Endocrine Abstracts

Introduction

Typical bronchial carcinoids (TBC) are rare well-differentiated neuroendocrine neoplasms (NEN) of the lung whose management can still be very challenging. In fact, the gold-standard treatment for TBC is total resection of the primary tumour; however, in case of metastatic disease adjuvant therapy with the mTOR inhibitor everolimus (eve) might be recommended. Unfortunately, prognosis may be very poor in cases showing moderate response rates to eve, since resistance to treatment is not uncommon. Previous studies have reported TGF-β’s ability to activate mTOR pathway and induce epithelial to mesenchymal transition (EMT) in cervical cancer. Moreover, preliminary results from our lab showed an overexpression of TGF-β/SMAD signalling and caspase activation in TBC cells, as well as an interplay between this pathway with the PI3K/mTOR pathway.

Aims

The present study focused on understanding how TGF-β signalling could interfere with TBC pathophysiology, which might possibly explain the reduced sensibility of these neoplasms to eve.

Materials and Methods

In vitro functional assays such as cell viability, migration, and caspase 3/7 activation were performed in the TBC cell line NCI-H727. Cell viability and caspase activation were performed by using specific kits, whereas migration was assessed through wound healing assay. Cells were treated with the mTOR inhibitor eve and TGF-β alone or combined with IGF-1 and paclitaxel (pac), considered as positive and negative controls, respectively.

Results

TGF-β or eve treatment alone had no effect on cell viability, whereas their combination reduced it by >10% vs. control (P = 0.009). TGF-β increased caspase activation by 14% vs. control (P = 0.04) and this effect was not accompanied by apoptosis induction. TGF-β also induced migration by 40% vs. control, whereas combined treatment with eve abrogated this effect by reducing it by 27% vs. control (P <0.0001). Moreover, combined treatment of TGF-β and pac significantly increased migration by >50% vs. pac treatment alone (P = 0.03), indicating that TGF-β was responsible for the observed increased migration in these cells, whereas combination with IGF-1 had no further effect vs. IGF-1 treatment alone.

Conclusions

TGF-β-induced caspase activation and cell migration could explain EMT and associated malignancy features found in many TBC. Given the interplay between TGF-β and mTOR, inhibition of both pathways could represent an alternative for the treatment of these NEN, which are orphans of an effective therapeutic algorithm.