Documented and projected actions in vitro of thyroid hormone as L -thyroxine (T4) on basal cell carcinoma of the skin
Main Article Content
Abstract
Thyroid hormone as L-thyroxine (T4) at physiological concentrations acts at its cell surface receptor on integrin avb3 to stimulate cancer cell proliferation1. These proliferation studies have been conducted in vitro, but pharmacological reduction of T4 and substitution of nuclear receptor ligand 3,3’,5-triiodo-L-thyronine (T3) is a state of euthyroid hypothyroxinemia that has been shown clinically to arrest tumor growth in patients with cancer. T3 is inactive at physiological levels at the plasma membrane integrin receptor. A preclinical study of human basal cell carcinoma (BCC) cells has shown that the integrin thyroid hormone receptor regulates BCC radiosensitivity. While the large majority of BCCs are very manageable clinically, a small number of such tumors are aggressive. In this review of documented and proposed effects of T4 on BCC cells, we raise the possibility that BCC aggressiveness reflects T4 actions on its thyrointegrin target. The functions affected by T4 at the integrin in other human cancers include enhanced cell proliferation, anti-apoptosis, immune checkpoint regulation and metastasis, as well as state of radiosensitivity. The importance of investigating this possible pathophysiology is that euthyroid hypothyroxinemia may be tested as a treatment option.
Keywords:
integrin, thyrointegrin, radioresistance, apoptosis, metastasis, L-thyroxine (T4), 3,5,3’-triiodo-L-thyronine (T3)
Article Details
How to Cite
DAVIS, Paul J. et al.
Documented and projected actions in vitro of thyroid hormone as L -thyroxine (T4) on basal cell carcinoma of the skin.
Medical Research Archives, [S.l.], v. 11, n. 12, jan. 2024.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/4370>. Date accessed: 16 may 2024.
doi: https://doi.org/10.18103/mra.v11i12.4370.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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2. Cheng SY, Leonard JL, Davis PJ. Molecular aspects of thyroid hormone actions. Endocr Rev. 2010 (Apr); 31(2):139-170.
3. Davis PJ, Davis FB, Mousa SA, Luidens MK, Lin H-Y. Membrane receptor for thyroid hormone: physiologic and pharmacologic implications. Annu Rev Pharmacol Toxicol. 2011; 51:99-115.
4. Desgrosellier JS, Cheresh DA. Integrins in cancer: biological implications and therapeutic opportunities. Nat Rev Cancer. 2010 (Jan); 10(1):9-22.
5. Lin H-Y, Glinsky GV, Mousa SA, Davis PJ. Thyroid hormone and anti-apoptosis in tumor cells. Oncotarget. 2014 Jun 20; 6(17):14735-14743.
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7. Luidens MK, Mousa SA, Davis FB, Lin H-Y, Davis PJ. Thyroid hormone and angiogenesis. Vascul Pharmacol. 2010 Mar-Apr; 52(3-4):142-145.
8. Rajabi M, Mousa SA. The roles of angiogenesis in cancer treatment. Biomedicines. 2017 Jun; 5(2):34.
9. Davis PJ, Lin H-Y, Hercbergs A, Mousa SA. Actions of L-thyroxine (T4) and tetraiodothyroacetic acid (tetrac) on gene expression in thyroid cancer cells. Genes (Basel). 2020 Jul 7; 11(7):755.
10. Davis PJ, Glinsky GV, Lin HY, Leith JT, Hercbergts A, Tang HY, Ashur-Fabian O, Incerpi S, Mousa SA. Cancer cell gene expression modulated from plasma membrane integrin v by thyroid hormone and nanoparticulate tetrac. Front Endocrinol (Lausanne). 2015 Jan 12; 5:240
11. Shinderman-Maman E, Cohen K, Weingarten C, Nabriski D, Twito O, Baraf L, Hercbergs A, Davis PJ, Werner H, Ellis M, Ashur-Fabian O. The thyroid hormone-v integrin axis in ovarian cancer: regulation of gene transcription and MAPK-dependent proliferation. Oncogene. 2016 Apr 14; 35 (15):1977.
12. Cohen K, Flint N, Shalev S, Erez D, Baharal T, Davis PJ, Hercbergs A, Ellis M, Ashur-Fabioan O. Thyroid hormone regulates adhesion, migration, and matrix metalloproteinase 9 activity via v integrin in myeloma cells. Oncotarget. 2014 Aug15;5 (15):6312-6322.
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16. Mathew A, Fuhrer D, Lahner H. Sunitinib-induced hypothyroidism and survival in pancreatic neuroendocrine tumors. Horm Metab Res. 2021(Dec); 53(12):794-800.
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18. Bilen MA, Patel A, Hess KR, Munoz J, Busidy NL, Whelan JJ, Janku F, Falchook GS, Hong DS, Meric-Bernstam FM, Habar MA, Naing A. Association between new-onset hypothyroidism and clinical response in patients treated with tyrosine kinase inhibitor therapy in phase I clinical trials. Cancer Chemother Pharmacol. 2016 Jul; 78(1):167-171.
19. Atkins MB, Mier JW, Parkinson DR, Gould JA, Berkman EM, Kaplan MM. Hypothyroidism after treatment with interleukin-2 and lymphokine-activatd killer cells. N Engl J Med. 1988 Jun 16; 318(24):1557-1563.
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23. Lupulesco A. Hormonal regulation of epidermal tumor development. J Invest Dermatol. 1981 Aug; 77(2):186-195.
24. 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 Feb 16; 16(4):367-373.
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28. Koyun E, Karadag R, Ozkanli S, Oguztuzun S, Kocdogan AK. Caspase-3, p53 and Bcl-2 expression in basal cell carcinoma of the eyelid. Postepy Dermatol Alergol. 2020 Aug; 37(4):535-539.
29. Mendez-Flores RG, Martinez-Fernandez DE, Vega-De La Torre DE, Zambrano-Roman M, Munoz-Valle JF, Toledo-Lelewer MG, Guevara-Gutierrez E, Ramirsez-Padilla M, Vales-Alvarado E. Role of Bcl-2, p53, and Ki-67 expression in basal cell carcinoma and their association with aggressive and non-aggressive histological phenotypes. Postepy Dermatol Allergol. 2022 Jun; 39(3):517-523.
30. Laga AC, Schaefer IM, Sholl LM, Fremnch CA, Hanna J. Metastatic basal cell carcinoma. Am J Clin Pathol. 2019(Nov 4); 152(6):706-717.
31. Lovett RD, Perez CA, Shapiro ST, Garcia DM. External irradiation of epithelial skin cancer. Int J Radiol Oncol Biol Phys. 1990 (Aug); 19(2):235-242.
32. Leith JT, Hercbergs A, Kenney S, Mousa SA, Davis PJ. Activation of tumor cell integrin v by radiation and reversal of activation by chemically modified tetraiodothyroacetic acid (tetrac). Endocr Res. 2018 Nov; 43(4):215-219.
33. Malinga NZ, Siwele SC, Steel HC, Kwofie LLI, Meyer PWA, Smit T, Anderson R, Rapoport BL, Kgokolo MCM. Systemic levels of the soluble co-inhibitory immune checkpoints, CTLA-4, LAG-3, POD-1/PD-L1 and TIM-3, are markedly increased in basal cell carcinoma. Translat Oncol. 2022; 19:101384.
34. Lin HY, Chin YT, Shin YG, Chen YR, Leinung M, Keating KA, Mousa SA, Davis PJ. In tumor cells, thyroid hormone analogues non-immunologically regulate PD-L1 and PD-1 accumulation that is anti-apoptotic. Oncotarget. 2018 Sept 24; 9(75):34033-34037.
35. Lin HY, Chin YT, Nana AW, Shih YJ, Lai HY, Tang HY, Leinung M, Mousa SA, Davis PJ. Actions of L-thyroxine and nano-diamino-tetrac (Nanotetrac) on PD-L1 in cancer cells. Steroids. 2016 Oct; 114:59-67.
36. Lin H-Y, Glinsky GV, Mousa SA, Davis PJ. Thyroid hormone and anti-apoptosis in tumor cells. Oncotarget. 2015 Jun 20; 6(17):14735-14743.
37. Erb P, Ji J, Wernli M, Kump E, Glaser A, Buchner SA. Role of apoptosis in basal cell and squamous cell carcinoma formation. Immunol Lett. 2005 Aug 15; 100(1):68-72.
38. Jee SH, Shen SC, Chiu HC, Tsai WL, Kuo ML. Overexpression of interleukin-6 in human basal carcinoma cell lines increases anti-apoptotic activity and tumorigenic potency. Oncogene. 2001 Jan 11; 20(2):198-208.
39. Hercbergs A, Mousa SA, Davis PJ. Nonthyroidal illness syndrome and thyroid hormone actions at integrin v. J Clin Endocrinol Metab. 2018 Aptr; 103(4):1291-1295.
40. McCuskey M, Basset-Seguin N, Dummer R, Lewis K, Schadendorf D, Sekulic A, Hou J, Wang L, Yue H, Hauschid A. Metastatic basal cell carcinoma: prognosis dependent on anatomic site and spread of disease. Eur J Cancer. 2014 Mar; 50(4):774-783.
41. Laga AC, Schaefer IM, Sholl LM, French CA, Hanna J. Metastatic basal cell carcinoma. Am J Clin Pathol. 2019 Nov 4; 152(6):707-717.
42. Mochel MC, Liaquat S, Moore JB, Hoang MP. Metastatic basal cell carcinoma: a clinicopathologic and immunohistochemical study of 22 cases. J Cutan Pathol. 2021 Mar; 48(3):374-383.
43. Mousa SA, Glinsky GV, Lin H-Y, Ashur-Fabian O, Hercbergs A, Keating KA, Davis PJ. Contributions of thyroid hormone to cancer metastasis. Biomedicines. 2018 Aug 22; 6(3):89.
44. Davis PJ, Mousa SA, Schechter GP, Lin H-Y. Platelet ATP, thyroid hormone receptor on integrin v and cancer metastasis. Horm Cancer. 2020 Feb; 11(1):13-16.
45. Schlesinger M. Role of platelets and platelet receptors in cancer metastasis. J Hematol Oncol. 2018; 11:125.
46. Krilaviciute A, Vincerzevskiene I, Smailyte G. Basal cell skin cancer and the risk of second primary cancers: a cancer registry-based study in Lithuania. Ann Epidemiol. 2016 Jul; 26(7):511-514.
47. Friedman GD, Tekawa IS. Association of basal cell skin cancers with other cancers (United States). Cancer Causes Control. 2000 Dec; 11(10)891-897.
48. Davis PJ, Tang HY, Hercbergs A, Lin HY, Keating KA, Mousa SA. Bioactivity of thyroid hormone analogs at cancer cells. Front Endocrinol (Lausanne). 2018 Dec 4; 9:739.
49. Davis PJ, Glinsky GV, Lin HY, Leith JT, Hercbergs A, Tang HY, Ashur-Fabian O, Incerpi S, Mousa SA. Cancer cell gene expression modulated from plasma membrane integrin v by thyroid hormone and nanoparticulate tetrac. Front Endocrinol (Lausanne). 2015 Jan 12; 5:240.
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51. Gionfra F, De Vito P, Pallottini V, Lin H-Y, Davis PJ, Pederson JZ, Incerpi S. The roles of thyroid hormones in hepatocyte proliferation and liver cancer. Front Endocrinol (Lausanne). 2019 Aug 30; 10:532.
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2. Cheng SY, Leonard JL, Davis PJ. Molecular aspects of thyroid hormone actions. Endocr Rev. 2010 (Apr); 31(2):139-170.
3. Davis PJ, Davis FB, Mousa SA, Luidens MK, Lin H-Y. Membrane receptor for thyroid hormone: physiologic and pharmacologic implications. Annu Rev Pharmacol Toxicol. 2011; 51:99-115.
4. Desgrosellier JS, Cheresh DA. Integrins in cancer: biological implications and therapeutic opportunities. Nat Rev Cancer. 2010 (Jan); 10(1):9-22.
5. Lin H-Y, Glinsky GV, Mousa SA, Davis PJ. Thyroid hormone and anti-apoptosis in tumor cells. Oncotarget. 2014 Jun 20; 6(17):14735-14743.
6. Leith JT, Mousa SA, Hercbergs A, Lin H-Y, Davis P. Radioresistance of cancer cells, integrin v and thyroid hormone. Oncotarget. 2018 Dec11; 9(97):37069-37075.
7. Luidens MK, Mousa SA, Davis FB, Lin H-Y, Davis PJ. Thyroid hormone and angiogenesis. Vascul Pharmacol. 2010 Mar-Apr; 52(3-4):142-145.
8. Rajabi M, Mousa SA. The roles of angiogenesis in cancer treatment. Biomedicines. 2017 Jun; 5(2):34.
9. Davis PJ, Lin H-Y, Hercbergs A, Mousa SA. Actions of L-thyroxine (T4) and tetraiodothyroacetic acid (tetrac) on gene expression in thyroid cancer cells. Genes (Basel). 2020 Jul 7; 11(7):755.
10. Davis PJ, Glinsky GV, Lin HY, Leith JT, Hercbergts A, Tang HY, Ashur-Fabian O, Incerpi S, Mousa SA. Cancer cell gene expression modulated from plasma membrane integrin v by thyroid hormone and nanoparticulate tetrac. Front Endocrinol (Lausanne). 2015 Jan 12; 5:240
11. Shinderman-Maman E, Cohen K, Weingarten C, Nabriski D, Twito O, Baraf L, Hercbergs A, Davis PJ, Werner H, Ellis M, Ashur-Fabian O. The thyroid hormone-v integrin axis in ovarian cancer: regulation of gene transcription and MAPK-dependent proliferation. Oncogene. 2016 Apr 14; 35 (15):1977.
12. Cohen K, Flint N, Shalev S, Erez D, Baharal T, Davis PJ, Hercbergs A, Ellis M, Ashur-Fabioan O. Thyroid hormone regulates adhesion, migration, and matrix metalloproteinase 9 activity via v integrin in myeloma cells. Oncotarget. 2014 Aug15;5 (15):6312-6322.
13. Hercbergs A, Lin H-Y, Mousa SA, Davis PJ. (Thyroid) Hormonal regulation of breast cancer cells. Front Endocrinol (Lausanne). 2023 Jan 11; 13:1109555.
14. Schmidinger M, Vogl UM, Bojic M, Lamm W, Heinzl H, Haitel A, Clodi M, Kramer G, Zielinski CC. Hypothyroidism in patients with renal cell carcinoma: blessing or curse? Cancer. 2011 Feb 1; 117(3):534-544.
15. Cristofanilli M, Yamamura Y, Kau S-W, Beveers T, Strom S, Patangan M Hsu L, Krishnamurthy S, Theriault RL, Horotbagyi GN. Thyroid hormone and breast cancer. Primary hypothyroidism is associatred with a reduced incidence of primary breast carcinoma. Cancer. 2005 Mar 15; 103(6):1122-1128
16. Mathew A, Fuhrer D, Lahner H. Sunitinib-induced hypothyroidism and survival in pancreatic neuroendocrine tumors. Horm Metab Res. 2021(Dec); 53(12):794-800.
17. 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 Jan; 20(1):72-76.
18. Bilen MA, Patel A, Hess KR, Munoz J, Busidy NL, Whelan JJ, Janku F, Falchook GS, Hong DS, Meric-Bernstam FM, Habar MA, Naing A. Association between new-onset hypothyroidism and clinical response in patients treated with tyrosine kinase inhibitor therapy in phase I clinical trials. Cancer Chemother Pharmacol. 2016 Jul; 78(1):167-171.
19. Atkins MB, Mier JW, Parkinson DR, Gould JA, Berkman EM, Kaplan MM. Hypothyroidism after treatment with interleukin-2 and lymphokine-activatd killer cells. N Engl J Med. 1988 Jun 16; 318(24):1557-1563.
20. Fabian ID, Rosner M, Fabian I, Vishnevskia-Dan V, Zioto O, Shinderman Maman E, Cohen K, Ellis M, Lin H-Y, Hercbergs A, Davis PJ, Ashur-Fabian O. Low thyroid hormone levels improve survival in murine model for ocular melanoma. Oncotarget. 2015 May 10; 6(13): 11038-11046.
21. Wu Y, Wang Z, Bai H, Gao Y. Thyroid dysfunction during PD-1 inhibitor treatment in patients with cancer: incidence and association with progression-free survival. Oncol Lett. 2022 Jul 13; 24(3):309.
22. Miro C, Di Cicco E, Ambrosio R, Mancir G, Di Girolamo D, Cicatiello AG, Sagliocchi S, Nappi A, De Stefano MA, Luongo C, Antonini D, Visconte F, Varricchio S, Ilardi G, Del Vecchio L, Staibano S, Boelen A, Bianpain C, Missero C, Salvatore D, Dentice M. Thyroid hormone induces progression and invasiveness of squamous cell carcinomas by promoting a ZEB-1/E-cadherin switch. Nat Commun. 2019 Nov 27; 10 (1):5410.
23. Lupulesco A. Hormonal regulation of epidermal tumor development. J Invest Dermatol. 1981 Aug; 77(2):186-195.
24. 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 Feb 16; 16(4):367-373.
25. Leith JT, Mousa SA, Hercbergs A, Lin H-Y, Davis PJ. Radioresistance of cancer cells, integrin vand thyroid hormone. Oncotarget. 2018 Dec; 9(97):37069-37075.
26. Lupu M, Caruntu C, Popa MI, Voiculescu VM, Zurac S, Boda D. Vascular patterns in basal cell carcinoma: dermoscopic, confocal and histopathological perspectives. Oncol Lett. 2019 May; 17(5):4112-4125.
27. Moujaess E, Merhy R, Kattan J, Sarkis A-S, Tomb R. Immune checkpoint inhibition for advanced or metastatic basal cell carcinoma: how much evidence do we need? Immunotherapy. 2021 Oct; 13(15):1293-1304.
28. Koyun E, Karadag R, Ozkanli S, Oguztuzun S, Kocdogan AK. Caspase-3, p53 and Bcl-2 expression in basal cell carcinoma of the eyelid. Postepy Dermatol Alergol. 2020 Aug; 37(4):535-539.
29. Mendez-Flores RG, Martinez-Fernandez DE, Vega-De La Torre DE, Zambrano-Roman M, Munoz-Valle JF, Toledo-Lelewer MG, Guevara-Gutierrez E, Ramirsez-Padilla M, Vales-Alvarado E. Role of Bcl-2, p53, and Ki-67 expression in basal cell carcinoma and their association with aggressive and non-aggressive histological phenotypes. Postepy Dermatol Allergol. 2022 Jun; 39(3):517-523.
30. Laga AC, Schaefer IM, Sholl LM, Fremnch CA, Hanna J. Metastatic basal cell carcinoma. Am J Clin Pathol. 2019(Nov 4); 152(6):706-717.
31. Lovett RD, Perez CA, Shapiro ST, Garcia DM. External irradiation of epithelial skin cancer. Int J Radiol Oncol Biol Phys. 1990 (Aug); 19(2):235-242.
32. Leith JT, Hercbergs A, Kenney S, Mousa SA, Davis PJ. Activation of tumor cell integrin v by radiation and reversal of activation by chemically modified tetraiodothyroacetic acid (tetrac). Endocr Res. 2018 Nov; 43(4):215-219.
33. Malinga NZ, Siwele SC, Steel HC, Kwofie LLI, Meyer PWA, Smit T, Anderson R, Rapoport BL, Kgokolo MCM. Systemic levels of the soluble co-inhibitory immune checkpoints, CTLA-4, LAG-3, POD-1/PD-L1 and TIM-3, are markedly increased in basal cell carcinoma. Translat Oncol. 2022; 19:101384.
34. Lin HY, Chin YT, Shin YG, Chen YR, Leinung M, Keating KA, Mousa SA, Davis PJ. In tumor cells, thyroid hormone analogues non-immunologically regulate PD-L1 and PD-1 accumulation that is anti-apoptotic. Oncotarget. 2018 Sept 24; 9(75):34033-34037.
35. Lin HY, Chin YT, Nana AW, Shih YJ, Lai HY, Tang HY, Leinung M, Mousa SA, Davis PJ. Actions of L-thyroxine and nano-diamino-tetrac (Nanotetrac) on PD-L1 in cancer cells. Steroids. 2016 Oct; 114:59-67.
36. Lin H-Y, Glinsky GV, Mousa SA, Davis PJ. Thyroid hormone and anti-apoptosis in tumor cells. Oncotarget. 2015 Jun 20; 6(17):14735-14743.
37. Erb P, Ji J, Wernli M, Kump E, Glaser A, Buchner SA. Role of apoptosis in basal cell and squamous cell carcinoma formation. Immunol Lett. 2005 Aug 15; 100(1):68-72.
38. Jee SH, Shen SC, Chiu HC, Tsai WL, Kuo ML. Overexpression of interleukin-6 in human basal carcinoma cell lines increases anti-apoptotic activity and tumorigenic potency. Oncogene. 2001 Jan 11; 20(2):198-208.
39. Hercbergs A, Mousa SA, Davis PJ. Nonthyroidal illness syndrome and thyroid hormone actions at integrin v. J Clin Endocrinol Metab. 2018 Aptr; 103(4):1291-1295.
40. McCuskey M, Basset-Seguin N, Dummer R, Lewis K, Schadendorf D, Sekulic A, Hou J, Wang L, Yue H, Hauschid A. Metastatic basal cell carcinoma: prognosis dependent on anatomic site and spread of disease. Eur J Cancer. 2014 Mar; 50(4):774-783.
41. Laga AC, Schaefer IM, Sholl LM, French CA, Hanna J. Metastatic basal cell carcinoma. Am J Clin Pathol. 2019 Nov 4; 152(6):707-717.
42. Mochel MC, Liaquat S, Moore JB, Hoang MP. Metastatic basal cell carcinoma: a clinicopathologic and immunohistochemical study of 22 cases. J Cutan Pathol. 2021 Mar; 48(3):374-383.
43. Mousa SA, Glinsky GV, Lin H-Y, Ashur-Fabian O, Hercbergs A, Keating KA, Davis PJ. Contributions of thyroid hormone to cancer metastasis. Biomedicines. 2018 Aug 22; 6(3):89.
44. Davis PJ, Mousa SA, Schechter GP, Lin H-Y. Platelet ATP, thyroid hormone receptor on integrin v and cancer metastasis. Horm Cancer. 2020 Feb; 11(1):13-16.
45. Schlesinger M. Role of platelets and platelet receptors in cancer metastasis. J Hematol Oncol. 2018; 11:125.
46. Krilaviciute A, Vincerzevskiene I, Smailyte G. Basal cell skin cancer and the risk of second primary cancers: a cancer registry-based study in Lithuania. Ann Epidemiol. 2016 Jul; 26(7):511-514.
47. Friedman GD, Tekawa IS. Association of basal cell skin cancers with other cancers (United States). Cancer Causes Control. 2000 Dec; 11(10)891-897.
48. Davis PJ, Tang HY, Hercbergs A, Lin HY, Keating KA, Mousa SA. Bioactivity of thyroid hormone analogs at cancer cells. Front Endocrinol (Lausanne). 2018 Dec 4; 9:739.
49. Davis PJ, Glinsky GV, Lin HY, Leith JT, Hercbergs A, Tang HY, Ashur-Fabian O, Incerpi S, Mousa SA. Cancer cell gene expression modulated from plasma membrane integrin v by thyroid hormone and nanoparticulate tetrac. Front Endocrinol (Lausanne). 2015 Jan 12; 5:240.
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