tumor cells but also a restrictive tumor effect on the cancer processes angiogenesis, hypoxia, and ECM remodeling.