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Endocrine Abstracts (2020) 70 AEP603 | DOI: 10.1530/endoabs.70.AEP603

University of Ferrara, Section of Endocrinology and Internal Medicine, Department of Medical Sciences, Italy

Introduction: Typical and atypical bronchial carcinoids (TBC and ABC) are well-differentiated neuroendocrine neoplasms (NEN). First-line treatment is radical removal of the primary tumour; however, management of metastatic BC is still challenging. Bronchial carcinoids (BC) may benefit from treatment with mTOR inhibitors, although response rates are moderate. TBC have shown reduced sensibility to mTOR inhibitors respect to ABC, notwithstanding its less aggressive behaviour. PI3K/AKT/mTOR crosstalk with TGF-β has been reported and could explain the differential sensitivity of BC to treatment. Previous studies have reported TGF-β’s ability to activate mTOR pathway and induce epithelial to mesenchymal transition (EMT), affecting cell survival, proliferation, migration and invasiveness.

Aims: The present study focused on understanding the possible crosstalk between TGF-β signalling and PI3K/AKT/mTOR in BC.

Materials and methods: Basal levels of TGF-β downstream proteins were analysed by Western blot in BC (4 TBC and 3 ABC). Functional assays (cells viability, migration and caspase 3/7 activation) were performed using TBC in vitro cell model (NCI-H727 cell line) after treatment with the mTOR inhibitor everolimus (Eve) at 100 nM concentration and/or 1 pM TGF-β.

Results: TGF-β/SMAD protein levels were higher in TBC vs ABC tissues. Mean differences (% TBC vs ABC) were as follows: TGF-βRI (17.85 ± 5.298; P = 0.007), TGF-βRII (50.07 ± 23.52; P = 0.04), Smad 2/3 (536.6 ± 159.9; P = 0.008). In addition, caspase 3 levels were higher in TBC vs ABC tissues (257.0 ± 131.8, P = 0.03). In NCI-H727 cells, TGF-β or Eve treatment alone had no effect on cell viability, whereas their combination slightly reduced it by >10% vs control (P = 0.009) and this effect was not accompanied by apoptosis induction. TGF-β, however, increased caspase activation by 14% vs control (P = 0.04). Combined treatment with Eve abrogated this effect. TGF-β induced migration in TBC cell model by 40% vs control, whereas combined treatment with Eve abrogated cell migration, reducing this phenomenon by 27% vs control (P < 0.0001).

Conclusion: TGF-β/SMAD and PI3K/AKT have major roles in cells pathophysiology and have been reported to be activated simultaneously in advanced states of tumorigenesis. We report an increased expression of TGF-β/SMAD proteins as well as enhanced caspase activation in TBC cells. The interplay between these pathways could explain TBC increased resistance to medical therapy by inducing EMT. Combined treatment with the mTOR inhibitor Eve abrogated TGF-β induced EMT and, therefore, inhibition of TGF-β/SMAD and PI3K/AKT/mTOR pathways could potentially reduce tumour malignancy in these cells.

Volume 70

22nd European Congress of Endocrinology

05 Sep 2020 - 09 Sep 2020

European Society of Endocrinology 

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