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

Abstract

Key Points• We elucidate a molecular mechanism by which thyroid hormones sustain TCL survival.• We demonstrate that the membrane receptor of THs, integrin avb3, constitutes a potential target for TCL.The interaction of lymphoid tumor cells with components of the extracellular matrix via integrin avb3 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 avb3 ligands, activated growth-related signaling pathways in T-cell lymphomas (TCLs). Specifically, TH-activated avb3 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 avb3 decreased VEGF production and induced TCL cell death in vitro and in human xenograft models. In sum, we show that integrin avb3 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. (Blood. 2015;125(5):841-851)

Thyroid hormones and tetrac: new regulators of tumour stroma formation via integrin αvβ3

“…In line with our observations, transduction of the thyroid hormone signal via integrin avb3 was shown to lead to transcription of angiogenesis-relevant genes FGF2 and VEGF in the chorioallantoic membrane (CAM) model, as well as in heart and T-cell lymphoma (Luidens et al 2010, Cayrol et al 2015. A direct effect of thyroid hormones on inflammatory mediators such as IL6 has been tentatively proposed based on the inhibition of proinflammatory cytokines by the iodothyronine antagonist tetrac (Hercbergs et al 2012).…”

Biomaterial-Based Modulation of Cancer

“…10.3), Patel et al reported that the viscoelastic properties of these hy- drogels are independent of their composition of adhesive additives-which has a unique effect on cell spreading, viability, and proliferation of cervical cancer and leukemia cell line models. Such engineered systems provide a platform to modulate the behavior of cancer cells and decouple some of the underlying microenvironment factors that induce tumorigenesis, affect tumor growth, and further tumor progression [35].…”

Hormony tarczycy w ośrodkowym układzie nerwowym (OUN) i ich wpływ na nowotworzenie, zwłaszcza na rozwój i przebieg glioblastoma multiforme — hipoteza badawcza

“…Jednakże w obecnym stanie wiedzy przyjęcie udziału hormonów tarczycy w patogenezie glejaka wielopostaciowego może już mieć wymiar praktyczny. Obniżenie stężenia TH w surowicy przedłużało remisje i czas przeżycia u chorych z glejakiem wielopostaciowym, który w GBM jest dramatycznie krótki [18,19], a stosowanie metabolitu T4-TRAK (kwas tetrajodotyrooctowy) w badaniach in vitro i na liniach komórkowych hamowało proliferację komórek glejaka oraz aktywność VEGF -ważnego regulatora stymulującego neoangiogenezę w procesach nowotworowych [88]. W tym samym czasie podanie TRAK zwiększało proces apoptozy [60].…”

“…Reduction of TH levels in blood serum prolonged the remission and lifespan in patients with glioblastoma multiforme; generally the patients' lifespan is extremely short in GBM [18,19]. The local application of T4 -TRAK metabolite (tetraiodothyroacetic acid) in studies conducted in vitro and on cell lines inhibited glial cell proliferation and activity of vascular endothelial growth factor (VEGF), an important stimulator of neo-angiogenesis in oncology [88]. At the same time, TRAK enhanced the apoptosis process [60].…”