Hypoxic Tumor-Derived Exosomes Induce M2 Macrophage Polarization via PKM2/AMPK to Promote Lung Cancer Progression

Hypoxia is a major regulator of tumor aggressiveness and metastasis in cancer progression. Exosomes (exos) play an important role in the communication between lung cancer and hypoxic microenvironment. However, the underlying mechanisms are largely undefined. Exos were isolated from A549 cells under hypoxia conditions. Transmission electron microscopy and nanoparticle tracking analysis were carried out to characterize exos. CCK-8 assay, flow cytometry, Western blot, wound healing, and transwell assays were performed to assess the proliferation, apoptosis, migration, and invasion of A549 cells, respectively. The M2 polarization of macrophages was evaluated by RT-qPCR and Western blot analysis. In vivo nude mice model was established to determine the regulatory effect of hypoxia/exos on the progression of lung cancer. Hypoxic A549 cell-derived exos (hypoxia/exos) promoted the proliferation and migration, and inhibited the apoptosis in A549 cells. The expression of PKM2 was significantly upregulated in hypoxia/exos. Hypoxic exosomal PKM2 induced M2 polarization of macrophages by activating AMPK pathway. Co-culture with hypoxia/exos-treated macrophages enhanced the migration, invasion, and epithelial-mesenchymal transition (EMT) in A549 cells. Moreover, treatment with hypoxia/exos facilitated the tumor growth and lung metastasis of A549 cells. Our findings reveal that hypoxic exosomal PKM2 induces M2 macrophage polarization via AMPK pathway, and thus exerts a simulative effect on the growth and metastasis of lung carcinoma.