Cancer-Associated Fibroblasts Are Activated in Incipient Neoplasia to Orchestrate Tumor-Promoting Inflammation in an NF-κB-Dependent Manner
Cancer-Associated Fibroblasts Are Activated in Incipient Neoplasia to Orchestrate Tumor-Promoting Inflammation in an NF-κB-Dependent Manner
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DOI：
10.1016/j.ccr.2009.12.041
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发表时间：
2010-02-17
期刊：
影响因子：
50.3
通讯作者：
Hanahan, Douglas
中科院分区：
文献类型：
--
作者：
Erez, Neta;Truitt, Morgan;Hanahan, Douglas
癌症相关成纤维细胞（CAF）通过刺激血管生成、癌细胞增殖和侵袭来支持肿瘤发生。我们证明，CAFs也介导肿瘤增强炎症。使用鳞状皮肤癌发生的小鼠模型，我们在从发育不良皮肤中分离的CAFs中发现了促炎基因特征。这种特征在来自随后的皮肤癌的CAF中得以保持，并且在小鼠的乳腺和胰腺肿瘤以及同源的人类癌症中是明显的。在从多步骤皮肤肿瘤发生的初始增生阶段分离的CAF中，炎症特征已经被激活。来自该途径的CAF促进巨噬细胞募集、新血管形成和肿瘤生长，当NF-κ B信号传导被抑制时，这些活性被消除。此外，我们表明，正常的皮肤成纤维细胞可以“教育”癌细胞表达促炎基因。
Cancer-associated fibroblasts (CAFs) support tumorigenesis by stimulating angiogenesis, cancer cell proliferation, and invasion. We demonstrate that CAFs also mediate tumor-enhancing inflammation. Using a mouse model of squamous skin carcinogenesis, we found a proinflammatory gene signature in CAFs isolated from dysplastic skin. This signature was maintained in CAFs from subsequent skin carcinomas and was evident in mammary and pancreatic tumors in mice and in cognate human cancers. The inflammatory signature was already activated in CAFs isolated from the initial hyperplastic stage in multistep skin tumorigenesis. CAFs from this pathway promoted macrophage recruitment, neovascularization, and tumor growth, activities that are abolished when NF-kappa B signaling was inhibited. Additionally, we show that normal dermal fibroblasts can be "educated" by carcinoma cells to express proinflammatory genes.