Abstract
Apoptotic cell clearance by phagocytes is essential in tissue homeostasis. We demonstrated that conditioned medium (CM) from macrophages exposed to apoptotic cancer cells inhibits the TGFβ1-induced epithelial–mesenchymal transition (EMT), migration, and invasion of cancer cells. Apoptotic 344SQ (ApoSQ) cell-induced PPARγ activity in macrophages increased the levels of PTEN, which was secreted in exosomes. Exosomal PTEN was taken up by recipient lung cancer cells. ApoSQ-exposed CM from PTEN knockdown cells failed to enhance PTEN in 344SQ cells, restore cellular polarity, or exert anti-EMT and anti-invasive effects. The CM that was deficient in PPARγ ligands, including 15-HETE, lipoxin A4, and 15d-PGJ2, could not reverse the suppression of PPARγ activity or the PTEN increase in 344SQ cells and consequently failed to prevent the EMT process. Moreover, a single injection of ApoSQ cells inhibited lung metastasis in syngeneic immunocompetent mice with enhanced PPARγ/PTEN signaling both in tumor-associated macrophages and in tumor cells. PPARγ antagonist GW9662 reversed the signaling by PPARγ/PTEN; the reduction in EMT-activating transcription factors, such as Snai1 and Zeb1; and the antimetastatic effect of the ApoSQ injection. Thus, the injection of apoptotic lung cancer cells may offer a new strategy for the prevention of lung metastasis.
Highlights
Metastasis is a complex multistep process of cancer cell dissemination and is extremely difficult to treat
Interaction between macrophages and UV-irradiated apoptotic lung cancer cells inhibits epithelial-to-mesenchymal transition (EMT) in cancer cells To determine whether the interaction between macrophages and apoptotic lung epithelial cancer cells inhibits EMT progression, 344SQ murine lung adenocarcinoma cells were treated with conditioned medium (CM) from RAW cells exposed to either UVirradiated apoptotic 344SQ (ApoSQ-exposed CM) or necrotic 344SQ cells (NecSQ-exposed CM), along with TGF-β1
Anti-EMT effects were not observed with another important control, in which the Apoptotic 344SQ (ApoSQ) or NecSQ medium was used to culture RAW cells (Supplementary Fig. S2e–h), suggesting that a factor released by apoptotic cancer cells does not allow macrophages to develop a similar ability to that observed in coculture
Summary
Metastasis is a complex multistep process of cancer cell dissemination and is extremely difficult to treat. Cytokines involved in wound healing and immune suppression are notorious for their roles in the tumor microenvironment, increasing the EMT process of tumor cells and promoting the evasion of antitumor immunity.[27] In particular, recent studies have provided evidence that the TGF-β1-induced EMT of many epithelial cancer cells may contribute to fibrotic diseases and cancer progression.[28,29] it was demonstrated that the in vitro and in vivo exposure of macrophages to apoptotic cells inhibits TGF-β1 or bleomycin-induced EMT in lung alveolar epithelial cells.[30] Whether the efferocytosis of apoptotic cells affects the multistep process of cancer cell dissemination, leading to cancer metastasis, has not been studied far. We provide in vivo evidence that the subcutaneous injection of apoptotic lung cancer cells decreases the number of visible lung metastases of the primary subcutaneous tumor via PPARγ/PTEN signaling
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