Adipocyte-derived exosomes promote lung cancer metastasis by increasing MMP9 activity via transferring MMP3 to lung cancer cells.

Jiaoli Wang,Xuefeng Fei,Lei Yu,Yilei Wu,Jufeng Guo,Shenglin Ma

doi:10.18632/oncotarget.18737

Abstract

Obesity is involved in tumor progression. However, the corresponding mechanisms remain largely unknown. Here, we report that adipocytes increase the invasive ability of tumor cells by producing exosomes with a high level of MMP3. Compared with 3T3-L1 cells, 3T3-L1 adipocytes are enriched in MMP3 protein and can transfer MMP3 to 3LL lung cancer cells. Then, MMP3 activates MMP9 activity in 3LL cells and promotes invasion in vitro and in vivo via MMP9. Furthermore, MMP3 protein levels in lung tumor tissues from obese patients are increased compared with those of non-obese patients. In addition, MMP3 protein levels are positively correlated with MMP9 activity in tumor tissues. Therefore, our results reveal a novel mechanism in the adipocyte-derived exosome-mediated promotion of lung tumor metastasis, which extends our knowledge regarding obesity and tumor progression.

Highlights

Lung cancer is the leading cause of cancer death among males in worldwide and has surpassed breast cancer as the leading cause of cancer death among females in more developed countries [1]
To determine whether adipocyte-derived exosomes played a role in 3LL cell migration or invasion, 3T3-EXO- or 3T3-A-EXO-pretreated 3LL cells were placed in the top chamber in serum-free media, whereas the bottom chamber contained media with 20% FCS
These results indicate that adipocyte-derived exosomes play a role in enhancing the invasive ability of 3LL cells in vitro

Summary

Introduction

Lung cancer is the leading cause of cancer death among males in worldwide and has surpassed breast cancer as the leading cause of cancer death among females in more developed countries [1]. Metastasis is the main cause of lung cancer therapy failure. A further understanding of the mechanisms of lung cancer metastasis is urgently needed. The mature adipocytestimulated expression of CCL19 and CCL21 in lymphatic endothelial cell, and expression of their receptor CCR7 in melanoma cells, which contributes to increased lymph node metastasis of melanoma in high-fat diet-fed mice [8]. Obesity is implicated in the increased metastasis of lung cancers. Mice fed a high-fat diet exhibit a significantly increased number and size of lung metastases compared www.impactjournals.com/oncotarget with those fed a control diet [10]. An adipocytederived cytokine associated with obesity, effectively enhances metastasis of the human lung cancer A549 cell line [11]. The mechanism by which obesity promotes lung cancer cell metastasis has yet to be explored

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Conclusion