肿瘤相关成纤维细胞如何增加癌细胞干性
创作:szx 审核:szx 2019年07月15日
  • 轴突导向因子-1(Netrin-1)在许多肿瘤中上调,在人结直肠癌中,轴突导向因子-1及其受体UNC5B的表达与肿瘤相关成纤维细胞(CAF)相关;
  • 在与癌细胞共培养时,结肠及肺部的CAF均可分泌轴突导向因子-1,后者在CAF中的上调与癌细胞干性增加相关;
  • 在细胞实验及小鼠实验中,使用单抗抑制轴突导向因子-1均可消除CAF介导的癌细胞干性增加;
  • 机制上,轴突导向因子-1单抗通过调节IL-6等细胞因子的表达,抑制了CAF与癌细胞的胞内信号。
主编推荐语
szx
Cancer Research上发表的一项最新研究,发现在结直肠癌及肺癌中,轴突导向因子-1不仅在癌细胞中上调,在肿瘤相关成纤维细胞(CAF)中的表达也显著增加。CAF中的轴突导向因子-1促进了癌细胞的干性,抑制轴突导向因子-1则可逆转。
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Cancer Research [IF:9.727]

Cancer-associated fibroblasts produce Netrin-1 to control cancer cell plasticity

肿瘤相关成纤维细胞产生轴突导向因子-1以调控癌细胞可塑性

10.1158/0008-5472.CAN-18-2952

2019-05-14, Article

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Netrin-1 is upregulated in a large fraction of human neoplasms. In multiple animal models, interference with netrin-1 is associated with inhibition of tumor growth and metastasis. Although netrin-1 upregulation was initially described in cancer cells, we report here that in the human colorectal cancer database, the expression of netrin-1 and its receptor UNC5B correlates with a cancer-associated fibroblasts (CAF) signature. Both colon and lung CAF secreted netrin-1 when co-cultured with respective cancer cells, and netrin-1 upregulation in CAF was associated with increased cancer cell stemness. Pharmacologic inhibition of netrin-1 with a netrin-1 monoclonal antibody (Net1-mAb) abrogated the CAF-mediated increase of cancer stemness both in co-culture experiments and in mice. Netrin-1 mAb inhibited intercellular signaling between CAF and cancer cells by modulating CAF-mediated expression of cytokines such as interleukin-6 (IL6). Together these data demonstrate that netrin-1 is upregulated not only in cancer cells but also in cancer-associated stromal cells. In addition to its direct activity on cancer cells, inhibition of netrin-1 may reduce pro-neoplastic CAF-cancer cell crosstalk, thus inhibiting cancer plasticity.

First Authors:
Pei-Ju Sung

Correspondence Authors:
Patrick Mehlen

All Authors:
Pei-Ju Sung,Nicolas Rama,Jeromine Imbach,Stephany Fiore,Benjamin Ducarouge,David Neves,Huei-Wen Chen,David Bernard,Pan-Chyr Yang,Agnès Bernet,Stephane Depil,Patrick Mehlen

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