Combination of anti-proliferative signalling activation for the treatment of pituitary tumors

PICECH F.; SOSA L.; MUKDSI J. H.; TORRES A. I.; PETITI J. P.

Córdoba

Jornada; XX Jornada de Investigación Científica JIC; 2019

Current therapies for pituitary adenomas focus on stimulating somatostatin receptors (SSTRs) that inhibit cell proliferation and hormone secretion. However, half of patients become resistant to the SST analogue Octreotide (OCT), with the search for alternative strategies that overcome such resistance deserving investigation. We here analysed the anti-proliferative TGFβ1 signalling in combination with SST activation as a way to effectively control cell proliferation and hormone secretion. First, the expression of SSTRs (SSTR2 and SSTR5) and TβRs (TβRI, TβRII) were found to be downregulated in different types of human pituitary tumours (6 GH-, 2 ACTH-secreting and 9 non-functioning pituitary adenomas -NFPA), compared to normal pituitaries (n=7) by IHC and western blot, suggesting a (lack of) receptor-mediated hyporesponsiveness. Then, GH3 somatolactotroph NFPA human derived and pituitary tumour cells were treated in vitro with OCT (10 and 100 nM), TGFβ1 (4 mg/ml) or a combination of both stimuli for 24h. The co-incubation of OCT/TGFβ1 increased mRNA expression of TβRI, SSTR2, and SSTR5 (by qPCR), being correlated to a decrease in cell proliferation (Ki67 quantification) and PRL secretion (by RIA) comparing to single treatments. Finally, the transient transfection to overexpress SSTR2 induced a significant decrease in GH3 proliferation, as measured by BrdU incorporation, with an additional reduction when these cell were stimulated with OCT/TGFβ1 combination.These findings suggest a possible crosstalk between somatostatin analogues and TGFβ1 modulating both cell proliferation and hormonal secretion in pituitary adenomas, with such interaction representing a promising approach in the context of tumour resistance.