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

Sachie Hiratsuka, Sachie Ishibashi, Takeshi Tomita, Akira Watanabe, Sachiko Akashi-Takamura, Masato Murakami, Hiroshi Kijima, Kensuke Miyake, Hiroyuki Aburatani and Yoshiro Maru ()
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Sachie Hiratsuka: Tokyo Women’s Medical University School of Medicine
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
Sachiko Akashi-Takamura: The Institute of Medical Science, The University of Tokyo
Masato Murakami: Institute of Medical Science, The University of Tokyo
Hiroshi Kijima: Tokai University School of Medicine
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

Nature Communications, 2013, vol. 4, issue 1, 1-10

Abstract: 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.

Date: 2013
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DOI: 10.1038/ncomms2856

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