转移
血管生成
医学
肝病学
肿瘤微环境
癌症研究
祖细胞
成纤维细胞生长因子
血管内皮生长因子
生长因子
癌症
病理
免疫学
内科学
生物
干细胞
受体
血管内皮生长因子受体
遗传学
作者
Alex Gordon-Weeks,Su Yin Lim,Arseniy E. Yuzhalin,Keaton Jones,Boštjan Markelc,K. Jin Kim,Jon N. Buzzelli,Emmanouil Fokas,Yuze Cao,Sean Smart,Ruth J. Muschel
出处
期刊:Hepatology
[Wiley]
日期:2017-05-02
卷期号:65 (6): 1920-1935
被引量:87
摘要
Hepatic metastases are amenable to ablation; however, many patients are not suitable candidates for such therapy and recurrence is common. The tumor microenvironment is known to be essential for metastatic growth, yet identification of plausible targets for cancer therapy in the microenvironment has proven elusive. We found that human colorectal cancer liver metastases and murine gastrointestinal experimental liver metastases are infiltrated by neutrophils. Plasticity in neutrophils has recently been shown to lead to both protumor and antitumor effects. Here, neutrophils promoted the growth of hepatic metastases, given that depletion of neutrophils in already established, experimental, murine liver metastases led to diminished metastatic growth. Decreased growth was associated with reductions in vascular density and branching suggestive of vessel normalization. Metastasis-associated neutrophils expressed substantially more fibroblast growth factor 2 (FGF2) than naïve neutrophils, indicating neutrophil polarization by the tumor microenvironment. Administration of FGF2 neutralizing antibody to mice bearing experimental liver metastases phenocopied neutrophil depletion by reducing liver metastatic colony growth, vascular density, and branching.Here, we show, using FGF2 as an example, that identification of factors responsible for the protumoral effects of infiltrating myeloid cells can be used to target established liver metastases. Such therapies could be utilized to limit disease progression and potentiate the effects of standard ablative therapies. (Hepatology 2017;65:1920-1935).
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