Florencia Cayrol
Helena Andrea Sterle
Maria Del Mar Montesinos- 1Laboratorio de Neuroinmunomodulación y Oncología Molecular, Instituto de Investigaciones Biomédicas (BIOMED)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)-Universidad Católica Argentina (UCA), Buenos Aires, Argentina
- 2Centro de Investigaciones en Bioquímica Clínica e Inmunología - Consejo Nacional de Investigaciones Científicas y Técnicas (CIBICI-CONICET), Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Cordoba, Argentina
Editorial on the Research Topic
Thyroid hormone actions in cancer
Thyroid hormones (THs) are well known for being key players in controlling cell metabolism, growth, and many other important physiological processes such as embryonic development and cell differentiation (1). THs exert their biological actions primarily through the binding of 3,5,3′-triiodo-l-thyronine (T3) to its nuclear receptor TR that subsequently homodimerizes (TR/TR) and/or heterodimerizes with retinoid X receptor –RXR- (TR/RXR) to regulate the transcription of target genes containing a TH-response element (TRE). Circulating TH levels are largely stable, in humans approximately 80% of serum T3 is derived from T4 by the iodothyronine deiodinases that are expressed in a tissue-specific manner in fetal and adult life. Importantly, deiodinase-mediated mechanisms within target cells can modulate TH signaling (2). In addition, it was described that both, T3 and T4 (l-thyroxine), activate membrane-bound receptors such as the integrin αvβ3 triggering different signaling pathways that ultimately modulate transcription of a complementary set of genes (3). T4 is the main form of TH produced by the thyroid gland, but it is only minimally active. In the last decades, scientific research has supported a relationship between THs and the pathophysiology of different cancer types (4, 5). In this sense, abnormal THs levels caused by thyroid dysfunction, the disruption of deiodinases, and TH nuclear or membrane receptors’ activity can affect tumor behavior. THs direct actions on cancer cells through genomic and non-genomic pathways can regulate malignant proliferation, differentiation, apoptosis, invasiveness, and angiogenesis in solid (6–8) and hematological (9–11) malignancies. In addition, local control of THs signaling provided by the regulation of deiodinase activity is associated with cancer development, progression, and recurrence by impacting virtually all the hallmarks of cancer (4, 12). Besides, alterations in deiodinase expression and activity are frequent in tumors (13). On the other hand, increasing evidence suggests that THs are modulators of the immune responses, including antitumor immunity, thus influencing tumor progression (14–17). Furthermore, the dysregulation of the thyroid status was also shown to affect the development, progression, and outcomes in cancer patients (18). In addition, some authors propose that tumor cells gain the ability to affect local and systemic homeostasis, including thyroid status, by the release of neurohormonal and immune mediators, that can control the main neuroendocrine centers such as the hypothalamus, pituitary, adrenals, and thyroid (19).
The knowledge of the mechanisms of THs actions in cancer could lead to the identification of new therapeutic targets or to the use of the modulation of the thyroid status to improve treatment outcomes in patients. The overall aim of this Research Topic entitled “Thyroid hormone actions in cancer” includes the contribution and significance of TH´s direct actions on tumor cell proliferation, survival, and dissemination; and the association of thyroid status with the risk and progression of oncologic pathologies. This Research Topic consists of two original research articles, one review, and one systematic review. These articles include the study of hepatocellular carcinoma, glioblastoma, thyroid cancer, and pituitary adenoma as the research oncologic models.
In the first original paper Godugu et al., evaluated whether TH analogs have a role in efferocytosis, a process by which apoptotic cells are removed by phagocytic cells. Using in vitro and in vivo glioblastoma models authors examined how the apoptosis induced by the hormone analog tetraiodothyroacetic acid (tetrac) and chemically modified tetrac actions initiated at the integrin αvβ3 on tumor cells, contribute to the clearance of apoptotic cells. In the other original research article, Lu et al. used Mendelian randomization (MR) analysis to estimate the causal effect of hypothyroidism on the risk for hepatocellular carcinoma (HCC). Single-nucleotide polymorphisms (SNPs) associated with hypothyroidism were screened via a genome-wide association study (GWAS). They found that hypothyroidism has a protective causal association with HCC. On the other hand, Wang et al. performed a systematic review of related original studies with the purpose of comprehensively evaluating the relationships between thyroid-related hormones and the risk of thyroid cancer (TC). The authors found a significant association between thyroid-related hormones (TSH, free T4, free T3) and the risk of TC in this study, but further research is needed to understand the underlying mechanisms. Finally, Li et al. showed a rare case of pituitary adenoma producing both GH and TSH simultaneously, which is associated with hyperthyroidism and acromegaly.
Author contributions
FC: writing–original draft, writing–review and editing. HS: writing–review and editing. MM: writing–review and editing. All authors contributed to the article and approved the submitted version.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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References
1. Mullur R, Liu YY, Brent GA. Thyroid hormone regulation of metabolism. Physiol Rev (2014) 94:355–82. doi: 10.1152/physrev.00030.2013
2. Russo SC, Salas-Lucia F, Bianco AC. Deiodinases and the metabolic code for thyroid hormone action. Endocrinology (2021) 162. doi: 10.1210/endocr/bqab059
3. Davis PJ, Mousa SA, Lin HY. Nongenomic actions of thyroid hormone: the integrin component. Physiol Rev (2021) 101:319–52. doi: 10.1152/physrev.00038.2019
4. Goemann IM, Romitti M, Meyer ELS, Wajner SM, Maia AL. Role of thyroid hormones in the neoplastic process: an overview. Endocr Relat Cancer (2017) 24:R367–85. doi: 10.1530/ERC-17-0192
5. Krashin E, Piekiełko-Witkowska A, Ellis M, Ashur-Fabian O. Thyroid hormones and cancer: a comprehensive review of preclinical and clinical studies. Front Endocrinol (Lausanne) (2019) 10. doi: 10.3389/fendo.2019.00059
6. Hall LC, Salazar EP, Kane SR, Liu N. Effects of thyroid hormones on human breast cancer cell proliferation. J Steroid Biochem Mol Biol (2008) 109:57–66. doi: 10.1016/j.jsbmb.2007.12.008
7. Meng R, Tang H-Y, Westfall J, London D, Cao JH, Mousa SA, et al. Crosstalk between integrin αvβ3 and estrogen receptor-α is involved in thyroid hormone-induced proliferation in human lung carcinoma cells. PloS One (2011) 6. doi: 10.1371/journal.pone.0027547
8. Zhang P, Chen L, Song Y, Li X, Sun Y, Xiao Y, et al. Tetraiodothyroacetic acid and transthyretin silencing inhibit pro-metastatic effect of l-thyroxin in anoikis-resistant prostate cancer cells through regulation of MAPK/ERK pathway. Exp Cell Res (2016) 347:350–9. doi: 10.1016/j.yexcr.2016.08.019
9. Cohen K, Ellis M, Shinderman E, Khoury S, Davis PJ, Hercbergs A, et al. Relevance of the thyroid hormones-αvβ3 pathway in primary myeloma bone marrow cells and to bortezomib action. Leuk Lymphoma (2015) 56:1107–14. doi: 10.3109/10428194.2014.947612
10. Cayrol F, Díaz Flaqué MC, Fernando T, Yang SN, Sterle HA, Bolontrade M, et al. Integrin αvβ3 acting as membrane receptor for thyroid hormones mediates angiogenesis in malignant T cells. Blood (2015) 125:841–51. doi: 10.1182/blood-2014-07-587337
11. Cayrol F, Revuelta MV, Debernardi M, Paulazo A, Phillip JM, Zamponi N, et al. Inhibition of integrin αVβ3 signaling improves the antineoplastic effect of bexarotene in cutaneous T-cell lymphoma. Mol Cancer Ther (2022) 21:1485–96. doi: 10.1158/1535-7163.MCT-22-0093
12. Goemann IM, Marczyk VR, Romitti M, Wajner SM, Maia AL. Current concepts and challenges to unravel the role of iodothyronine deiodinases in human neoplasias. Endocr Relat Cancer (2018) 25:R625–45. doi: 10.1530/ERC-18-0097
13. Nappi A, De Stefano MA, Dentice M, Salvatore D. Deiodinases and cancer. Endocrinology (2021) 162. doi: 10.1210/endocr/bqab016
14. van der Spek AH, Fliers E, Boelen A. Thyroid hormone metabolism in innate immune cells. J Endocrinol (2017) 232:R67–81. doi: 10.1530/JOE-16-0462
15. Wenzek C, Boelen A, Westendorf AM, Engel DR, Moeller LC, Führer D, et al. The interplay of thyroid hormones and the immune system - where we stand and why we need to know about it. Eur J Endocrinol (2022) 186:R65–77. doi: 10.1530/EJE-21-1171
16. Del Mar Montesinos M, Pellizas C. Thyroid hormone action on innate immunity. Front Endocrinol (Lausanne) (2019) 10. doi: 10.3389/fendo.2019.00350
17. Sterle HA, Arcos MLB, Valli E, Paulazo MA, Méndez Huergo SP, Blidner AG, et al. The thyroid status reprograms T cell lymphoma growth and modulates immune cell frequencies. J Mol Med (2016) 94:417–29. doi: 10.1007/s00109-015-1363-2
18. Ma Z, Song P, Ji D, Zheng M, Qiu G, Liu Z, et al. Thyroid hormones as biomarkers of lung cancer: a retrospective study. Ann Med (2023) 55. doi: 10.1080/07853890.2023.2196088
Keywords: thyroid hormone receptor, thyroid status, integrin alpha V beta 3, cancer progression, antitumor immunity, deiodinases
Citation: Cayrol F, Sterle HA and Montesinos MDM (2023) Editorial: Thyroid hormone actions in cancer. Front. Endocrinol. 14:1219871. doi: 10.3389/fendo.2023.1219871
Received: 09 May 2023; Accepted: 18 May 2023;
Published: 25 May 2023.
Edited and Reviewed by:
Antonino Belfiore, University of Catania, ItalyCopyright © 2023 Cayrol, Sterle and Montesinos. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Florencia Cayrol, ZmxvcmVuY2lhX2NheXJvbEB1Y2EuZWR1LmFy