scholarly journals Tetrac as an anti-angiogenic agent in cancer

2019 ◽  
Vol 26 (6) ◽  
pp. R287-R304 ◽  
Author(s):  
Kathrin A Schmohl ◽  
Peter J Nelson ◽  
Christine Spitzweg
Keyword(s):  
Growth Factor ◽  
Thyroid Hormone ◽  
Thyroid Hormones ◽  
Integrin Αvβ3 ◽  
Growth Factor Receptors ◽  
Cell Surface Receptor ◽  
Endothelial Cell Proliferation ◽  
Tumour Stroma ◽  
Vascular Growth ◽  
Vascular Growth Factor

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.

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

2019 ◽  
Vol 128 (06/07) ◽  
pp. 462-468
Author(s):  
Kathrin Alexandra Schmohl ◽  
Andrea Maria Müller ◽  
Peter Jon Nelson ◽  
Christine Spitzweg
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Stem Cell ◽  
Thyroid Hormone ◽  
Mesenchymal Stem Cell ◽  
Thyroid Hormones ◽  
Cell Biology ◽  
Integrin Αvβ3 ◽  
Tumour Microenvironment ◽  
Cell Surface Receptor

AbstractNon-classical thyroid hormone signalling via cell surface receptor integrin αvβ3, expressed on most cancer cells and proliferating endothelial cells, has been shown to drive tumour cell proliferation and survival, as well as angiogenesis. Tumours develop within a complex microenvironment that is composed of many different cell types, including mesenchymal stem cells. These multipotent progenitor cells actively home to growing tumours where they differentiate into cancer-associated fibroblast-like cells and blood vessel-stabilising pericytes and thus support the tumour’s fibrovascular network. Integrin αvβ3 expression on mesenchymal stem cells makes them susceptible to thyroid hormone stimulation. Indeed, our studies demonstrated – for the first time – that thyroid hormones stimulate the differentiation of mesenchymal stem cells towards a carcinoma-associated fibroblast-/pericyte-like and hypoxia-responsive, pro-angiogenic phenotype, characterised by the secretion of numerous paracrine pro-angiogenic factors, in addition to driving their migration, invasion, and recruitment to the tumour microenvironment in an experimental hepatocellular carcinoma model. The deaminated thyroid hormone metabolite tetrac, a specific inhibitor of thyroid hormone action at the integrin site, reverses these effects. The modulation of mesenchymal stem cell signalling and recruitment by thyroid hormones via integrin αvβ3 adds a further layer to the multifaceted effects of thyroid hormones on tumour progression, with important implications for the management of cancer patients and suggests a novel mechanism for the anti-tumour activity of tetrac.

scholarly journals Molecular Functions of Thyroid Hormone Signaling in Regulation of Cancer Progression and Anti-Apoptosis

2019 ◽  
Vol 20 (20) ◽  
pp. 4986 ◽  
Author(s):  
Yu-Chin Liu ◽  
Chau-Ting Yeh ◽  
Kwang-Huei Lin
Keyword(s):  
Cell Proliferation ◽  
Thyroid Hormone ◽  
Thyroid Hormones ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Integrin Αvβ3 ◽  
Cell Surface Receptor ◽  
Therapeutic Effects ◽  
Physiological Processes ◽  
Risk Of Cancer

Several physiological processes, including cellular growth, embryonic development, differentiation, metabolism and proliferation, are modulated by genomic and nongenomic actions of thyroid hormones (TH). Several intracellular and extracellular candidate proteins are regulated by THs. 3,3,5-Triiodo-L-thyronine (T3) can interact with nuclear thyroid hormone receptors (TR) to modulate transcriptional activities via thyroid hormone response elements (TRE) in the regulatory regions of target genes or bind receptor molecules showing no structural homology to TRs, such as the cell surface receptor site on integrin αvβ3. Additionally, L-thyroxine (T4) binding to integrin αvβ3 is reported to induce gene expression through initiating non-genomic actions, further influencing angiogenesis and cell proliferation. Notably, thyroid hormones not only regulate the physiological processes of normal cells but also stimulate cancer cell proliferation via dysregulation of molecular and signaling pathways. Clinical hypothyroidism is associated with delayed cancer growth. Conversely, hyperthyroidism is correlated with cancer prevalence in various tumor types, including breast, thyroid, lung, brain, liver and colorectal cancer. In specific types of cancer, both nuclear thyroid hormone receptor isoforms and those on the extracellular domain of integrin αvβ3 are high risk factors and considered potential therapeutic targets. In addition, thyroid hormone analogs showing substantial thyromimetic activity, including triiodothyroacetic acid (Triac), an acetic acid metabolite of T3, and tetraiodothyroacetic acid (Tetrac), a derivative of T4, have been shown to reduce risk of cancer progression, enhance therapeutic effects and suppress cancer recurrence. Here, we have reviewed recent studies focusing on the roles of THs and TRs in five cancer types and further discussed the potential therapeutic applications and underlying molecular mechanisms of THs.

Nongenomic Actions of Thyroid Hormone: The Integrin Component

2021 ◽  
Vol 101 (1) ◽  
pp. 319-352
Author(s):  
Paul J. Davis ◽  
Shaker A. Mousa ◽  
Hung-Yun Lin
Keyword(s):  
Thyroid Hormone ◽  
Cell Surface ◽  
Cancer Biology ◽  
Molecular Mechanisms ◽  
Integrin Αvβ3 ◽  
Mitogen Activated Protein Kinase ◽  
Cell Surface Receptor ◽  
Cell Defense ◽  
Chemically Modified ◽  
Vascular Growth Factor

The extracellular domain of plasma membrane integrin αvβ3 contains a cell surface receptor for thyroid hormone analogues. The receptor is largely expressed and activated in tumor cells and rapidly dividing endothelial cells. The principal ligand for this receptor is l-thyroxine (T4), usually regarded only as a prohormone for 3,5,3′-triiodo-l-thyronine (T3), the hormone analogue that expresses thyroid hormone in the cell nucleus via nuclear receptors that are unrelated structurally to integrin αvβ3. At the integrin receptor for thyroid hormone, T4 regulates cancer and endothelial cell division, tumor cell defense pathways (such as anti-apoptosis), and angiogenesis and supports metastasis, radioresistance, and chemoresistance. The molecular mechanisms involve signal transduction via mitogen-activated protein kinase and phosphatidylinositol 3-kinase, differential expression of multiple genes related to the listed cell processes, and regulation of activities of other cell surface proteins, such as vascular growth factor receptors. Tetraiodothyroacetic acid (tetrac) is derived from T4 and competes with binding of T4 to the integrin. In the absence of T4, tetrac and chemically modified tetrac also have anticancer effects that culminate in altered gene transcription. Tumor xenografts are arrested by unmodified and chemically modified tetrac. The receptor requires further characterization in terms of contributions to nonmalignant cells, such as platelets and phagocytes. The integrin αvβ3 receptor for thyroid hormone offers a large panel of cellular actions that are relevant to cancer biology and that may be regulated by tetrac derivatives.

scholarly journals XPS Modeling of Immobilized Recombinant Angiogenin and Apoliprotein A1 on Biodegradable Nanofibers

Nanomaterials ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. 879
Author(s):  
Anton Manakhov ◽  
Elizaveta Permyakova ◽  
Sergey Ershov ◽  
Svetlana Miroshnichenko ◽  
Mariya Pykhtina ◽  
...  
Keyword(s):  
Tissue Engineering ◽  
Growth Factor ◽  
Photoelectron Spectroscopy ◽  
Antioxidant Activities ◽  
Fluorescent Microscopy ◽  
X Ray ◽  
Vascular Growth ◽  
Vascular Growth Factor ◽  
And Migration ◽  
Protein Density

The immobilization of viable proteins is an important step in engineering efficient scaffolds for regenerative medicine. For example, angiogenin, a vascular growth factor, can be considered a neurotrophic factor, influencing the neurogenesis, viability, and migration of neurons. Angiogenin shows an exceptional combination of angiogenic, neurotrophic, neuroprotective, antibacterial, and antioxidant activities. Therefore, this protein is a promising molecule that can be immobilized on carriers used for tissue engineering, particularly for diseases that are complicated by neurotrophic and vascular disorders. Another highly important and viable protein is apoliprotein A1. Nevertheless, the immobilization of these proteins onto promising biodegradable nanofibers has not been tested before. In this work, we carefully studied the immobilization of human recombinant angiogenin and apoliprotein A1 onto plasma-coated nanofibers. We developed a new methodology for the quantification of the protein density of these proteins using X-ray photoelectron spectroscopy (XPS) and modeled the XPS data for angiogenin and apoliprotein A1 (Apo-A1). These findings were also confirmed by the analysis of immobilized Apo-A1 using fluorescent microscopy. The presented methodology was validated by the analysis of fibronectin on the surface of plasma-coated poly(ε-caprolactone) (PCL) nanofibers. This methodology can be expanded for other proteins and it should help to quantify the density of proteins on surfaces using routine XPS data treatment.

scholarly journals Inhibition by Thyroid Hormones of Cell Migration Activated by IGF-1 and MCP-1 in THP-1 Monocytes: Focus on Signal Transduction Events Proximal to Integrin αvβ3

2021 ◽  
Vol 9 ◽  
Author(s):  
Elena Candelotti ◽  
Roberto De Luca ◽  
Roberto Megna ◽  
Mariangela Maiolo ◽  
Paolo De Vito ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Plasma Membrane ◽  
Cell Migration ◽  
Thyroid Hormone ◽  
Thyroid Hormones ◽  
Integrin Αvβ3 ◽  
Membrane Receptor ◽  
Αvβ3 Integrin ◽  
Plasma Membrane Receptor ◽  
Cell Migration And Proliferation

Interaction between thyroid hormones and the immune system is reported in the literature. Thyroid hormones, thyroxine, T4, but also T3, act non-genomically through mechanisms that involve a plasma membrane receptor αvβ3 integrin, a co-receptor for insulin-like growth factor-1 (IGF-1). Previous data from our laboratory show a crosstalk between thyroid hormones and IGF-1 because thyroid hormones inhibit the IGF-1-stimulated glucose uptake and cell proliferation in L-6 myoblasts, and the effects are mediated by integrin αvβ3. IGF-1 also behaves as a chemokine, being an important factor for tissue regeneration after damage. In the present study, using THP-1 human leukemic monocytes, expressing αvβ3 integrin in their cell membrane, we focused on the crosstalk between thyroid hormones and either IGF-1 or monocyte chemoattractant protein-1 (MCP-1), studying cell migration and proliferation stimulated by the two chemokines, and the role of αvβ3 integrin, using inhibitors of αvβ3 integrin and downstream pathways. Our results show that IGF-1 is a potent chemoattractant in THP-1 monocytes, stimulating cell migration, and thyroid hormone inhibits the effect through αvβ3 integrin. Thyroid hormone also inhibits IGF-1-stimulated cell proliferation through αvβ3 integrin, an example of a crosstalk between genomic and non-genomic effects. We also studied the effects of thyroid hormone on cell migration and proliferation induced by MCP-1, together with the pathways involved, by a pharmacological approach and docking simulation. Our findings show a different downstream signaling for IGF-1 and MCP-1 in THP-1 monocytes mediated by the plasma membrane receptor of thyroid hormones, integrin αvβ3.

scholarly journals Paracrine potential of fibroblasts exposed to cigarette smoke extract with vascular growth factor induction

2013 ◽  
Vol 123 (9) ◽  
pp. 2228-2236 ◽  
Author(s):  
Craig M. Berchtold ◽  
Adam Coughlin ◽  
Zachary Kasper ◽  
Susan L. Thibeault
Keyword(s):  
Growth Factor ◽  
Cigarette Smoke ◽  
Cigarette Smoke Extract ◽  
Vascular Growth ◽  
Vascular Growth Factor

scholarly journals Association of Acute Endophthalmitis With Intravitreal Injections of Corticosteroids or Anti–Vascular Growth Factor Agents in a Nationwide Study in France

2018 ◽  
Vol 136 (12) ◽  
pp. 1352 ◽  
Author(s):  
Florian Baudin ◽  
Eric Benzenine ◽  
Anne-Sophie Mariet ◽  
Alain M. Bron ◽  
Vincent Daien ◽  
...  
Keyword(s):  
Growth Factor ◽  
Intravitreal Injections ◽  
Nationwide Study ◽  
Vascular Growth ◽  
Vascular Growth Factor

scholarly journals Myopericytoma arising from myopericytosis—a hitherto unrecognized entity within the lung

2020 ◽  
Author(s):  
Ulrike Gruber-Moesenbacher ◽  
Alicia Morresi- Hauff ◽  
Katja Behr ◽  
Helmut Popper
Keyword(s):  
Differential Diagnosis ◽  
Growth Factor ◽  
Kinase Inhibitors ◽  
Antiangiogenic Therapy ◽  
Angiogenesis Inhibitor ◽  
Precursor Lesion ◽  
Specific Therapy ◽  
Vascular Growth ◽  
Vascular Growth Factor ◽  
Pulmonary Tumors

AbstractTwo cases of myopericytosis combined with pericytoma originating within the lung are reported. These are rare pulmonary tumors. The differential diagnosis for hemangiopericytoma and pericytic tumors with glomus elements is discussed. Both myopericytic lesions mimic other lesions, which are more commonly seen in the lung. Based on the expression of vascular growth factor receptors 2 and 3, an antiangiogenic therapy was suggested for the patient with the myopericytoma. A treatment with an angiogenesis inhibitor resulted in a regression of the tumor, but not the precursor lesion. Probably a more specific therapy using tyrosine kinase inhibitors for VEGFR2/3 might better control these myopericytic proliferations.

Angiogenesis and Vascular Growth Factor Receptor Expression in Malignant Melanoma

1999 ◽  
Vol 104 (6) ◽  
pp. 1666-1674 ◽  
Author(s):  
Eric Y. Lin ◽  
Michael Piepkorn ◽  
Rochelle Garcia ◽  
David Byrd ◽  
Raymond Tsou ◽  
...  
Keyword(s):  
Growth Factor ◽  
Malignant Melanoma ◽  
Growth Factor Receptor ◽  
Receptor Expression ◽  
Vascular Growth ◽  
Vascular Growth Factor
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