M1-like tumor-associated macrophages cascade a mesenchymal/stem-like phenotype of oral squamous cell carcinoma via the IL6/Stat3/THBS1 feedback loop

Journal of Experimental & Clinical Cancer Research

Yan’an Wang¹  Meng Xiao¹  Zhuowei Tian¹  Guisong Xu¹  Yuanhe You¹  Zhong Du¹  Kailiu Wu¹  Meilu Dai² 

[1] Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China;College of Stomatology, Shanghai Jiao Tong University, Shanghai, China;National Center for Stomatology; National Clinical Research Center for Oral Disease, Shanghai, China;Shanghai Key Laboratory of Stomatology and Shanghai Research Institute of Stomatology, Shanghai, China;Department of Orthodontics, Shanghai Stomatological Hospital & School of Stomatology, and Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases, Fudan University, Shanghai, China;

关键词: Macrophage;    Oral squamous cell carcinoma;    Epithelial-mesenchymal transfer;    Cancer-stem like cells;    Interleukin 6;   

DOI  :  10.1186/s13046-021-02222-z

来源: Springer

【 摘 要 】

BackgroundTumor-associated macrophages (TAMs) have a leading position in the tumor microenvironment. Previously, we have demonstrated that M1-like TAMs activated by exosome-transferred THBS1 promote malignant migration in oral squamous cell carcinoma (OSCC). However, the functional roles and associated molecular mechanisms of the activated M1-like TAMs need to be further clarified in OSCC.MethodsConditioned Media (CM) were harvested from the exosome activated M1-like TAMs. We measured the malignant behaviors of OSCC under the treatment of CM from M1-like TAMs by performing colony forming assays, invasion assays, wound-healing assays, spheroid forming assays and in vivo xenograft experiments. The underlying mechanisms were investigated by RNA-seq, cytokines analysis, intracellular signaling pathway analysis, ChIP assays, bioinformatics analysis and validation.ResultsM1-like TAMs significantly promoted the epithelial-mesenchymal transition (EMT) process, and induced the cancer-stem like cells (CSCs) by upregulating the expression of MME and MMP14 in OSCC cells. Cytokine analysis revealed a shark increase of IL6 secretion from M1-like TAMs. Blocking IL6 in the CM from M1-like TAMs could significantly weaken its effects on the colony forming, invasion, migration, microsphere forming and xenograft forming abilities of OSCC cells. Cellular signaling assays indicated the activation of Jak/Stat3 pathway in the OSCC cells treated by the CM from M1-like TAMs. Blocking the activation of the Jak/Stat3 pathway could significantly weaken the effects of M1-like TAMs on the colony forming, invasion, migration, microsphere forming and xenograft forming abilities of OSCC cells. Further RNA-seq analysis and bioinformatics analysis revealed an increased expression of THBS1 in the OSCC cells treated by M1-like TAMs. Bioinformatics prediction and ChIP assays revealed the activation of Stat3 by CM from M1-like TAMs could directly promote the transcription of THBS1 in OSCC cells.ConclusionsWe proposed that M1-like TAMs could cascade a mesenchymal/stem-like phenotype of OSCC via the IL6/Stat3/THBS1 feedback loop. A better understanding on the functional roles and associated molecular mechanisms of M1-like TAMs might facilitate the development of novel therapies for supplementing the current treatment strategies for OSCC patients.

【 授权许可】

CC BY