Research Abstract


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

2013年5月14日 Nature Communications 4 : 1853 doi: 10.1038/ncomms2856


平塚 佐千枝1,2, 石橋 幸江1, 富田 毅1, 渡辺 亮3*, 赤司(高村) 祥子4, 村上 正人5**, 鬼島 宏6***,三宅 健介4, 油谷 浩幸3 & 丸 義朗1

  1. 東京女子医科大学 薬理学教室
  2. 独立行政法人 科学技術振興機構 さきがけ
  3. 東京大学 先端科学技術研究センター ゲノムサイエンス分野
  4. 東京大学医科学研究所 感染・免疫部門 感染遺伝学分野
  5. 東京大学医科学研究所
  6. 東海大学 医学部 病理学

    *現所属先: 京都大学 IPS細胞研究所
    **現所属先: ノバルティス生物医学研究所(スイス)
    ***現所属先: 弘前大学大学院 医学研究科

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.