Study Of Adipocyte-derived Exosomes Promote Lung Cancer Metastasis Through MMP3-dependent Activation Of MMP9

Obesity and tumor metastasis are closely related.Remote metastasis of tumor is more frequently found in obese patients,but the underlying remains largely unknown.Exosomes play a critical role in tumor metastasis.We found that adipocyte-derived exosomes(Adi-EXO)increased invasive ability of lung tumor cells in vitro,and this effect was partially MMP3 and totally MMP9 dependent.Moreover,when compared with pro-adipocyte-derived exosomes,Adi-EXO contained high level of MMP3 protein,Exosomes has been reported to mediate protein transfer between cells.MMP3 is natural activator of MMP9.Whether exosomes from adipocytes are involved in the tumor metastasis is still unknown.Therefore,we hypothesize that whether Adi-EXO increase invasive ability of lung tumor cells through transfer of MMP3 protein to lung tumor cells,subsequently leading to MMP9 activation.In this study,we will further verify our hypothesis in vitro and in vivo.In addition,we will analyze the MMP3 protein level and MMP9 activity in tumor tisues from obese and non-obese patients,and elucidate their correlation.In this study,we evaluated the effect of 3T3-L1 adipocyte-derived exosomes(3T3-A-EXO)on murine 3LL Lewis lung cancer cells.We found 3T3-A-EXO promote 3LL tumor cell invasion in vitro through increasing MMP9 activity but not protein level.3T3-A-EXO enriched in MMP3 mRNA and protein,which could be transferred into 3LL tumor cells.After transfer,MMP3 showed robust ability to activate MMP9 and promote tumor metastasis in vivo.Our results revealed a novel mechanism of obesity-induced lung cancer metastasis.