Abstract

Tumor-associated macrophages (TAMs) are a major component of the tumor microenvironment and have been shown to contribute to tumor aggressiveness. However, the detailed mechanisms underlying the pro-metastatic effect of TAMs on gastric cancer are not clearly defined. Here, we show that TAMs are enriched in gastric cancer. TAMs are characterized by M2-polarized phenotype and promote migration of gastric cancer cells in vitro and in vivo. Furthermore, we find that M2-derived exosomes determine the TAMs-mediated pro-migratory activity. Using mass spectrometry, we identify that apolipoprotein E (ApoE) is highly specific and effective protein in M2 macrophages-derived exosomes. Moreover, TAMs are uniquely immune cells population expressed ApoE in gastric cancer microenvironment. However, exosomes derived from M2 macrophages of Apoe−/− mice have no significant effect on the migration of gastric cancer cells in vitro and in vivo. Mechanistically, M2 macrophage-derived exosomes mediate an intercellular transfer of ApoE-activating PI3K-Akt signaling pathway in recipient gastric cancer cells to remodel the cytoskeleton-supporting migration. Collectively, our findings signify that the exosome-mediated transfer of functional ApoE protein from TAMs to the tumor cells promotes the migration of gastric cancer cells.

Highlights

  • Tumor microenvironment (TME) has a critical role in tumor progression and metastasis[1]

  • The results of the characterization of macrophages showed the heterogeneity across 19 solid cancers, and macrophages were enriched in stomach adenocarcinoma (STAD) (Fig. 1a)

  • The infiltration of immune cellular profiles demonstrated that macrophages were dominant in the TME of gastric cancer (GC) (Fig. 1b)

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Summary

Introduction

Tumor microenvironment (TME) has a critical role in tumor progression and metastasis[1]. A plethora of elegant studies focusing on TAMs have shown that TAMs are associated with tumor progression and metastasis through intercellular communication with cancer cells, research into the communication between TAMs and tumor cells has been limited to soluble factors, such as proinflammatory cytokines, Official journal of the Cell Death Differentiation Association. Recent evidence suggests that exosomes are a vital communication medium between different cell types in the TME9,10. Most of the current studies are focused on cancer cell-secreted exosomes[12,13,14], and little is known about TAM-derived exosomes and their influence on cancer cells. The phenotype of TAMs is regulated by specific tumor-derived chemokines and exosomes. A recent study has suggested that tumor-derived exosomal miRNA regulates the polarization of tumor-promoting M2 macrophages[15]. The regulation of tumor progression and metastasis by TAM-derived exosomes is not clearly defined. The exosomal profile of TAMs remains largely unknown, and it is unclear whether there are exclusively TAMderived exosomes that are functionally essential for tumor progression

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