Cayrol Florencia, Díaz Flaqué María Celeste, Fernando Tharu, Yang Shao Ning, Sterle Helena Andrea, Bolontrade Marcela, Amorós Mariana, Isse Blanca, Farías Ricardo Norberto, Ahn Haelee, Tian Ye F, Tabbò Fabrizio, Singh Ankur, Inghirami Giorgio, Cerchietti Leandro, Cremaschi Graciela Alicia
Neuroimmunomodulation and Molecular Oncology Department, Institute for Biomedical Research (BIOMED), National Research Council of Argentina (CONICET), Catholic University of Argentina (UCA), Buenos Aires, Argentina;
Division of Hematology and Oncology, Department of Medicine, Weill Cornell Medical College, Cornell University, New York, NY;
Blood. 2015 Jan 29;125(5):841-51. doi: 10.1182/blood-2014-07-587337. Epub 2014 Dec 8.
The interaction of lymphoid tumor cells with components of the extracellular matrix via integrin αvβ3 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 αvβ3 ligands, activated growth-related signaling pathways in T-cell lymphomas (TCLs). Specifically, TH-activated αvβ3 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 αvβ3 decreased VEGF production and induced TCL cell death in vitro and in human xenograft models. In sum, we show that integrin αvβ3 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.
淋巴样肿瘤细胞通过整合素αvβ3与细胞外基质成分的相互作用可使肿瘤存活和生长。在多个组织中，这种整合素已被证实是甲状腺激素（THs）的膜受体。我们发现，作为可溶性整合素αvβ3配体的THs可激活T细胞淋巴瘤（TCLs）中与生长相关的信号通路。具体而言，TH激活的αvβ3整合素信号传导部分通过上调血管内皮生长因子（VEGF）促进TCL增殖和血管生成。因此，整合素αvβ3的基因或药物抑制可降低VEGF的产生，并在体外和人异种移植模型中诱导TCL细胞死亡。总之，我们表明整合素αvβ3将促生存信号转导至TCL细胞核，提示了一种内分泌调节TCL病理生理学的新机制。针对这一机制可能构成一种有效且潜在低毒性的无化疗治疗TCL患者的方法。
