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Primary tumours modulate innate immune signalling to create pre-metastatic vascular hyperpermeability foci

Author

Listed:
  • Sachie Hiratsuka

    (Tokyo Women’s Medical University School of Medicine
    PRESTO, Japan Science and Technology Agency (JST))

  • Sachie Ishibashi

    (Tokyo Women’s Medical University School of Medicine)

  • Takeshi Tomita

    (Tokyo Women’s Medical University School of Medicine)

  • Akira Watanabe

    (Research Center for Advanced Science and Technology, The University of Tokyo
    Present address: Institute for Integrated Cell-Material Sciences (iCeMS), Kyoto University, Kyoto, Japan)

  • Sachiko Akashi-Takamura

    (The Institute of Medical Science, The University of Tokyo)

  • Masato Murakami

    (Institute of Medical Science, The University of Tokyo
    Present address: Histology, Oncology DA, Novartis Institute for Biomedical Research, Basel, Switzerland)

  • Hiroshi Kijima

    (Tokai University School of Medicine
    Present address: Department of Vascular Biology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan)

  • Kensuke Miyake

    (The Institute of Medical Science, The University of Tokyo)

  • Hiroyuki Aburatani

    (Research Center for Advanced Science and Technology, The University of Tokyo)

  • Yoshiro Maru

    (Tokyo Women’s Medical University School of Medicine)

Abstract

In mouse models of lung metastasis, before the appearance of significant metastases, localized changes in vascular permeability have been observed, which appear to set the stage for tumour growth. However, it is unclear whether this is also true in human patients. Here, we show that MD-2, a coreceptor for Toll-like receptor 4 that has a key role in the innate immune response, triggers the formation of regions of hyperpermeability in mice by upregulating C-C chemokine receptor type 2 (CCR2) expression. The CCR2–CCL2 system induces the abundant secretion of permeability factors such as serum amyloid A3 and S100A8. Disruption of MD-2 or CCR2 abrogates the formation of hyperpermeable regions, resulting in reduced tumour cell homing. Furthermore, fibrinogen, which is processed during permeability-mediated coagulation, is also localized in areas of elevated CCR2 expression in tumour-bearing human lungs. Our findings raise the possibility that CCR2 upregulation might represent a marker for regions of increased susceptibility to metastatic homing in lung cancer.

Suggested Citation

  • Sachie Hiratsuka & Sachie Ishibashi & Takeshi Tomita & Akira Watanabe & Sachiko Akashi-Takamura & Masato Murakami & Hiroshi Kijima & Kensuke Miyake & Hiroyuki Aburatani & Yoshiro Maru, 2013. "Primary tumours modulate innate immune signalling to create pre-metastatic vascular hyperpermeability foci," Nature Communications, Nature, vol. 4(1), pages 1-10, October.
    • Handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms2856
    DOI: 10.1038/ncomms2856
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    Cited by:

    1. Yibing Han & Takeshi Tomita & Masayoshi Kato & Norihiro Ashihara & Yumiko Higuchi & Hisanori Matoba & Weiyi Wang & Hikaru Hayashi & Yuji Itoh & Satoshi Takahashi & Hiroshi Kurita & Jun Nakayama & Nobu, 2023. "Citrullinated fibrinogen-SAAs complex causes vascular metastagenesis," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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