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Macrophage-mediated transfer of cancer-derived components to stromal cells contributes to establishment of a pro-tumor microenvironment

Oncogene volume 38, pages 2162–2176 (2019)Cite this article

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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.

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Acknowledgements

We thank members of the Bioscience Education and Research Support Center (BERSC) in Akita University for technical assistance.

Funding

This work was supported by JSPS KAKENHI Grants (Nos. 17K19579 and 16H04691 to M. Tanaka), a Research Grant from the Princess Takamatsu Cancer Research Fund (14-24620 to M. Tanaka), the Takeda Science Foundation, and Project Mirai Cancer Research grants to M. Tanaka.

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Authors and Affiliations

  1. Department of Molecular Medicine and Biochemistry, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan

    Michinobu Umakoshi, So Takahashi, Go Itoh, Sei Kuriyama, Yuto Sasaki & Masamitsu Tanaka

  2. Department of Cellular and Organ Pathology, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan

    Michinobu Umakoshi, Daichi Maeda & Akiteru Goto

  3. Department of Gastroenterology and Neurology, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan

    So Takahashi

  4. Department of Life Science, Faculty and Graduate School of Engineering and Resource Science, Akita University, 1-1 Tegata Gakuenmachi, Akita, 010-8502, Japan

    Yuto Sasaki

  5. Division of Pathology, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwa-shi, Chiba, 277-0882, Japan

    Kazuyoshi Yanagihara

  6. Department of Surgical Oncology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka, 545-8545, Japan

    Masakazu Yashiro

  7. Department of Clinical Genomics, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suitashi, Osaka, 565-0871, Japan

    Daichi Maeda

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  1. Michinobu Umakoshi
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Correspondence to Akiteru Goto or Masamitsu Tanaka.

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Umakoshi, M., Takahashi, S., Itoh, G. et al. Macrophage-mediated transfer of cancer-derived components to stromal cells contributes to establishment of a pro-tumor microenvironment. Oncogene 38, 2162–2176 (2019). https://doi.org/10.1038/s41388-018-0564-x

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