RRC ID 54741
著者 Umakoshi M, Takahashi S, Itoh G, Kuriyama S, Sasaki Y, Yanagihara K, Yashiro M, Maeda D, Goto A, Tanaka M.
タイトル Macrophage-mediated transfer of cancer-derived components to stromal cells contributes to establishment of a pro-tumor microenvironment.
ジャーナル Oncogene
Abstract Tumor-derived extracellular vesicles (TEVs) secreted into the blood create a pre-metastatic niche in distant organs; however, it is unclear how TEVs are delivered and how they affect stromal cells in the tumor microenvironment. Tumor-associated macrophages (TAMs) have pivotal roles in cancer progression by interacting with cancer cells and other stromal cells. Here, we report a novel function of TAMs: delivery and transmission of TEV contents. TEV-incorporating macrophages (TEV-MΦs) showed increased invasiveness and were disseminated widely. Upon contact with host stromal cells (peritoneal mesothelial cells (PMCs), fibroblasts, and endothelial cells), TEV-MΦs released membrane blebs containing TEVs, a process dependent upon localized activation of caspase-3 in MΦs. Scattered blebs were incorporated into stromal cells, leading to transfer of cancer-derived RNA and proteins such as TGF-β, activated Src, Wnt3, and HIF1α. TEV-MΦ-secreted blebs containing cancer-derived components contributed to myofibroblastic changes in recipient stromal cells. TEVs delivered by MΦs penetrated deep into the parenchyma of the stomach in TEV-injected mice, and transmitted TEVs to PMCs lining the stomach surface; this process induced PMCs to undergo mesothelial-mesenchymal transition. PMCs infiltrated the gastric wall and created a niche, thereby promoting tumor invasion. Depletion of MΦs prevented these events. Moreover, TEV-MΦs created a pro-metastatic niche. Taken together, these results suggest a novel function for TAMs: transfer of cancer-derived components to surrounding stromal cells and induction of a pro-tumor microenvironment via an increase in the number of CAF-like cells.
巻・号 38(12)
ページ 2162-2176
公開日 2019-3-1
DOI 10.1038/s41388-018-0564-x
PII 10.1038/s41388-018-0564-x
PMID 30459356
MeSH Cell Line, Tumor Cell Membrane / metabolism Epithelial-Mesenchymal Transition Extracellular Vesicles / metabolism Humans Macrophages / cytology* Neoplasm Invasiveness Stromal Cells / pathology* Tumor Microenvironment*
IF 6.634
引用数 6
リソース情報
ヒト・動物細胞 LLC(RCB0558) B16/BL6(RCB2638)