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Integrin αVβ3 acting as membrane receptor for thyroid hormones mediates angiogenesis in malignant T cells

Florencia Cayrol, María Celeste Díaz Flaqué, Tharu Fernando, Shao Ning Yang, Helena Andrea Sterle, Marcela Bolontrade, Mariana Amorós, Blanca Isse, Ricardo Norberto Farías, Haelee Ahn, Ye F. Tian, Fabrizio Tabbò, Ankur Singh, Giorgio Inghirami, Leandro Cerchietti and Graciela Alicia Cremaschi

Key points

  • We elucidated a molecular mechanism by which thyroid hormones sustain T-cell lymphoma survival.

  • We demonstrated that the membrane receptor of thyroid hormones, i.e. integrin αvβ3, constitutes a potential target for T-cell lymphoma.

Abstract

The interaction of lymphoid tumor cells with components of the extracellular matrix via the integrin αvβ3 allows tumor survival and growth. This integrin was demonstrated to be the membrane receptor for thyroid hormones in several tissues. We found that thyroid hormones (THs), acting as soluble integrin αvβ3 ligands, activated growth-related signaling pathways in T-cell lymphomas (TCL). Specifically, TH-activated αvβ3 integrin signaling promoted TCL proliferation and angiogenesis, in part, via the up-regulation of VEGF. Consequently, genetic or pharmacologic inhibition of integrin αvβ3 decreased VEGF production and induced TCL cell death in vitro and in human xenografts models. In sum, we here show that integrin αVβ3 transduces pro-survival 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 for TCL patients.

  • Submitted July 14, 2014.
  • Accepted November 27, 2014.