Inhibition of JAK2/STAT3 reduces tumor‐induced angiogenesis and myeloid‐derived suppressor cells in head and neck cancer

• Published in: Molecular carcinogenesis 2018-03, Vol.57 (3), p.429-439
• Main Authors: Liu, Jian‐Feng, Deng, Wei‐Wei, Chen, Lei, Li, Yi‐Cun, Wu, Lei, Ma, Si‐Rui, Zhang, Wen‐Feng, Bu, Lin‐Lin, Sun, Zhi‐Jun
• Format: Article
• Language: English
• Subjects: Angiogenesis; Angiogenesis Inhibitors - pharmacology; Angiogenesis Inhibitors - therapeutic use; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Carcinoma, Squamous Cell - blood supply; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; CD11b antigen; Cell Line, Tumor; Head & neck cancer; head and neck cancer; Head and Neck Neoplasms - blood supply; Head and Neck Neoplasms - drug therapy; Head and Neck Neoplasms - metabolism; Head and Neck Neoplasms - pathology; Human Umbilical Vein Endothelial Cells; Humans; Hypoxia-inducible factor 1; Immune system; Immunohistochemistry; Immunosuppression; Inhibition; Janus kinase 2; Janus Kinase 2 - antagonists & inhibitors; Janus Kinase 2 - metabolism; MDSC; Metastases; Mice, Transgenic; Microvasculature; Myeloid-Derived Suppressor Cells - drug effects; Myeloid-Derived Suppressor Cells - metabolism; Myeloid-Derived Suppressor Cells - pathology; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - metabolism; Neovascularization, Pathologic - pathology; Rodents; Signal Transduction - drug effects; Squamous cell carcinoma; STAT3; Stat3 protein; STAT3 Transcription Factor - antagonists & inhibitors; STAT3 Transcription Factor - metabolism; Suppressor cells; Transgenic mice; Tumor Microenvironment - drug effects; Tyrphostins - pharmacology; Tyrphostins - therapeutic use; VEGFA
• ISSN: 0899-1987; 1098-2744
• DOI: 10.1002/mc.22767

Angiogenesis is an essential event in tumor growth and metastasis, and immune system also contributes to the tumor evasion. Emerging evidences have suggested the bidirectional link between angiogenesis and immunosuppression. Myeloid‐derived suppressor cell (MDSC) is a kind of immunosuppressive cells and plays an important role in this process. However, the actual regulatory mechanisms of angiogenesis and MDSCs in head and neck squamous cell carcinoma (HNSCC) were unclear. In this study, through analyzing the immunohistochemistry staining of human HNSCC tissue microarray, we found that the microvascular density (MVD) was significantly increased in HNSCC patients. We also characterized angiogenic factors p‐STAT3, VEGFA, CK2, and MDSCs marker CD11b in HNSCC tissue array, and found the close expression correlation among these markers. To determine the role of JAK2/STAT3 pathway in tumor microenvironment of HNSCC, we utilized AG490 (an inhibitor of JAK2/STAT3) for further research. Results showed that inhibition of JAK2/STAT3 suppressed angiogenesis by decreasing VEGFA and HIF1‐α both in vitro and vivo. Moreover, in HNSCC transgenic mouse model, inhibiting JAK2/STAT3 not only suppressed angiogenesis but also reduced MDSCs in the tumor microenvironment through suppressing VEGFA and CK2. Our findings demonstrated the close relationship between angiogenesis and MDSCs in HNSCC, and inhibition of JAK2/STAT3 could reduce tumor‐induced angiogenesis and decrease MDSCs.