Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
Clin Cancer Res. 2019 Jan 1;25(1):414-425. doi: 10.1158/1078-0432.CCR-18-0663. Epub 2018 Oct 12.
Thyroid-stimulating hormone (TSH) suppression is widely used to treat well-differentiated thyroid cancer, whereas its role in poorly differentiated thyroid cancer (PDTC) is undetermined. Besides thyrocytes, TSH also binds to stromal cells, comprising tumor microenvironments. This study aimed to investigate the effects of TSH on tumor microenvironments in PDTC.
An ectopic tumor model using PDTC cells (BHP10-3SCp and FRO), which exhibit TSH/cAMP-independent cell growth, was treated with TSH. IHC was performed using tissue microarrays from 13 PDTCs.
TSH treatment significantly enhanced tumor growth of PDTCs with increased vascularity but not that of breast cancer cells, suggesting this effect is unique to thyroid cancer cells, not stromal cells. TSH significantly upregulated and expressions in BHP10-3SCp cells via AKT and ERK signaling, resulting in higher concentrations of VEGF-A and CXCL8 in conditioned medium of TSH-treated BHP10-3SCp cells (TSH-CM) compared with controls. TSH-CM treatment enhanced tube formation potentials of endothelial cells, and blocking VEGF and/or CXCL8 reduced them. Blocking VEGF and/or CXCL8 also reduced TSH-dependent tumor growth with reduced tumor vasculature . TSH-treated tumors showed increased macrophage densities, and macrophage inhibition reduced TSH-dependent tumor growth . In human PDTCs, preoperative TSH levels were positively associated with VEGF-A and tumor size, and the expression of VEGF-A was positively correlated with CD31, CD163, and CXCL8, and their clinical poor prognosis.
Aberrant TSH receptor signaling modulates tumor angiogenesis by stimulating VEGF-A and CXCL8 secretion from PDTC cells and enhances tumor growth; thus, TSH suppression is beneficial for treating PDTCs.
促甲状腺激素（TSH）抑制被广泛用于治疗分化良好的甲状腺癌，但其在分化差的甲状腺癌（PDTC）中的作用尚不确定。除了甲状腺细胞外，TSH 还与构成肿瘤微环境的基质细胞结合。本研究旨在探讨 TSH 对 PDTC 肿瘤微环境的影响。
使用表现出 TSH/cAMP 非依赖性细胞生长的 PDTC 细胞（BHP10-3SCp 和 FRO）建立异位肿瘤模型，并对其进行 TSH 处理。使用来自 13 例 PDTC 患者的组织微阵列进行免疫组织化学分析。
TSH 处理显著增强了 PDTC 肿瘤的生长，增加了血管生成，但对乳腺癌细胞没有这种作用，这表明这种作用是甲状腺癌细胞特有的，而不是基质细胞。TSH 通过 AKT 和 ERK 信号显著上调了 BHP10-3SCp 细胞中的 和 表达，导致 TSH 处理的 BHP10-3SCp 细胞条件培养基（TSH-CM）中 VEGF-A 和 CXCL8 的浓度高于对照组。TSH-CM 处理增强了内皮细胞的管形成潜力，而阻断 VEGF 和/或 CXCL8 则降低了它们的管形成潜力。阻断 VEGF 和/或 CXCL8 也降低了 TSH 依赖性肿瘤生长，减少了肿瘤血管生成。TSH 处理的肿瘤显示巨噬细胞密度增加，巨噬细胞抑制减少了 TSH 依赖性肿瘤生长。在人类 PDTC 中，术前 TSH 水平与 VEGF-A 和肿瘤大小呈正相关，VEGF-A 的表达与 CD31、CD163 和 CXCL8 呈正相关，并且与临床预后不良相关。
异常的 TSH 受体信号通过刺激 PDTC 细胞中 VEGF-A 和 CXCL8 的分泌来调节肿瘤血管生成，并增强肿瘤生长；因此，TSH 抑制对治疗 PDTC 有益。
