Aberrant Thyroid-Stimulating Hormone Receptor Signaling Increases VEGF-A and CXCL8 Secretion of Thyroid Cancer Cells, Contributing to Angiogenesis and Tumor Growth

Abstract

Purpose: 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. Experimental Design: 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. Results: 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 TSHdependent 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. Conclusions: 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.

H. pylori infection induces CXCL8 expression and promotes gastric cancer progress through downregulating KLF4

“…23,24 CXCL8 is highly expressed in various carcinomas and is associated with a poor prognosis. [25][26][27][28] In vitro, H. pylori infection or CagA transduction significantly upregulated CXCL8 expression at the RNA and protein levels. These data show that CXCL8 is positively related to H. pylori infection in GC cells.…”

Integrative analysis of genomic and transcriptomic characteristics associated with progression of aggressive thyroid cancer

“…Although we demonstrated that the cell viability was regulated by inhibition of the activated JAK-STAT signaling in RAS -positive ATC cell line in vitro, inhibition of Notch signaling did not affect BRAF V600E -positive ATC cell lines. It is possible that the effect might not have been shown, since there would be other pathways that regulate VEGF-Notch signaling 32 . In addition to the aforementioned pathways, previous reports showed that cell lines with CDKN2A /p16 loss is linked to response to CDK4/6 inhibitors, such as palbociclib 33–35 and to resistance to BRAF V600E -selective inhibitor, vemurafenib, in metastatic BRAF V600E PTC cells 36 .…”

Amarogentin Inhibits Liver Cancer Cell Angiogenesis after Insufficient Radiofrequency Ablation via Affecting Stemness and the p53-Dependent VEGFA/Dll4/Notch1 Pathway

“…Sublethal heat treatment was used to mimic iRFA cells. That is, the iRFA cell model was generated as previously reported [ 8 ]. Briefly, HepG2 and Huh7 cells (5 × 10 4 ) were plated in a 6-well plate and cultured for 12 h before incubation in a 50°C water bath for 10 min.…”

“…VEGFA, as one of the most recognized and effective endothelial growth factors, mobilizes the endothelial progenitor cells to participate in tumor angiogenesis [ 7 ]. Uncontrollably, VEGFA secretion accelerates the malignant changes of cancer under hypoxia or heat stimulation [ 8 ]. Thus, VEGFA secretion is always through a complicated network involving in hypoxia-inducible factor 1, cytokines, hormones, etc.…”