Abstract
BackgroundAdipose tissue macrophages (ATMs) particularly contribute to the progression of obesity-related tumor. However, the mechanisms that the tumor-adipocyte crosstalk may enable the properties and plasticity of macrophages remain still unclear. MethodsSurvival probabilities for recurrence-free survival (RFS) were estimated by the Kaplan–Meier method based on immunohistochemistry and immunofluorescence images. 3T3-L1 cells were co-cultivated with 4T1 and MDA-MB-231 cells. Then the co-cultivated media were used to treat THP-1/RAW264.7 cells. The ATMs markers were detected by immunofluorescence and Western blot. Transwell migration assay, was conducted to determine the migration capability of ATMs. RT-PCR and ELISA were used to detect the expression and secretion level of chemokines, respectively. Immunofluorescence imaging and Western blot were used to investigate the role of SOCS6/STAT3 signaling pathway in the polarization of ATMs. microRNA mimic and inhibitor, and xenograft models were used to explore the role of miR-155 in the polarization of ATMs.ResultsWe demonstrate that CD163-positive macrophages aggregated to surround adipocytes in breast cancer tissues, which was associated with tumor relapse. Thereafter, the eliminated macrophages partially inhibited adipocytes-induced tumor proliferation. The expression of chemokines, CCL2 and CCL5, elevated in tumor-adipocyte microenvironment and contributed to macrophage recruit and M2-like polarization via phosphorylating STAT3. Consistently, inhibiting chemokines and their receptors or suppressing the phosphorylation of STAT3 significantly decreased tumor burden in vivo. In coculture of tumor cells and adipocytes, the level of exosomal miRNA-155 was high, then it promoted the generation and release of CCL2 and CCL5 from adipocytes through targeting SOCS6/STAT3 pathway. Inhibition of exosomal miRNA-155 in tumor cells reduced the CCL2 and CCL5 levels in tumor-adipocytes coculture, and further retarded tumor growth. Likewise, the exosomes stimulated autophagy in macrophages in TFE3-depending way. ConclusionThese results suggest a novel target of tumor-adipocyte-macrophage interconnect that could facilitate obesity-induced tumor progression.
Development of a novel target module redirecting UniCAR T cells to Sialyl Tn-expressing tumor cells