Involvement of the gp130 cytokine transducer in MtT/S pituitary somatotroph tumour development in an autocrine-paracrine model

Abstract

Objective: gp130 cytokines are placed as auto-paracrine regulators of pituitary function, since they, as well as their receptors, have been shown to be expressed in and to act in normal and tumoral anterior pituitary cells. The objective of this work was to study their involvement in a model that shows the interaction between different cellular types that participate in a tumorigenic process. Design: The dependence of a pituitary somatotrophic cell line (MtT/S) on a gp130 cytokine-producing folliculostellate (FS) cell line (TtT/GF) for tumorigenesis in vivo has been described. In order to study the participation of gp130 cytokines in the auto-paracrine stimulation of MtT/S growth, we generated MtT/S gp130 sense (gp130-S) and gp130 antisense (gp130-AS) clones stably transfected with pcDNA3/gp130 sense and pcDNA3/gp130 antisense vectors respectively. Methods and results: Functional characterization studies revealed that gp130-AS clones have an inhibited gp130 signalling, and proliferation studies showed that they have an impaired response to gp130 cytokines but respond normally to other independent stimuli. When injected into nude mice, MtT/S clones respond differently depending on cell number; at high concentrations MtT/S clones alone generated tumours equivalent in size to tumours derived from MtT/S plus TtT/GF cells. At low concentrations, MtT/S sense and control clones generated tumours of smaller size than tumours derived from these same clones plus TtT/GF cells, showing a dependence on FS cells. In both cases MtT/S gp130-AS clones had impaired tumour development. Furthermore, vessel density was significantly lower in tumours derived from gp130-AS plus TtT/GF cells. Conclusions: This study underlines the importance of gp130 cytokines in proliferation and establishes its role in auto-paracrine pituitary growth regulation.European Journal of Endocrinology 151 595-604

Programmed cell senescence: role of IL-6 in the pituitary

“…In both cases, MtT/S antisense had an impaired tumor development. Moreover, vessel density was significantly lower in tumors derived from MtT/S antisense plus TtT/GF cells (Graciarena et al 2004). In these interactive processes, paracrine IL-6 plays a prominent role by stimulating tumor cell proliferation, tumor neovascularization and extracellular matrix remodeling.…”

“…In vitro studies have shown additional evidence of this. The rat somatotrophic pituitary MtT/S cells overexpressing (sense) or lacking (antisense) gp130 protein were coinoculated with the TtT/GF cell, a mouse FS-like cell line, in nude mice (Graciarena et al 2004). At low cell concentration, MtT/S sense and control clones generated tumors of a smaller size than those derived from these same clones plus TtT/GF cells, showing a clear dependence on FS cells.…”

“…Pituitary tumorigenesis appears to be regulated by extrinsic and intrinsic factors. It has been demonstrated that paracrine IL-6's effects may allow initial pituitary cell growth (required for senescence bypass) , Arzt 2001, Graciarena et al 2004, whereas autocrine IL-6 in the same tumor triggers senescence and restrains aggressive growth and malignant transformation (Sapochnik et al 2016). This review provides an insight into the current understanding of the role of IL-6 in the regulation of pituitary pathogenesis, focusing in the autocrine action of IL-6.…”

Pituitary Stem Cells During Normal Physiology and Disease

“…An observation that was indicative of the potential of these cluster cells was that actively proliferating cells, as marked by immunofluorescence of Ki67, were readily detected in close proximity to the cell clusters in both mouse and human ACP (Gaston-Massuet et al 2011). Several of the identified cytokines and growth factors have been shown to play a role in normal pituitary physiology as well as in pituitary adenomas (Arzt et al 1999(Arzt et al , 2009Graciarena et al 2004). Future work aims to reveal the mechanisms whereby cell clusters may induce paracrine cell transformation and promote tumour growth as well as the cell of origin of the ACP tumour mass.…”

The role of the tumour microenvironment in immunotherapy

“…This results in tumour expansion by concomitantly stimulating tumour cell proliferation and tumour neovascularisation (Renner et al 2009). In nude mice studies, it was found that cytokines binding to the shared gp130 subunit of the IL-6 receptor contributed to tumour progression (Graciarena et al 2004, Renner et al 2009). The authors have not identified which cytokines were responsible for the effect.…”