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

Abstract

Background Tumor-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. Methods Conditioned 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. Results M1-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. Conclusions We 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.

Lymph Node Metastasis-Related Gene ITGA4 Promotes the Proliferation, Migration, and Invasion of Gastric Cancer Cells by Regulating Tumor Immune Microenvironment

“…Previous studies have shown that TAMs can be polarized into tumor supporting M2 like macrophages and tumor inhibiting M1 like macrophages [24][25][26]. You et al [27] found that M1 like TAMs significantly promoted the epithelial mesenchymal transformation (EMT) process and induced the formation of cancer stem cells by upregulating the expression of MME and MMP14 in oral squamous cell carcinoma. M1 like TAMs promote the invasion and migration of cell colonies by activating the JAK/STAT3 pathway.…”

Identification of Immune and Hypoxia Risk Classifier to Estimate Immune Microenvironment and Prognosis in Cervical Cancer

“…The IL-6/STAT3 pathway is a classic signaling that can induce enhanced EMT process in cancers [ 64 ]. You et al revealed the function role of IL-6/STAT3 pathway in promoting the malignant progression in oral squamous cell carcinoma patients, and further research is urgently needed to establish a more applicable therapeutic strategy targeting STAT3 pathway [ 65 ].…”

Macrophages Are a Double-Edged Sword: Molecular Crosstalk between Tumor-Associated Macrophages and Cancer Stem Cells

“…In oral squamous cell carcinoma cells, M1 TAMs can promote EMT and induce the CSC phenotype by upregulating the expression of MME and MMP14. However, M1 TAMs secrete IL-6, increasing CSC stemness by activating the JAK/STAT3 pathway [ 141 ]. These findings indicate that TAMs secrete IL-6 through the TLR4 signaling pathway and STAT3 pathway and that IL-6 promotes the chemoresistance and invasiveness of CSCs by activating the JAK/STAT3 pathway and WNT pathway in CSCs, forming a CSC–TAM–CSC positive feedback loop.…”