Hypoxic Macrophage-derived Exosomes Mediate Colorectal Cancer Progression through Targeting the Hippo Signaling Pathway

Abstract Background The crosstalk between tumor cells and macrophages under hypoxia contributes to colorectal cancer (CRC) progression. Playing an important role in tumor growth by promoting macrophages to polarize to M2-like macrophages, hypoxic tumor cell-derived exosomes have been reported to be important mediators in this crosstalk. However, whether hypoxic macrophage-derived exosomes (HMDEs) modulate CRC progression remains unknown. Methods Exosomes from cell culture medium were separated, quantitated, and verified by transmission electronic microscopy and nanoparticle tracking analysis (NTA). Western blotting, real-time quantitative PCR, luciferase reporter assay, Co-immunoprecipitation, chromatin immunoprecipitation, Cell Counting Kit-8 assay, flow cytometry, and immunofluorescence staining were employed to explore the mechanisms by which HMDEs in regulate CRC development under hypoxia. BALB/c-nu/nu mice were utilized to verify CRC proliferation in vivo . Results Hypoxia promoted exosome release from macrophages, which could contribute to CRC progression by enhancing cell-cycle transition and inhibiting cell apoptosis. In the context of hypoxia, Hif-1α was highly overexpressed and it could directly bind to the − 521‒ -516 bp and − 401‒ -391 bp regions of the Hsp90 promoter, regulating Hsp90 expression and leading to high levels of Hsp90 protein in HMDEs. Binding to Lats1, Hsp90 inactivated Lats1 and inhibited Yap phosphorylation so as to inactivate the Hippo signaling pathway which was responsible for HMDEs-mediated CRC growth in vivo and in vitro . Conclusions We have demonstrated that hypoxic macrophage-derived exosomal Hsp90 induced CRC progression by inactivation of the Hippo signaling pathway, which promoted CRC cell proliferation. Therefore, our study provides a novel understanding of the crosstalk between macrophages and CRC cells under hypoxia.