Integrin αvβ3 acting as membrane receptor for thyroid hormones mediates angiogenesis in malignant T cells

The interaction of lymphoid tumor cells with components of the extracellular matrix via integrin alpha v beta 3 allows tumor survival and growth. This integrin was demonstrated to be the membrane receptor for thyroid hormones (THs) in several tissues. We found that THs, acting as soluble integrin alpha v beta 3 ligands, activated growth-related signaling pathways in T-cell lymphomas (TCLs). Specifically, TH-activated alpha v beta 3 integrin signaling promoted TCL proliferation and angiogenesis, in part, via the upregulation of vascular endothelial growth factor (VEGF). Consequently, genetic or pharmacologic inhibition of integrin alpha v beta 3 decreased VEGF production and induced TCL cell death in vitro and in human xenograft models. In sum, we show that integrin alpha v beta 3 transduces prosurvival signals into TCL nuclei, suggesting a novel mechanism for the endocrine modulation of TCL pathophysiology. Targeting this mechanism could constitute an effective and potentially low-toxicity chemotherapy-free treatment of TCL patients.