M1 Macrophages Enhance Survival and Invasion of Oral Squamous Cell Carcinoma by Inducing GDF15-Mediated ErbB2 Phosphorylation

Abstract

M2 macrophages are generally recognized to have a protumor role, while the effect of M1 macrophages in cancer is controversial. Here, the in vitro and in vivo effects of conditioned medium from M1 macrophages (M1-CM) on oral squamous cell carcinoma (OSCC) cells and a potential mechanism were studied. CCK-8, colony formation, EdU labeling, xenograft growth, and Transwell assays were utilized to observe cell survival/proliferation and migration/invasion, respectively, in OSCC cell lines treated with basic medium (BM) and M1-CM. The ErbB2 phosphorylation inhibitor (CI-1033) and GDF15 knockout cell lines were used to appraise the role of ErbB2 and GDF15 in mediating the effects of M1-CM. Compared with BM, M1-CM significantly enhanced the survival/proliferation of SCC25 cells. The migration/invasion of SCC25 and CAL27 cells also increased. Mechanically, M1-CM promoted GDF15 expression and increased the phosphorylation of ErbB2, AKT, and ErK. CI-1033 significantly declined the M1-CM-induced activation of p-AKT and p-ErK and its protumor effects. M1-CM stimulated enhancement of p-ErbB2 expression was significantly decreased in cells with GDF15 gene knockout vs without. In xenograft, M1-CM pretreatment significantly promoted the carcinogenic potential of OSCC cells. Our results demonstrate that M1 macrophages induce the proliferation, migration, invasion, and xenograft development of OSCC cells. Mechanistically, this protumor effect of M1 macrophages is partly associated with inducing GDF15-mediated ErbB2 phosphorylation.