Tetrac as an anti-angiogenic agent in cancer

Abstract

The thyroid hormones T3 and T4 have emerged as pro-angiogenic hormones with important implications for cancer management. Endogenous circulating hormone levels may help stimulate cancer progression and limit the effectiveness of anticancer therapy, though clinical data remain inconclusive. The capacity of thyroid hormones to modulate angiogenesis is mediated through non-canonical mechanisms initiated at the cell surface receptor integrin αvβ3. This integrin is predominantly expressed on tumour cells, proliferating endothelial cells and tumour stroma-associated cells, emphasising its potential relevance in angiogenesis and tumour biology. Thyroid hormone/integrin αvβ3 signalling results in the activation of intracellular pathways that are commonly associated with angiogenesis and are mediated through classical pro-angiogenic molecules such as vascular endothelial growth factor. The naturally occurring T4 analogue tetrac blocks the pro-angiogenic actions of thyroid hormones at the integrin receptor, in addition to agonist-independent anti-angiogenic effects. Tetrac reduces endothelial cell proliferation, migration and tube formation through a reduction in the transcription of vascular growth factors/growth factor receptors, hypoxia-inducible factor-1α, pro-angiogenic cytokines and a number of other pro-angiogenic genes, while at the same time stimulating the expression of endogenous angiogenesis inhibitors. It further modulates vascular growth factor activity by disrupting the crosstalk between integrin αvβ3 and adjacent growth factor receptors. Moreover, tetrac disrupts thyroid hormone-stimulated tumour recruitment, differentiation and the pro-angiogenic signalling of tumour stromaassociated mesenchymal stem cells. Tetrac affects tumour-associated angiogenesis via multiple mechanisms and interferes with other cancer cell survival pathways. In conjunction with its low toxicity and high tissue selectivity, tetrac is a promising candidate for clinical application.

Network Pharmacology-Based Study on the Molecular Biological Mechanism of Action for Compound Kushen Injection in Anti-Cancer Effect

“…The main role of thyroid hormone is to promote the metabolism of matter and energy, maintain the body's growth and development, and at the same time regulates angiogenesis. Natural thyroid hormone analogs can affect tumor-associated angiogenesis and are important implications for cancer treatment [43]. One study revealed that advanced glycation end products and their receptors (AGE-RAGE) interactions are associated with prostate cancer and may be enhanced prostate cancer cell proliferation by the PI3K/Akt signaling pathway [44].…”

3,5-T2—A Janus-Faced Thyroid Hormone Metabolite Exerts Both Canonical T3-Mimetic Endocrine and Intracrine Hepatic Action

“…T3 exerts the majority of known thyroid hormone (TH) effects at the tissue and cellular level, including hypothalamic and pituitary negative feedback regulation of the hypothalamuspituitary-thyroid-periphery (HPTP) axis (4)(5)(6). Over the last years, some evidence has been presented that T4 also binds to cell membrane-located ανβ3 integrin receptors which exert rapid signaling via various kinase and intracellular pathways, especially in tumor cells and stem cells (7,8). The T4 metabolite Tetrac, a deaminated side chain metabolite, present in human serum at concentrations similar to those of T3 (3,9) antagonizes such T4 (and also T3) actions at the integrin receptor signaling.…”

Thyroid Hormone Effects on Mesenchymal Stem Cell Biology in the Tumour Microenvironment

“…In cancer patients, endogenous circulating thyroid hormone levels have been implicated in cancer progression and impairment of anti-cancer therapy, though clinical data remain ambiguous [3]. A more complete understanding of the regulation of cancer progression by thyroid hormones is essential to avoid pitfalls in cancer patient treatment and, besides, possibly exploit it for cancer gene therapy.…”

“…A decade and a half since the discovery of a thyroid hormone binding site on integrin αvβ3, a plethora of downstream effects relevant to tumour biology have been described, including stimulation of tumour cell proliferation and angiogenesis [1][2][3]. This phenomenon is of course undesirable in cancer patients and, indeed, over the past century, several clinical and experimental studies have implicated thyroid hormones in cancer progression [3][4][5][6][7]. Integrin αvβ3 is abundantly expressed on most cancer cells and the growing endothelium associated with tumours, but also on mesenchymal stem cells (MSCs), important progenitors for tumour stromaassociated cell types [8,9].…”