Effect of the monoclonal antibody TRC105 in combination with Sunitinib on renal tumor derived endothelial cells
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Alessia Brossa1, Lola Buono1 and Benedetta Bussolati1
1Department of Molecular Biotechnology and Health Sciences, University of Torino, Turin, Italy
Benedetta Bussolati, email: [email protected]
Keywords: TRC105; Sunitinib; tumor stem cells; angiogenic therapy; renal cell carcinoma
Received: October 18, 2017 Accepted: April 05, 2018 Published: April 27, 2018
Anti-angiogenic therapy is an important strategy to limit growth, development and expansion of solid tumors. However, resistance to VEGF-targeting agents may develop, due to activation of alternative pro-angiogenic pathways, indicating the need of multiple target strategy. Here we obtained tumor endothelial cells (TEC) either from total renal carcinomas or from renal cancer stem cells (CSC-TEC) and we tested the effect of a CD105 targeting monoclonal antibody, TRC105, alone or in association with anti-VEGF drugs. We demonstrated that TRC105 impaired the ability of TEC and CSC-TEC to organize in tubular structures, whereas it did not limit proliferation or survival. The combination of TRC105 with different anti-angiogenic drugs showed a synergistic effect of TRC105 only in combination with the tyrosine kinase inhibitor Sunitinib. In particular, TRC105 plus Sunitinib reduced tubulogenesis, proliferation and survival of CSC-TEC and tumor-derived TEC in a similar manner. At a molecular level, we showed that the combination of TRC105 and Sunitinib induced the phosphorylation of Smad 2/3 to promote endothelial cell death. Moreover, TRC105 enhanced the inhibitory effect of Sunitinib on VEGF signaling and reduced VEGFR2-Akt-Creb activation, suggesting a molecular cooperation between the two drugs. Our results highlight that the combined inhibition of VEGF and TGF-β pathway may have a potential use in renal cell carcinoma therapy.
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