Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Köln, Germany.
Br J Cancer. 2013 Jul 23;109(2):422-32. doi: 10.1038/bjc.2013.242. Epub 2013 May 14.
Locomotion of cancer cells can be induced by TNF and other motogenic factors secreted by cells of the tumour microenvironment such as macrophages. Based on our recent findings that the TNF receptor adaptor protein FAN mediates TNF-induced actin reorganisation and regulates the directed migration of immune cells responding to chemotactic cues, we addressed the role of FAN in cancer cell motility and the formation of invadopodia, a crucial feature in tumour invasion.
In B16 mouse melanoma cells, FAN was downregulated and the impact on FAN on cell motility and invasion was determined using in vitro assays and in vivo animal models.
Like FAN(-/-) murine embryonic fibroblasts, FAN-deficient B16 melanoma cells showed defective motility responses to TNF in vitro. In vivo FAN-deficient B16 melanoma cells produced significantly less disseminated tumours after i.v. injection into mice. Danio rerio used as a second in vivo model also revealed impaired spreading of FAN-deficient B16 melanoma cells. Furthermore, FAN mediated TNF-induced paxillin phosphorylation, metalloproteinase activation and increased extracellular matrix degradation, the hallmarks of functionally active invadopodia.
The results of our study suggest that FAN through promoting melanoma cellular motility and tumour invasiveness is critical for the tumour-promoting action of TNF.
肿瘤微环境中的细胞如巨噬细胞分泌的 TNF 和其他趋动因子可以诱导癌细胞的运动。基于我们最近的发现，TNF 受体衔接蛋白 FAN 介导 TNF 诱导的肌动蛋白重组，并调节对趋化信号做出反应的免疫细胞的定向迁移，我们研究了 FAN 在癌细胞运动和侵袭过程中形成侵袭小窝（肿瘤侵袭的关键特征）中的作用。
在 B16 小鼠黑色素瘤细胞中，下调 FAN 并使用体外实验和体内动物模型确定 FAN 对细胞运动和侵袭的影响。
与 FAN(-/-) 鼠胚胎成纤维细胞一样，FAN 缺陷的 B16 黑色素瘤细胞在体外对 TNF 的运动反应有缺陷。体内 FAN 缺陷的 B16 黑色素瘤细胞在静脉注射到小鼠后产生的弥散性肿瘤明显减少。作为第二个体内模型的 Danio rerio 也显示 FAN 缺陷的 B16 黑色素瘤细胞的扩散受到损害。此外，FAN 介导 TNF 诱导的桩蛋白磷酸化、金属蛋白酶激活和细胞外基质降解增加，这是功能活跃的侵袭小窝的特征。
我们的研究结果表明，FAN 通过促进黑色素瘤细胞的运动和肿瘤侵袭性，对于 TNF 的肿瘤促进作用至关重要。
