The Cancer Cell Oxygen Sensor PHD2 Promotes Metastasis via Activation of Cancer-Associated Fibroblasts
The Cancer Cell Oxygen Sensor PHD2 Promotes Metastasis via Activation of Cancer-Associated Fibroblasts
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DOI：
10.1016/j.celrep.2015.07.010
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发表时间：
2015-08-11
期刊：
影响因子：
8.8
通讯作者：
Carmeliet, Peter
中科院分区：
文献类型：
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作者：
Kuchnio, Anna;Moens, Stijn;Carmeliet, Peter
关于氧传感器脯氨酰羟化酶2（PHD 2）在癌症中的作用的几个问题尚未得到解决。首先，尚未在自发肿瘤模型中研究PHD 2在转移中的作用。在这里，我们表明，全球PHD 2单倍缺陷减少转移，而不影响肿瘤生长。其次，目前尚不清楚PHD 2是否通过影响癌症相关成纤维细胞（CAF）来调节癌症。我们表明PHD 2单倍缺陷通过两种机制减少转移：（1）通过减少CAF活化，基质产生和CAF收缩，这一作用令人惊讶地依赖于癌细胞中的PHD 2缺失，但不依赖于CAF;（2）通过改善肿瘤血管正常化。第三，在恶性肿瘤和基质细胞中伴随的PHD 2抑制（模拟PHD 2抑制剂治疗）的作用是未知的。我们表明，全球PHD 2单倍缺陷，诱导不仅在肿瘤发病前，而且在肿瘤发病后，受损的转移。这些发现证明了PHD 2治疗潜力的研究。
Several questions about the role of the oxygen sensor prolyl-hydroxylase 2 (PHD2) in cancer have not been addressed. First, the role of PHD2 in metastasis has not been studied in a spontaneous tumor model. Here, we show that global PHD2 haplodeficiency reduced metastasis without affecting tumor growth. Second, it is unknown whether PHD2 regulates cancer by affecting cancer-associated fibroblasts (CAFs). We show that PHD2 haplodeficiency reduced metastasis via two mechanisms: (1) by decreasing CAF activation, matrix production, and contraction by CAFs, an effect that surprisingly relied on PHD2 deletion in cancer cells, but not in CAFs; and (2) by improving tumor vessel normalization. Third, the effect of concomitant PHD2 inhibition in malignant and stromal cells (mimicking PHD2 inhibitor treatment) is unknown. We show that global PHD2 haplodeficiency, induced not only before but also after tumor onset, impaired metastasis. These findings warrant investigation of PHD2's therapeutic potential.