Integrin-Mediated Actions of Thyroid Hormone Analogues on Tumor Cell Chemosensitivity, Integrin-Growth Factor Receptor Crosstalk and Inflammatory Gene Expression

Abstract

Tetraiodothyroacetic acid (tetrac) and its nanoparticulate formulation induce apoptosis in cancer cells, oppose angiogenesis about xenografted human tumors and block cancer cell repair of double-stranded DNA breaks. These nongenomic actions of tetrac are initiated at a tetrac-thyroid hormone receptor on plasma membrane integrin v3. In this review, we examine additional anti-cancer activities of tetrac formulations at v3 and what is known about their mechanisms. These activities include 1) reversal of cancer cell chemoresistance (= induction of chemosensitization) and 2) disruption of crosstalk between v3 and nearby cell surface growth factor receptors. In addition, nanoparticulate tetrac 3) alters expression of differentially-regulated inflammation-relevant genes that may be important to inflammation-supported cancer. For example, the agent downregulates genes whose products mediate cytokine responses and upregulates suppressor of cytokine signaling, SOCS4. Such actions of tetrac formulations define a multi-target functional profile, although the activities of tetrac begin at a single anatomic plasma membrane receptor on integrin v3.

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

“…Furthermore, there is growing evidence that thyroid hormones increase the motility of avb3-expressing immune cells, and, possibly by similar mechanisms, nerve cell migration (De Vito et al 2012). An array of growth factors, including PDGF, insulin-like growth factor 1 (IGF1), HGF, EGF and VEGF, as well as chemokines, such as RANTES/CCL5, CCL22 and, to a lower extent, SDF-1/CXCL12 and their respective receptors, have been implicated in MSC migration (Ponte et al 2007, Spaeth et al 2008) and many of these have been shown in this and other studies to be regulated by thyroid hormones via differential gene expression and receptor crosstalk (Davis et al 2011, Hercbergs et al 2012. Modulation of recruitment and engraftment efficiency of MSCs is of clinical interest, in settings of tissue regeneration, in the context of general tumour growth and the emerging field of MSC-based gene delivery in cancer therapy (Knoop et al 2011, Knoop et al 2013, Uchibori et al 2014.…”

“…While tetrac is known to exert low-grade thyromimetic effects intracellularly (Moreno et al 2008), it was shown to have anti-tumour effects in vitro and in vivo in various cancer models via modulation of tumour cell proliferation, apoptosis and angiogenesis by T 3 /T 4 antagonistic action mediated through integrin avb3 (Yalcin et al 2009, Davis et al 2011. Further anti-tumour activity of tetrac includes the suppression of invasiveness/metastasis, increased radio-and chemosensitisation and antagonism of inflammation (Davis et al 2011, Hercbergs et al 2012, Yalcin et al 2013. These effects are thought to be largely mediated by avb3 expressed on the tumour cells themselves.…”

“…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). Integrin avb3 has been shown to engage in crosstalk with tyrosine kinase growth factor receptors such as EGF receptor, FGF receptor, platelet-derived growth factor (PDGF) receptor and VEGF receptor, which are all expressed by MSCs (Spaeth et al 2008, Davis et al 2011, Hercbergs et al 2012. Explanations for the changes in the expression levels of markers of CAF-like differentiation shown here could involve binding of CM-derived growth factors to their respective receptors on MSCs or autocrine stimulation by growth factors secreted by MSCs in response to CM, with potentiation of the signal through integrin avb3 crosstalk.…”

“…Explanations for the changes in the expression levels of markers of CAF-like differentiation shown here could involve binding of CM-derived growth factors to their respective receptors on MSCs or autocrine stimulation by growth factors secreted by MSCs in response to CM, with potentiation of the signal through integrin avb3 crosstalk. A further indirect effect could involve an enhanced expression of hypoxia-inducible factor 1 alpha (HIF-1a) that was shown to be increased upon T 3 binding to integrin avb3 transduced by the phosphoinositide 3-kinase (PI3K) pathway, which in turn stimulates the secretion of HIF-responsive genes, such as VEGF, FGF2, IL6, SDF1 and TGFB1 (Davis et al 2011, Hercbergs et al 2012. However, the exact mechanisms behind the synergistic effects of CM and T 3 /T 4 on MSC differentiation remain to be elucidated.…”

Thyroid hormone regulates adhesion, migration and matrix metalloproteinase 9 activity via αvβ3 integrin in myeloma cells

“…These actions are regulated via the αvβ3 integrin and are MAPK-mediated. Disruption of the thyroid-integrin signaling by use of RGD or tetrac, a specific blocker of the thyroid hormone binding site upon the integrin [16, 17], impaired the production of MMP-9 in myeloma cell lines and primary BM cells from myeloma patients.…”