Department of Internal Medicine IV, University Hospital of Munich, LMU Munich, Munich, Germany.
Institute of Pathology, School of Medicine, Technical University of Munich, Munich, Germany.
Endocr Relat Cancer. 2020 Dec;27(12):685-697. doi: 10.1530/ERC-20-0353.
Thyroid hormones are emerging as critical regulators of tumour growth and progression. To assess the contribution of thyroid hormone signalling via integrin αvβ3, expressed on many tumour cells, endothelial cells, and stromal cells, to tumour growth, we compared the effects of thyroid hormones vs tetrac, a specific inhibitor of thyroid hormone action at integrin αvβ3, in two murine xenograft tumour models with and without integrin αvβ3 expression. Integrin αvβ3-positive human anaplastic thyroid cancer cells SW1736 and integrin αvβ3-negative human hepatocellular carcinoma cells HuH7 were injected into the flanks of nude mice. Tumour growth was monitored in euthyroid, hyperthyroid, hypothyroid, and euthyroid tetrac-treated mice. In SW1736 xenografts, hyperthyroidism led to a significantly increased tumour growth resulting in a decreased survival compared to euthyroid mice, while tumour growth was significantly reduced and, hence, survival prolonged in hypothyroid and tetrac-treated mice. Both proliferation and vascularisation, as determined by Ki67 and CD31 immunofluorescence staining, respectively, were significantly increased in tumours from hyperthyroid mice as compared to hypothyroid and tetrac-treated mice. No differences in tumour growth, survival, or Ki67 staining were observed between the different groups in integrin αvβ3-negative HuH7 xenografts. Vascularisation, however, was significantly decreased in hypothyroid and tetrac-treated mice compared to euthyroid and hyperthyroid mice. Apoptosis was not affected in either tumour model, nor were cell proliferation or apoptosis in vitro. Tumour growth regulation by thyroid hormones in αvβ3-positive tumours has important implications for cancer patients, especially those with thyroid dysfunctions and thyroid cancer patients treated with thyrotropin-suppressive L-thyroxine doses.
甲状腺激素正成为肿瘤生长和进展的关键调节因子。为了评估整合素αvβ3 信号通路在肿瘤生长中的作用，我们比较了甲状腺激素与 tetrac（整合素αvβ3 的甲状腺激素作用特异性抑制剂）在两种表达整合素αvβ3 的和不表达整合素αvβ3 的小鼠异种移植肿瘤模型中的作用。将整合素αvβ3 阳性的人甲状腺未分化癌细胞 SW1736 和整合素αvβ3 阴性的人肝癌细胞 HuH7 注射到裸鼠的侧腹。在甲状腺功能正常、甲状腺功能亢进、甲状腺功能减退和甲状腺功能正常 tetrac 治疗的小鼠中监测肿瘤生长。在 SW1736 异种移植瘤中，甲状腺功能亢进导致肿瘤生长明显增加，与甲状腺功能正常的小鼠相比，生存时间缩短，而甲状腺功能减退和 tetrac 治疗的小鼠肿瘤生长明显减少，因此生存时间延长。Ki67 和 CD31 免疫荧光染色分别确定的增殖和血管生成在甲状腺功能亢进小鼠的肿瘤中均显著增加，与甲状腺功能减退和 tetrac 治疗的小鼠相比。在整合素αvβ3 阴性 HuH7 异种移植瘤中，不同组之间的肿瘤生长、生存或 Ki67 染色无差异。然而，与甲状腺功能正常和甲状腺功能亢进的小鼠相比，甲状腺功能减退和 tetrac 治疗的小鼠的血管生成明显减少。在两种肿瘤模型中，凋亡均不受影响，体外细胞增殖和凋亡也不受影响。在αvβ3 阳性肿瘤中，甲状腺激素对肿瘤生长的调节对癌症患者，尤其是甲状腺功能异常和接受促甲状腺素抑制 L-甲状腺素剂量治疗的甲状腺癌患者具有重要意义。
