Abstract
BackgroundTreatment strategies targeting tumor-associated macrophages (TAMs) have been proposed in cancer areas. The functional alterations of macrophages in the microenvironment during the tumorigenesis of human epithelial cancer remain poorly understood. Here, we explored phenotypic alteration of macrophages during the development of oral squamous cell carcinoma (OSCC).MethodsConditioned media (CM) and exosome supernatants were harvested from normal oral epithelium, oral leukoplakia cells and OSCC cells. We measured phenotypic alteration of macrophages using flow cytometry, luminex assays, and quantitative real-time PCR assay. Intracellular signaling pathway analysis, mass spectrometry proteomics, western blotting, enzyme-linked immunosorbent assay, immunohistochemical staining, and bioinformatics analysis were performed to uncover the underlying mechanisms.ResultsTHP-1-derived and PBMCs derived macrophages exhibited an M1-like phenotype but not M2-like phenotype, when treated with CM from OSCC cells but not with the CM from normal epithelium or leukoplakia cells. Further investigations revealed that macrophages were activated by taking up exosomes released from OSCC cells through p38, Akt, and SAPK/JNK signaling at the early phase. We further provided evidences that THBS1 derived from OSCC exosomes participated in the polarization of macrophages to an M1-like phenotype. Reciprocally, CM from exosomes induced M1-like TAMs and significantly promoted migration of OSCC cells.ConclusionsWe proposed a novel paracrine loop between cancer cells and macrophages based on exosomes from OSCC. Therefore, target management of M1-like TAMs polarized by exosomes shows great potential as a therapeutic target for the control of cancerous migration in OSCC.
Highlights
Treatment strategies targeting tumor-associated macrophages (TAMs) have been proposed in cancer areas
Conditioned media from oral squamous cell carcinoma (OSCC) cells polarizes macrophages to the M1-like phenotype The development of OSCC from normal epithelium is characterized by a specific transformation process at the precancerous condition
To investigate functional and phenotypical plasticity of macrophages during the transformation of OSCC, we performed our studies by using Human immortal oral epithelial cell line cells (HIOEC), Oral leukoplakia cell line cells (Leuk1), SCC25 and Cal27
Summary
Treatment strategies targeting tumor-associated macrophages (TAMs) have been proposed in cancer areas. We explored phenotypic alteration of macrophages during the development of oral squamous cell carcinoma (OSCC). Among immunological effector cells associated with tumor microenvironment, macrophages have been widely recognized to participate in cancer-related inflammation, Xiao et al Journal of Experimental & Clinical Cancer Research (2018) 37:143. Increasing evidence suggests that TAMs are not composed of a homogeneous population but are a mixed population of macrophages harboring both M1 and M2 phenotypes that have been detected in several malignant solid tumors [17,18,19]. A mixed population of macrophages with M1 and M2 phenotypes was detected in vitro in several types of cancer cells [12, 18, 19]. It is urgent to fully understand the education of TAMs when considering the heterogeneity among various tissue-derived cancers
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