Abstract
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 VEGF-A and CXCL8 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 in vivo. TSH-treated tumors showed increased macrophage densities, and macrophage inhibition reduced TSH-dependent tumor growth in vivo. 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.
Highlights
Thyroid cancer is the most common endocrine malignancy, and its incidence has robustly increased over the past 4 decades [1]
In human poorly differentiated thyroid cancer (PDTC), preoperative thyroid-stimulating hormone (TSH) levels were positively associated with vascular endothelial growth factor-A (VEGF-A) and tumor size, and the expression of VEGF-A was positively correlated with CD31, CD163, and CXCL8, and their clinical poor prognosis
The present study demonstrated that TSH stimulated secretion of angiogenic factors such as VEGF-A and CXCL8 in PDTC cells, which showed TSH/cAMP-independent cell growth, through TSH/AKT and ERK pathways
Summary
Thyroid cancer is the most common endocrine malignancy, and its incidence has robustly increased over the past 4 decades [1]. The long-term use of levothyroxine (T4) to suppress the endogenous pituitary excretion of thyroid-stimulating hormone (TSH), so-called T4 suppression therapy, has been generally considered for thyroid cancer patients at intermediate or high risk for recurrence [4,5,6,7]. TSH is a well-known growth factor for thyrocytes that leads to TSH-dependent growth of the thyroid gland, and higher serum TSH concentrations have been found to increase the oncogenic risk or tumor aggressiveness in well-differentiated thyroid cancer (WDTC) [8,9,10]. The suppression of serum TSH concentration by administering levothyroxine was found to improve relapse-free and overall survival in high-risk patients with WDTC [11,12], which supports the proposal that TSH suppression exerts inhibitory effects on the progression of WDTC. T4 suppression therapy has long been used as an essential therapeutic strategy for the treatment of WDTC, especially in high-risk cases [4,5,6,7]
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