Inhibition of mTOR in head and neck cancer cells alters endothelial cell morphology in a paracrine fashion

Abstract : Head and neck squamous cell carcinoma (HNSCC) represent aggressive classes of tumors with a high mortality rate. The mammalian target of rapamycin (mTOR) pathway is instrumental in their initiation and expansion. Although results from pre-clinical models promise mTOR targeting as a potent novel therapeutic approach, its impact on the tumor microenvironment, such as endothelial cells is only scarcely investigated. Here, we first confirmed the effects of mTOR pharmacological inhibition on cell viability, clonogenicity, and proliferation in HNSCC human cell lines, HN26, and HN30. While Everolimus and Torin1 potently blunted mTOR-based proliferation of HN26 and HN30 lines, endothelial cells were left intact. To further explore the possibility of a paracrine bystander action of HNSCC-treated cells on endothelial cells, conditioned medium from Everolimus-and Torin1-challenged HN26 and HN30 cells were collected and applied to naive human endothelial cells. Although endothelial cell viability was again not modified, morphology and mobility were changed. Indeed, spreading of endothelial cells was altered upon challenge with mTOR-pretreated tumor conditioned-media, as measured via cell impedance and imagery. Interestingly, this was associated with an augmentation of focal adhesion kinase (FAK) active phosphorylation and enhanced migratory behavior. From a molecular standpoint, the production of vascular endothelial growth factor was elevated in treated HNSCC cells and might contribute to FAK phosphorylation. Although mTOR inhibition in tumor cells did hinder their growth, it also favors the release of factors that subsequently enable endothelial cell migration. Further studies will address how this paracrine action may affect tumor-driven angiogenesis upon pharmacological treatments. K E Y W O R D S adhesion, head and neck cancer, mTOR, signaling pathway
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Molecular Carcinogenesis, Wiley, 2018, Epub ahead of print. 〈10.1002/mc.22911〉
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Andressa Duarte, Gwennan André-Grégoire, Kilian Trillet, An Thys, Nicolas Bidère, et al.. Inhibition of mTOR in head and neck cancer cells alters endothelial cell morphology in a paracrine fashion. Molecular Carcinogenesis, Wiley, 2018, Epub ahead of print. 〈10.1002/mc.22911〉. 〈inserm-01908781〉

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