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Cited by 18Angiogenesis and VEGF in CancerCell Adhesion Molecules ResearchSynthesis and biological activity

Tetrac as an anti-angiogenic agent in cancer

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Schmohl, Kathrin A, Nelson, Peter J, Spitzweg, Christine·2019·Endocrine-Related Cancer
DOI 10.1530/erc-19-0058
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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 stroma-associated 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.

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Cited by

Sorted by citations

Authors
Schmohl, K. A., Nelson, P. J., & Spitzweg, C.
Affiliations
LMU Klinikum (DE)
Corresponding author
Spitzweg, Christine
ORCID
Venue
Endocrine-Related Cancer
Publisher
Bioscientifica
Published
2019-06
Volume
26
Issue
6
Pages
R287-R304
ISSN
  • 1351-0088 (ISSN-L)
  • 1479-6821
DOI
10.1530/erc-19-0058
OpenAlex
W2944432197
Cited by
18
References
4
Citations by year
2026: 2 · 2025: 3 · 2024: 2 · 2023: 3 · 2022: 2 · 2021: 2 · 2020: 2 · 2019: 2
FWCI
0.18
Type
journal article
Language
en
Open access
Locations
  • Endocrine Related Cancer (publishedVersion)
  • PubMed (publishedVersion)
Funders
Deutsche Forschungsgemeinschaft (SPP1629, SFB824, SP 581/6-2, NE 648/5-2, project C8)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
  • Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
  • Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
Keywords
tetrac, angiogenesis inhibitors, thyroid hormones, T3 and T4, integrin αvβ3, angiogenesis, tumor stroma, mesenchymal stem cells, vascular endothelial growth factor, hypoxia-inducible factor-1α, endothelial cell proliferation and migration, tumor hypoxia
MeSH terms
Animals, Humans, Neoplasms, Neovascularization, Pathologic, Thyroxine, Neovascularization, Physiologic, Angiogenesis Inhibitors, Mesenchymal Stem Cells

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