Shaker A. Mousa
Aleck Hercbergs
Hung-Yun Lin
Kelly A. Keating
Paul J. Davis1,6*- 1Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselear, NY, United States
- 2Department of Radiation Oncology, The Cleveland Clinic, Cleveland, OH, United States
- 3PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
- 4Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan
- 5Traditional Herbal Medicine Research Center of Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan
- 6Department of Medicine, Albany Medical College, Albany, NY, United States
L-Thyroxine (T4) is the principal ligand of the thyroid hormone analogue receptor on the extracellular domain of integrin αvβ3. The integrin is overexpressed and activated in cancer cells, rapidly dividing endothelial cells, and platelets. The biologic result is that T4 at physiological concentration and without conversion to 3,3’,5-triiodo-L-thyronine (T3) may stimulate cancer cell proliferation and cancer-relevant angiogenesis and platelet coagulation. Pro-thrombotic activity of T4 on platelets is postulated to support cancer-linked blood clotting and to contribute to tumor cell metastasis. We examine some of these findings as they may relate to cancers of the thyroid. Differentiated thyroid cancer cells respond to physiological levels of T4 with increased proliferation. Thus, the possibility exists that in patients with differentiated thyroid carcinomas in whom T4 administration and consequent endogenous thyrotropin suppression have failed to arrest the disease, T4 treatment may be stimulating tumor cell proliferation. In vitro studies have shown that tetraiodothyroacetic acid (tetrac), a derivative of T4, acts via the integrin to block T4 support of thyroid cancer and other solid tumor cells. Actions of T4 and tetrac or chemically modified tetrac modulate gene expression in thyroid cancer cells. T4 induces radioresistance via induction of a conformational change in the integrin in various cancer cells, although not yet established in thyroid cancer cells. The thyroid hormone receptor on integrin αvβ3 mediates a number of actions of T4 on differentiated thyroid cancer cells that support the biology of the cancer. Additional studies are required to determine whether T4 acts on thyroid cancer cells.
Introduction
The extracellular domain of plasma membrane integrin αvβ3 contains a receptor for thyroid hormone analogues (1). The functions of this site on the integrin have been examined in several reviews (2, 3). Integrins are transmembrane dimer proteins that are important to cell-cell interactions and to plasma membrane interactions with extracellular matrix proteins (4). L-thyroxine (T4) is, at physiological concentrations, the principal ligand of the cell surface iodothyronine receptor on αvβ3, rather than serving in the role of a prohormone for 3,3’,5-triiodo-L-thyronine (T3) that acts intracellularly at nuclear receptors and on mitochondria (3, 5).
Integrin αvβ3 with its T4 receptor on the integrin is overexpressed by cancer cells and frequently is also activated in tumor cells, assuming a configuration that fosters cell-cell interaction and binding of extracellular proteins (4). We have shown that activation of αvβ3, i.e., an extended conformation, is regulated by radiation and thyroid hormone analogues (6). Overexpression and activation of the protein renders tumor cells susceptible to actions of T4 to stimulate proliferation, to support cancer cell defense pathways such as anti-apoptosis (7) and radioresistance (8), and to enhance cancer-related angiogenesis (2, 3, 9, 10). Preclinical studies have shown a variety of tumor cells to proliferate in response to physiological concentrations of T4 (11–14). A derivative of T4, tetraiodothyroacetic acid (tetrac), blocks actions of T4 on tumor cell αvβ3 (3). Preliminary clinical evidence indicates that lowering of systemic T4 levels and maintaining normal metabolic state with T3 (euthyroid hypothyroxinemia) (15) slows growth of multiple types of solid tumors. Clinical hypothyroidism has been shown in multiple reports specifically to slow the clinical course of renal cell carcinoma (16), breast cancer (17), glioblastoma (18), and head-and-neck cancers (19). Such evidence confirms that T3 has little activity at the integrin receptor for thyroid hormone analogues.
Among the solid tumor cells whose proliferation in vitro have been shown to be stimulated by T4 are thyroid cancers, such as differentiated follicular thyroid carcinoma (20). Such tumors are usually thyrotropin (TSH)-dependent and managed clinically with exogenous T4 in modest excess to suppress host pituitary TSH production. The recognition of the thyroid hormone receptor for T4 on integrin αvβ3 and its contribution to differentiated thyroid cancer cell proliferation raises the possibility that when TSH suppression is sometimes ineffective in thyroid tumor management, the tumor is manifesting T4-dependence, rather than TSH-dependence, as we have pointed out elsewhere (21). T4 can convey radioresistance to tumors via αvβ3 (6, 8). A question may then arise in thyroid cancer management when radiation therapy by several mechanisms has been ineffective, whether endogenous T4 or TSH-suppressive T4 is contributing to the reduced effectiveness of the radiation. This review examines these treatment scenarios.
Control of Growth of Differentiated Thyroid Cancers and Thyroid Hormones
Pituitary TSH is a principal host growth factor for differentiated papillary and follicular thyroid cancers. Suppression of this factor via negative feedback inhibition with exogenous L-thyroxine is a routine component of management of these tumors. The TSH acts at a specific cell surface G protein-coupled receptor (GPCR) in differentiated thyroid carcinomas. The discovery of the cell surface receptor for thyroid hormone analogues on the extracellular domain of integrin αvβ3 that is overexpressed by cancer cells and active endothelial cells raised the possibility that thyroid hormones as T4 might be, like TSH, a circulating growth factor for solid tumors, including thyroid cancers. In such a clinical setting, the relative importance of the TSH receptor and the integrin thyroid hormone analogue receptor can be an issue. In practical terms, however, the management strategy of T4 administration in patients with differentiated thyroid cancers is usually effective in arresting tumor growth; this indicates that the TSH receptor is of greater importance than the integrin receptor for T4 in most patients. We have pointed out, however, that when suppression of endogenous TSH with T4 is ineffective and thyroid cancer grows appreciably, the tumor is likely to be T4- and integrin-dependent (21).
As mentioned above, the integrin-dependent, trophic effect of T4 on cancers of various tissues is complex and involves increased expression of genes relevant to cell division, anti-apoptosis, tumor-relevant angiogenesis, and radioresistance (2, 3). Tetrac and chemically modified tetrac arrest the growth of two xenograft models of human differentiated follicular thyroid carcinoma (22). A component of this response was shown to be anti-angiogenesis. These results indicate that the integrin αvβ3 thyroid hormone receptor contributes to regulation of tumor growth. We have shown that both follicular thyroid carcinoma and papillary thyroid carcinoma cells proliferate in vitro with exposure to physiological concentrations of T4 and that this response is dependent upon activation of mitogen-activated protein kinase MAPK (23). The tetrac effects and involvement of MAPK in these actions of T4 on thyroid cancers indicate involvement of a direct, nongenomic action of T4 on the tumor cells. Thus, in clinical settings when endogenous TSH is fully suppressed by administration of T4, but differentiated thyroid cancer cells continue to proliferate, the proliferation may reflect actions of T4 at the thyroid hormone receptor on the tumor cell surface integrin (21). A wholly different form of thyroid cancer, medullary carcinoma of the thyroid gland, has also been shown to have T4-dependent proliferation (24).
Whether T4 may also render poorly differentiated thyroid cancers more aggressive has not as yet been determined. T3 is not an active ligand of the thyroid hormone receptor on integrin αvβ3 and there is clinical evidence that T3 instead of T4 may be safely administered to patients with a variety of cancers, for example, with systemic methimazole inhibition of thyroid gland synthesis of iodothyronines (15).
Gene Expression in T4-Treated Thyroid Cancer Cells
Modulation in various types of tumor cells—e.g., glioblastoma, pancreatic cancer, kidney—of the expression of specific genes by hormone ligands at the thyroid hormone receptor on integrin αvβ3 has been recently reviewed (2, 23). Of particular importance are actions of T4 to enhance signal transduction in papillary and follicular thyroid cancer cells (MAPK/ERK pathway) and on apoptosis-relevant genes (23). T4 prevents thyroid cancer cell accumulation of pro-apoptotic p21, c-Fos, and c-Jun proteins by blocking induction of expression of the genes for these moieties. Additional information is needed about the effects of T4 and other hormone analogues on gene expression in thyroid cancers.
Thyrotropin (TSH) Receptor and Integrin αvβ3
The TSH receptor (TSHR) is a trans-membrane GPCR that is internalized periodically (25) and may move to the trans-Golgi network (TGN) in thyroid cells. This can lead to downstream protein kinase A (PKA) signaling to the nucleus (26). Integrin trafficking is also an extensive process (27), and we have shown that T4 stimulates tumor cell internalization of αvβ3 (28) and function of the αv monomer as a coactivator protein in the nucleus. T4 can activate PKA (29, 30). Various GPCRs are known to interact with integrins (31), and extracellular matrix proteins such as vitronectin or fibronectin have been shown to bind to αvβ3 (3) and with TSHR (32), altering functions of the proteins or promoting internalization. This body of evidence has not, however, been examined in thyroid cancer cells for the possibility that TSHR and αvβ3 traffick together in these cells when T4 binds to the integrin. Were such coupling to occur, then circulating levels of TSH would have reduced cancer cell target TSHRs to which to bind and act. One additional note of possible relevance is that, under certain circumstances, TSH may modulate abundance of αvβ3 in specific tissues, such as endothelium (33). It would appear worthwhile for the trafficking of the integrin and TSHR to be studied concurrently in thyroid cancer cells in the presence and absence of T4.
A recent review has concluded that TSH suppression in patients with intermediate-risk or high- risk differentiated thyroid cancers may be of limited benefit (34). It will be of interest and importance to determine whether this is a function of increased susceptibility of such tumors to T4-induction of radioresistance via integrin αvβ3.
Tumor Cell Respiration/ATP Production and the Thyroid Hormone Analogue Receptor on Integrin αvβ3
We have recently reported that a large number of tumor cell respiration-linked genes are regulated from the integrin by thyroid hormone analogues. This study depended upon a tetrac-containing agent to probe the function of thyroid hormone analogue receptor function. Among the genes affected were multiple ATP synthases and NADH dehydrogenases (35). Prior to this study, the control of cell respiration—in normal cells, as well as tumor cells—was thought to be an exclusive function of T3 at the level of mitochondria and of ATP production-related genes in the nucleus of cells. An implication of these tetrac-based observations is that T4 may regulate respiration in cancer cells from the cell surface integrin. This possibility has not yet been explored.
Metastasis of Thyroid Carcinomas and Possible Roles of T4
We have indicated elsewhere that certain actions of T4 on tumor cells and on platelets may support the process of metastasis from primary cancers (36). These actions of T4 include cell proliferation, cell migration, platelet-tumor cell interaction, and angiogenesis (36, 37). The T4 antagonist, tetrac, acts at αvβ3 to inhibit the metastatic process in a breast cancer model (36). Such inhibition needs to be examined in a thyroid cancer metastasis model (38).
Possible Actions of Thyroid Hormone Analogues Other Than T4 and Tetrac on Thyroid Cancer Biology
In the context of thyroid hormone actions in normal, nonmalignant cells, T3 is the active form of the hormone (3, 5, 39). We have shown elsewhere and emphasized here that in cancer cells and dividing endothelial cells, however, T4 and tetrac are the active forms of the hormone. We would note that reverse T3 (rT3) also appears in certain tumor cells to have proliferative activity at the integrin (40, 41), but not at nuclear receptors. rT3 activity has not yet been examined for activity in thyroid cancer cells.
Immune Checkpoint PD-L1/PD-1 and Thyroid Carcinoma
The programmed cell death protein 1 (PD-1) and the programmed death ligand 1 (PD-L1) are an immune checkpoint that has been well-studied in different types of thyroid carcinomas (42–44). Tumor production of PD-L1 is a marker of aggressiveness. We know from studies in a variety of solid tumors other than thyroid cancer that express PD-L1 that the thyroid hormone analogue receptor on integrin αvβ3 regulates release of PD-L1 (45). Tetrac and chemically modified tetrac will prevent tumor cell production/release of PD-L1. It is thus of some importance for the behavior of PD-L1 production to be studied as a function of ambient T4 in thyroid carcinomas. That is, the use of T4 to suppress endogenous TSH in patients with aggressive differentiated thyroid cancers may undesirably support PD-L1 production by the tumor and block any host anti-tumor immune response that is present.
Thyroid Hormones and Radioresistance in Cancer Cells
Leith and co-workers (8, 46) have reported that the thyroid hormone analogue receptor on integrin αvβ3 regulates the state of radioresistance of certain cancer cells. This appears to be a function of hormone-linked changes in the conformation of the integrin (6) that require hormone-binding to αvβ3. These observations raise the possibility that host thyroid gland-produced T4 or exogenous T4 intended to suppress endogenous TSH may lessen the impact of therapeutic radiation on the thyroid tumor. However, the T4-radioresistance studies have been conducted in tumor cells other than thyroid carcinoma and require repetition in thyroid cancer cells.
Various factors that appear to contribute to radioresistance of thyroid cancers have recently been summarized in a radioiodine refractoriness score (47). The factors in this score include history of cigarette smoking and local tumor extension. We suggest that circulating free T4 quartile levels be considered, together with other measures (47, 48) for such evaluation.
Tetrac as a Pharmacological Inhibitor of Integrin-Dependent Actions of T4
It has been noted in several sections of this review that the T4 analogue, tetrac, or chemical modifications of tetrac, can block trophic actions of T4 on thyroid cancer cells. Several chemical modifications of tetrac have been developed and tested preclinically as prospective anticancer agents (14, 49, 50). Tetrac also has intrinsic anticancer activity in the absence of T4 (3, 5).
Discussion
We have emphasized in this review the contribution of the thyroid hormone analogue receptor on integrin αvβ3 to the behaviors of thyroid cancer cells. From the standpoint of tumor cell biology, T4 is the principally active iodothyronine at this plasma membrane hormone receptor site in differentiated thyroid cancer cells. T3 in physiological concentrations has little or no bioactivity at this receptor. Differentiated human follicular and papillary thyroid carcinoma cells proliferate in response to T4, but poorly differentiated/anaplastic thyroid cancer cells have not been specifically examined for responses to T4. Medullary carcinoma of the thyroid gland is responsive to T4 (24). The proliferative activity of T4 is opposed by tetrac or chemically modified tetrac in the thyroid carcinoma cells in which actions of T4 have been examined.
We emphasize here that the actions of thyroid hormone analogues on thyroid cancers need to be explored more fully. TSH is a critical growth factor for the majority of thyroid cancers. But if T4 is a trophic factor for thyroid cancers and is being employed clinically as a suppressor of host TSH, we need to know whether the tumor cells in patients who have not responded to TSH suppression are now T4-dependent (21). This can be determined by imposition of the state of euthyroid hypothyroxinemia (15). Metastasis of thyroid cancer may also have some dependence on availability of T4 to thyroid tumor cells.
PD-L1 is an important product of certain thyroid cancer cells (42–44). We know from studies in a variety of nonthyroid cancer cells that T4 enhances the production of this immune checkpoint component that blocks immune attacks on cancer cells. When thyroid cancers progress in the context of satisfactory suppression of host TSH, we may also ask whether immune checkpoint actions of T4 in the TSH-suppression treatment approach is blocking any immune system activity that might be present and potentially relevant to clinical management.
We have raised the possibility elsewhere that T4 may contribute to the metastatic activity of cancers (36). In distant metastases of various types of cancer, the interaction of platelets and tumor cells that is fostered by T4 may contribute to metastasis formation (37). It is not clear what the factors are that lead to local—particularly, central—lymph node metastases from differentiated thyroid cancers (51). We propose that local T4 production by thyroid cancer cells may be a factor that contributes to local, as well as distant, metastasis. The actions of T4 at tumor sites will also foster angiogenesis that is cancer- relevant (9, 10).
There is a substantial literature on specific microRNA (miRNA) elaboration by thyroid cancers (52–54). Abundance of these moieties in thyroid tumors may correlate with tumor type and size, metastasis, and recurrence. The possible influence of T4 on specific miRNA production in thyroid tumors has not yet been determined.
Other molecular mechanisms may be involved in the genesis of thyroid cancers (55, 56), such as a multicomponent signaling system involving fibroblast growth factor receptor, mutated BRAF signaling, and other communication pathways (57). It may be useful to examine such a mechanism for participation by T4 because of its nongenomic actions on a variety of signal transduction pathways (3).
A panel of interleukins may contribute to regulation of thyroid cancer cell proliferation and migration (58). Acting at the receptor on integrin αvβ3, thyroid hormone analogues regulate the inflammatory response via various interleukins and chemokines (59). Aside from relevance to neoplasia, cytokine storms potentiated by T4 have been proposed to support infection-related inflammatory states (60).
Finally, T4 may support radioresistance in a variety of tumor cells, but T4 has not yet been examined for such an effect in thyroid cancers. It is routine to withhold TSH-suppressive T4 administration in thyroid cancer patients until ablative radioactive iodine has been administered. An effect of withholding T4 should be a change in conformation of integrin αvβ3 to the non-radioresistant configuration (6). The extent of conformation change of integrin αvβ3 can be readily examined immunologically and graded in thyroid tumor biopsy prior to radio-ablation. When the extended conformation is in excess in cancer cells, a formula might be developed for consideration of brief administration of a tetrac-containing agent before radiation treatment. The molecular basis of tetrac-induced radiosensitivity involves multiple signal transduction pathways in the tumor cells (8).
Author Contributions
PD reviewed the literature and wrote the paper. All authors contributed to the article and approved the submitted version.
Conflict of Interest
SM and PD are the founders of NanoPharmaceuticals LLC, that is developing chemically modified forms of tetrac for application to management of various types of cancer, and PD is Chief Scientific Officer at the company.
The remaining 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.
References
1. Bergh JJ, Lin HY, Lansing L, Mohamed SN, Davis FB, Mousa S, et al. Integrin αVβ3 Contains a Cell Surface Receptor Site for Thyroid Hormone That Is Linked to Activation of Mitogen-Activated Protein Kinase and Induction of Angiogenesis. Endocrinology (2005) 146(7):2864–71. doi: 10.1210/en.2005-0102
2. Davis PJ, Goglia F, Leonard JL. Nongenomic Actions of Thyroid Hormone. Nat Rev Endocrinol (2016) 12(2):111–21. doi: 10.1038/nrendo.2015.205
3. Davis PJ, Mousa SA, Lin HY. Nongenomic Actions of Thyroid Hormone: The Integrin Component. Physiol Rev (2021) 101(1):319–52. doi: 10.1152/physrev.00038.2019
4. Desgrosellier JS, Cheresh DA. Integrins in Cancer: Biological Implications and Therapeutic Opportunities. Nat Rev Cancer (2010) 10(1):9–22. doi: 10.1038/nrc2748
5. Cheng SY, Leonard JL, Davis PJ. Molecular Aspects of Thyroid Hormone Actions. Endocr Rev (2010) 31(2):139–70. doi: 10.1210/er.2009-0007
6. Leith JT, Hercbergs A, Kenney S, Mousa SA, Davis PJ. Activation of Tumor Cell Integrin αvβ3 by Radiation and Reversal of Activation by Chemically Modified Tetraiodothyroacetic Acid (Tetrac). Endocr Res (2018) 43(4):215–9. doi: 10.1080/07435800.2018.1456550
7. Lin HY, Glinsky GV, Mousa SA, Davis PJ. Thyroid Hormone and Anti-Apoptosis in Tumor Cells. Oncotarget (2015) 6(17):14735–43. doi: 10.18632/oncotarget.4023
8. Leith JT, Mousa SA, Hercbergs A, Lin HY, Davis PJ. Radioresistance of Cancer Cells, Integrin αvβ3 and Thyroid Hormone. Oncotarget (2018) 9(97):37069–75. doi: 10.18632/oncotarget.26434
9. Mousa SA, Lin HY, Tang HY, Hercbergs A, Luidens MK, Davis PJ. Modulation of Angiogenesis by Thyroid Hormone and Hormone Analogues: Implications for Cancer Management. Angiogenesis (2014) 17(3):463–9. doi: 10.1007/s10456-014-9418-5
10. Davis PJ, Sudha T, Lin HY, Mousa SA. Thyroid Hormone, Hormone Analogs, and Angiogenesis. Compr Physiol (2015) 6(1):353–62. doi: 10.1002/cphy.c150011
11. Ashur-Fabian O, Zloto O, Fabian I, Tsarfaty G, Ellis M, Steinberg DM, et al. Tetrac Delayed the Onset of Ocular Melanoma in an Orthotopic Mouse Model. Front Endocrinol (Lausanne) (2018) 9:775. doi: 10.3389/fendo.2018.00775
12. Bharali DJ, Yalcin M, Davis PJ, Mousa SA. Tetraiodothyroacetic Acid-Conjugated PLGA Nanoparticles: A Nanomedicine Approach to Treat Drug-Resistant Breast Cancer. Nanomedicine (Lond) (2013) 8(12):1943–54. doi: 10.2217/nnm.12.200
13. Debreli Coskun M, Sudha T, Bharali DJ, Celikler S, Davis PJ, Mousa SA. αvβ3 Integrin Antagonists Enhance Chemotherapy Response in an Orthotopic Pancreatic Cancer Model. Front Pharmacol (2020) 11:95. doi: 10.3389/fphar.2020.00095
14. Sudha T, Bharali DJ, Sell S, Darwish NHE, Davis PJ, Mousa SA. Nanoparticulate Tetrac Inhibits Growth and Vascularity of Glioblastoma Xenografts. Horm Cancer (2017) 8(3):157–65. doi: 10.1007/s12672-017-0293-6
15. Hercbergs A, Johnson RE, Ashur-Fabian O, Garfield DH, Davis PJ. Medically Induced Euthyroid Hypothyroxinemia may Extend Survival in Compassionate Need Cancer Patients: An Observational Study. Oncologist (2015) 20(1):72–6. doi: 10.1634/theoncologist.2014-0308
16. Schmidinger M, Vogl UM, Bojic M, Lamm W, Heinzl H, Haitel A, et al. Hypothyroidism in Patients With Renal Cell Carcinoma: Blessing or Curse? Cancer (2011) 117(3):534–44. doi: 10.1002/cncr.25422
17. Cristofanilli M, Yamamura Y, Kau SW, Bevers T, Strom S, Patangan M, et al. Thyroid Hormone and Breast Carcinoma. Primary Hypothyroidism is Associated With a Reduced Incidence of Primary Breast Carcinoma. Cancer (2005) 103(6):1122–8. doi: 10.1002/cncr.20881
18. Hercbergs AA, Goyal LK, Suh JH, Lee S, Reddy CA, Cohen BH, et al. Propylthiouracil-Induced Chemical Hypothyroidism With High-Dose Tamoxifen Prolongs Survival in Recurrent High Grade Glioma: A Phase I/II Study. Anticancer Res (2003) 23(1B):617–26.
19. Nelson M, Hercbergs A, Rybicki L, Strome M. Association Between Development of Hypothyroidism and Improved Survival in Patients With Head and Neck Cancer. Arch Otolaryngol Head Neck Surg (2006) 132(10):1041–6. doi: 10.1001/archotol.132.10.1041
20. Lin HY, Tang HY, Shih A, Keating T, Cao G, Davis PJ, et al. Thyroid Hormone Is a MAPK-Dependent Growth Factor for Thyroid Cancer Cells and Is Anti-Apoptotic. Steroids (2007) 72(2):180–7. doi: 10.1016/j.steroids.2006.11.014
21. Davis PJ, Hercbergs A, Luidens MK, Lin HY. Recurrence of Differentiated Thyroid Carcinoma During Full TSH Suppression: Is the Tumor Now Thyroid Hormone Dependent? Horm Cancer (2015) 6(1):7–12. doi: 10.1007/s12672-014-0204-z
22. Yalcin M, Bharali DJ, Dyskin E, Dier E, Lansing L, Mousa SS, et al. Tetraiodothyroacetic Acid and Tetraiodothyroacetic Acid Nanoparticle Effectively Inhibit the Growth of Human Follicular Thyroid Cell Carcinoma. Thyroid (2010) 20(3):281–6. doi: 10.1089/thy.2009.0249
23. Davis PJ, Lin HY, Hercbergs A, Mousa SA. Actions of L-thyroxine (T4) and Tetraiodothyroacetic Acid (Tetrac) on Gene Expression in Thyroid Cancer Cells. Genes (Basel) (2020) 11(7):755. doi: 10.3390/genes11070755
24. Yalcin M, Dyskin E, Lansing L, Bharali DJ, Mousa SS, Bridoux A, et al. Tetraiodothyroacetic Acid (Tetrac) and Nanoparticulate Tetrac Arrest Growth of Medullary Carcinoma of the Thyroid. J Clin Endocrinol Metab (2010) 95(4):1972–80. doi: 10.1210/jc.2009-1926
25. Lahuna O, Quellari M, Achard C, Nola S, Meduri G, Navarro C, et al. Thyrotropin Receptor Trafficking Relies on the hScrib-βPIX-GIT1-ARF6 Pathway. EMBO J (2005) 24(7):1364–74. doi: 10.1038/sj.emboj.7600616
26. Godbole A, Lyga S, Lohse MJ, Calebiro D. Internalized TSH Receptors en Route to the TGN Induce Local Gs-protein Signaling and Gene Transcription. Nat Commun (2017) 8(1):443. doi: 10.1038/s41467-017-00357-2
27. Moreno-Layseca P, Icha J, Hamidi H, Ivaska J. Integrin Trafficking in Cells and Tissues. Nat Cell Biol (2019) 21(2):122–32. doi: 10.1038/s41556-018-0223-z
28. Lin HY, Su YF, Hsieh MT, Lin S, Meng R, London D, et al. Nuclear Monomeric Integrin αv in Cancer Cells Is a Coactivator Regulated by Thyroid Hormone. FASEB J (2013) 27(8):3209–16. doi: 10.1096/fj.12-227132
29. Lin HY, Thacorf HR, Davis FB, Davis PJ. Potentiation by Thyroxine of Interferon-Gamma-Induced Antiviral State Requires PKA and PKC Activities. Am J Physiol (1996) 271(4 Pt 1):C1256–61. doi: 10.1152/ajpcell.1996.271.4.C1256
30. Lu CC, Tsai SC. Involvement of the cyclic-AMP-dependent Protein Kinase A Pathway in Thyroxine Effects on Calcitonin Secretion From TT Cells. Horm Metab Res (2011) 43(1):31–6. doi: 10.1055/s-0030-1265216
31. Teoh CM, Tam JK, Tran T. Integrin and GPCR Crosstalk in the Regulation of ASM Contraction Signaling in Asthma. J Allergy (Cairo) (2012) 2012:341282. doi: 10.1155/2012/341282
32. Ghinea N, Baratti-Elbaz C, De Jesus-Lucas A, Milgrom E. TSH Receptor Interaction With the Extracellular Matrix: Role on Constitutive Activity and Sensitivity to Hormonal Stimulation. Mol Endocrinol (2002) 16(5):912–23. doi: 10.1210/mend.16.5.0820
33. Yan Y, Jiang F, Lai Y, Wang H, Liu A, Wang C, et al. Effect of Thyrotropin on Osteopontin, Integrin αvβ3 and VCAM-1 in the Endothelium Via Activation of Akt. Int J Mol Sci (2016) 17(9):1484. doi: 10.3390/ijms17091484
34. Klubo-Gwiezdzinska J, Auh S, Gershengorn M, Daley B, Bikas A, Burman K, et al. Association of Thyrotropin Suppression With Survival Outcomes in Patients With Intermediate- and High-Risk Differentiated Thyroid Cancer. JAMA Netw Open (2019) 2(2):e187754. doi: 10.1001/jamanetworkopen.2018.7754
35. Davis PJ, Glinsky GV, Thangirala S, Lin HY, Mousa SA. (2018). Abstract: Regulation of Cancer Cell Metabolism Via the Thyroid Hormone Analogue Receptor on Integrin αVβ3: Action of P-bi-TAT (tetrac-PEG) at the Receptor,presented at: AACR Metabolism and Cancer Conference, New York, NY, September 29, 2018.
36. Mousa SA, Glinsky GV, Lin HY, Ashur-Fabian O, Hercbergs A, Keating KA, et al. Contributions of Thyroid Hormone to Cancer Metastasis. Biomedicines (2018) 6(3):89. doi: 10.3390/biomedicines6030089
37. Davis PJ, Mousa SA, Schechter GP, Lin HY. Platelet ATP, Thyroid Hormone Receptor on Integrin αvβ3 and Cancer Metastasis. Horm Cancer (2020) 11(1):13–6. doi: 10.1007/s12672-019-00371-4
38. Xiong Y, Kotian S, Zeiger MA, Zhang L, Kebebew E. miR-126-3p Inhibits Thyroid Cancer Cell Growth and Metastasis, and is Associated With Aggressive Thyroid Cancer. PloS One (2015) 10(8):e0130496. doi: 10.1371/journal.pone.0130496
39. Brent GA. Mechanisms of Thyroid Hormone Action. J Clin Invest (2012) 122(9):3035–43. doi: 10.1172/JCI60047
40. Davis PJ, Tang HY, Hercbergs A, Lin HY, Keating KA, Mousa SA. Bioactivity of Thyroid Hormone Analogs at Cancer Cells. Front Endocrinol (Lausanne) (2018) 9:739. doi: 10.3389/fendo.2018.00739
41. Lin HY, Tang HY, Leinung M, Mousa SA, Hercbergs A, Davis PJ. Action of Reverse T3 on Cancer Cells. Endocr Res (2019) 44(4):148–52. doi: 10.1080/07435800.2019.1600536
42. Bai Y, Niu D, Huang X, Jia L, Kang Q, Dou F, et al. PD-L1 and PD-1 Expression are Correlated With Distinctive Clinicopathological Features in Papillary Thyroid Carcinoma. Diagn Pathol (2017) 12(1):72. doi: 10.1186/s13000-017-0662-z
43. Chowdhury S, Veyhl J, Jessa F, Polyakova O, Alenzi A, MacMillan C, et al. Programmed Death-Ligand 1 Overexpression is a Prognostic Marker for Aggressive Papillary Thyroid Cancer and its Variants. Oncotarget (2016) 7(22):32318–28. doi: 10.18632/oncotarget.8698
44. Fu G, Polyakova O, MacMillan C, Ralhan R, Walfish PG. Programmed Death - Ligand 1 Expression Distinguishes Invasive Encapsulated Follicular Variant of Papillary Thyroid Carcinoma From Noninvasive Follicular Thyroid Neoplasm With Papillary-Like Nuclear Features. EBioMedicine (2017) 18:50–5. doi: 10.1016/j.ebiom.2017.03.031
45. Lin HY, Chin YT, Shih YJ, Chen YR, Leinung M, Keating KA, et al. In Tumor Cells, Thyroid Hormone Analogues Non-Immunologically Regulate PD-L1 and PD-1 Accumulation That Is Anti-Apoptotic. Oncotarget (2018) 9(75):34033–7. doi: 10.18632/oncotarget.26143
46. Leith JT, Davis PJ, Mousa SA, Hercbergs AA. In Vitro Effects of Tetraiodothyroacetic Acid Combined With X-Irradiation on Basal Cell Carcinoma Cells. Cell Cycle (2017) 16(4):367–73. doi: 10.1080/15384101.2016.1269044
47. Li G, Lei J, Song L, Jiang K, Wei T, Li Z, et al. Radioiodine Refractoriness Score: A Multivariable Prediction Model for Postoperative Radioiodine-Refractory Differentiated Thyroid Carcinomas. Cancer Med (2018) 7(11):5448–56. doi: 10.1002/cam4.1794
48. Dadu R, Cabanillas ME. Optimizing Therapy for Radioactive Iodine-Refractory Differentiated Thyroid Cancer: Current State of the Art and Future Directions. Minerva Endocrinol (2012) 37(4):335–56.
49. Chin YT, He ZR, Chen CL, Chu HC, Ho Y, Su PY, et al. Tetrac and NDAT Induce Anti-Proliferation Via Integrin αvβ3 in Colorectal Cancers With Different K-RAS Status. Front Endocrinol (Lausanne) (2019) 10:130. doi: 10.3389/fendo.2019.00130
50. Rajabi M, Godugu K, Sudha T, Bharali DJ, Mousa SA. Triazole Modified Tetraiodothyroacetic Acid Conjugated to Polyethylene Glycol: High Affinity Thyrointegrin αvβ3 Antagonist With Potent Anticancer Activities in Glioblastoma Multiforme. Bioconjug Chem (2019) 30(12):3087–97. doi: 10.1021/acs.bioconjchem.9b00742
51. Raffaelli M, De Crea C, Sessa L, Fadda G, Lombardi CP, Bellantone R. Risk Factors for Central Neck Lymph Node Metastases in Follicular Variant vs. Classic Papillary Thyroid Carcinoma. Endocrine (2018) 62(1):64–70. doi: 10.1007/s12020-018-1607-3
52. Lima CR, Gomes CC, Santos MF. Role of microRNAs in Endocrine Cancer Metastasis. Mol Cell Endocrinol (2017) 456:62–75. doi: 10.1016/j.mce.2017.03.015
53. Pamedytyte D, Simanaviciene V, Dauksiene D, Leipute E, Zvirbliene A, Sarauskas V, et al. Association of microRNA Expression and BRAF(V600E) Mutation With Recurrence of Thyroid Cancer. Biomolecules (2020) 10(4):625. doi: 10.3390/biom10040625
54. Yoruker EE, Terzioglu D, Teksoz S, Uslu FE, Gezer U, Dalay N. MicroRNA Expression Profiles in Papillary Thyroid Carcinoma, Benign Thyroid Nodules and Healthy Controls. J Cancer (2016) 7(7):803–9. doi: 10.7150/jca.13898
55. Giannetta E, Isidori AM, Durante C, Di Gioia C, Longo F, Tombolini V, et al. Anaplastic Thyroid Carcinoma and Foscarnet Use in a Multitarget Treatment Documented by 18F-FDG PET/CT: A Case Report. Medicine (2017) 96(6):e5621. doi: 10.1097/md.0000000000005621
56. Prete A, Borges de Souza P, Censi S, Muzza M, Nucci N, Sponziello M. Update on Fundamental Mechanisms of Thyroid Cancer. Front Endocrinol (Lausanne) (2020) 11:102. doi: 10.3389/fendo.2020.00102
57. Kondo T, Zheng L, Liu W, Kurebayashi J, Asa SL, Ezzat S. Epigenetically Controlled Fibroblast Growth Factor Receptor 2 Signaling Imposes on the RAS/BRAF/mitogen-Activated Protein Kinase Pathway to Modulate Thyroid Cancer Progression. Cancer Res (2007) 67(11):5461–70. doi: 10.1158/0008-5472.CAN-06-4477
58. Xi C, Zhang GQ, Sun ZK, Song HJ, Shen CT, Chen XY, et al. Interleukins in Thyroid Cancer: From Basic Researches to Applications in Clinical Practice. Front Immunol (2020) 11:1124. doi: 10.3389/fimmu.2020.01124
59. Davis PJ, Glinsky GV, Lin HY, Incerpi S, Davis FB, Mousa SA, et al. Molecular Mechanisms of Actions of Formulations of the Thyroid Hormone Analogue, Tetrac, on the Inflammatory Response. Endocr Res (2013) 38(2):112–8. doi: 10.3109/07435800.2013.778865
Keywords: thyroid hormone, L-thyroxine (T4), integrin αvβ3, thyrotropin (TSH), tetraiodothyroacetic acid (tetrac), follicular thyroid carcinoma, differentiated thyroid cancers
Citation: Mousa SA, Hercbergs A, Lin H-Y, Keating KA and Davis PJ (2021) Actions of Thyroid Hormones on Thyroid Cancers. Front. Endocrinol. 12:691736. doi: 10.3389/fendo.2021.691736
Received: 07 April 2021; Accepted: 31 May 2021;
Published: 21 June 2021.
Edited by:
Michihisa Umetani, University of Houston, United StatesReviewed by:
Rosalba Senese, University of Campania Luigi Vanvitelli, ItalyElisa Giannetta, Sapienza University of Rome, Italy
Copyright © 2021 Mousa, Hercbergs, Lin, Keating and Davis. 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: Paul J. Davis, cGRhdmlzLm9yZHdheXN0QGdtYWlsLmNvbQ==; orcid.org/0000-0002-6794-4917