M2 macrophage-derived exosome facilitates metastasis in non-small-cell lung cancer via delivering integrin αvβ3

Abstract Background The most prevalent cause of cancer death is metastasis. Immunological components of tumour microenvironment, especially tumour-associated macrophages, play a vital role in cancer metastasis. However, the underlying mechanisms of tumour-associated macrophages on non-small-cell lung cancer (NSCLC) metastasis remain largely unexplored. Methods The distribution of macrophages in tumor microenvironment, especially in lung cancer, was analyzed by online database and immunohistochemistry. The model of M2 macrophage was successfully established in vitro and M2 macrophage-derived exosomes were identified by transmission electron microscope imaging, nanoparticle tracking analysis and western blot. The role of M2 macrophage-derived exosomes (M2-exos) in promoting metastasis of lung cancer cells was identified by transwell assay, wound healing assay, immunofluorescence in vitro, and by tumor model in vivo. The mechanism that M2-exos facilitates metastasis via delivering integrin αvβ3 and activating the FAK signaling was investigated using western blot, transwell assays, immunofluorescence assays. Finally, the expression levels of integrin αvβ3 were assessed in clinical samples by immunohistochemistry. Results We demonstrated that M2-polarized phenotypic macrophages facilitate the migration and invasion of cancer cells in vitro and in vivo through intercellular delivering M2-exos. Importantly, we found that M2-exos had considerably higher levels of integrin αvβ3. The impact of M2 macrophage-mediated invasion and migration of NSCLC cells was clearly decreased when integrin αvβ3 was blocked. Mechanistically, exosomal integrin αvβ3 produced from M2 macrophages successfully triggered the FAK signaling pathway in recipient cells, boosting the migratory and invasive abilities of NSCLC cells. Clinically, we found that metastatic NSCLC patients had greater integrin αvβ3 expression, which was associated with worse prognosis. Conclusions This study reveals a novel mechanism that M2 macrophage-derived exosomal integrin αvβ3 significantly increased NSCLC cells migration and invasion. integrin αvβ3 can be used as a potential prognostic marker, and blocking integrin αvβ3 could be a viable treatment option for preventing tumour progression and metastasis.