VEGF Secretion by Neuroendocrine Tumor Cells Is Inhibited by Octreotide and by Inhibitors of the PI3K/AKT/mTOR Pathway

Abstract

Gastroenteropancreatic (GEP) endocrine tumors are hypervascular tumors able to synthesize and secrete high amounts of VEGF. We aimed to study the regulation of VEGF production in GEP endocrine tumors and to test whether some of the drugs currently used in their treatment, such as so- matostatin analogues and mTOR inhibitors, may interfere with VEGF secretion. We therefore analyzed the effects of the somatostatin analogue octreotide, the mTOR inhibitor rapamycin, the PI3K inhibitor LY294002, the MEK1 inhibitor PD98059 and the p38 inhibitor SB203850 on VEGF secretion, assessed by ELISA and Western blotting, in three murine endocrine cell lines, STC-1, INS-r3 and INS-r9. Octreotide and rapamycin induced a significant decrease in VEGF production by all three cell lines; LY294002 significantly inhibited VEGF production by STC-1 and INS-r3 only. We detected no effect of PD98059 whereas SB203850 significantly inhibited VEGF secretion in INS-r3 and INS-r9 cells only. By Western blotting analysis, we observed decreased intracellular levels of VEGF and HIF-1α under octreotide, rapamycin and LY294002. For rapamycin and LY294002, this effect was likely mediated by the inhibition of the mTOR/HIF-1/VEGF pathway. In addition to its well-known anti-secretory effects, octreotide may also act through the inhibition of the PI3K/Akt pathway, as suggested by the decrease in Akt phosphorylation detected in all three cell lines. In conclusion, our study points out to the complex regulation of VEGF synthesis and secretion in neoplastic GEP endocrine cells and suggests that the inhibition of VEGF production by octreotide and rapamycin may contribute to their therapeutic effects.

Filamin-A is required to mediate SST2 effects in pancreatic neuroendocrine tumours

“…In fact, a positive relationship between FLNA and vascular endothelial growth factor (VEGF) was found in patients with lung cancer (Uramoto et al 2010), suggesting that FLNA is implicated in angiogenesis through links with VEGF. Interestingly, it has been demonstrated that VEGF pathway is overexpressed in neuroendocrine tumours (Ö berg et al 2013), this pathway being inhibited by somatostatin analogues (Villaume et al 2010).…”

Antitumor Effects of Somatostatin Analogs in Neuroendocrine Tumors

“…1) [12,13]. There are 25 years of evidence that octreotide controls the symptoms of severe diarrhea and flushing in patients with carcinoid syndrome [14 -16] [3].…”

Everolimus Reduces 89Zr-Bevacizumab Tumor Uptake in Patients with Neuroendocrine Tumors

“…An attractive candidate is VEGF-A. mTOR inhibition reduced VEGF-A excretion by NET cell lines (11). Additionally, in renal cancer xenografts, sensitivity to mTOR inhibition correlated with reductions in tumor hypoxia-inducible factor 1a messenger RNA translation, VEGF-A expression, and angiogenesis (12).…”