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–mesenchym...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 PPARγactivity 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 PPARγligands,including 15-HETE,lipoxin A4,and 15d-PGJ2,could not reverse the suppression of PPARγactivity 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 tumorassociated macrophages and in tumor cells.PPARγantagonist 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.展开更多
基金supported by the Basic Science Research Program through the National Research Foundation of Korea(NRF)funded by the Ministry of Science,ICT,Future Planning(2015R1A2A1A15053112,2017R1A2B2004864,and 2010-0027945).
文摘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 PPARγactivity 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 PPARγligands,including 15-HETE,lipoxin A4,and 15d-PGJ2,could not reverse the suppression of PPARγactivity 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 tumorassociated macrophages and in tumor cells.PPARγantagonist 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.
