Hypoxia and loss of PHD2 inactivate stromal fibroblasts to decrease tumour stiffness and metastasis.
Hypoxia and loss of PHD2 inactivate stromal fibroblasts to decrease tumour stiffness and metastasis.
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DOI：
10.15252/embr.201540107
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发表时间：
2015-10
期刊：
影响因子：
7.7
通讯作者：
Erler JT
中科院分区：
文献类型：
--
作者：
Madsen CD;Pedersen JT;Venning FA;Singh LB;Moeendarbary E;Charras G;Cox TR;Sahai E;Erler JT
癌症相关成纤维细胞（CAF）与肿瘤细胞相互作用，促进生长和转移。在这里，我们表明CAF激活是可逆的：慢性缺氧使CAF失活，导致收缩力丧失，周围细胞外基质重塑减少，最终损害CAF介导的癌细胞侵袭。缺氧抑制脯氨酰羟化酶结构域蛋白2（PHD 2），导致缺氧诱导因子（HIF）-1 α稳定化，αSMA和骨膜蛋白表达减少，肌球蛋白II活性降低。CAFs中PHD 2的缺失表型模仿缺氧的作用，这可以通过同时耗尽HIF-1α来预防。在原位乳腺癌模型中用PHD抑制剂DMOG治疗显著降低了肺和肝的自发转移，与降低的肿瘤硬度和成纤维细胞活化相关。与肿瘤细胞共注射的CAF中的PHD 2消耗类似地防止CAF诱导的肺和肝转移。我们的数据表明，CAFs向较不活跃状态的逆转是可能的，并且可能具有重要的临床意义。
Cancer‐associated fibroblasts (CAFs) interact with tumour cells and promote growth and metastasis. Here, we show that CAF activation is reversible: chronic hypoxia deactivates CAFs, resulting in the loss of contractile force, reduced remodelling of the surrounding extracellular matrix and, ultimately, impaired CAF‐mediated cancer cell invasion. Hypoxia inhibits prolyl hydroxylase domain protein 2 (PHD2), leading to hypoxia‐inducible factor (HIF)‐1α stabilisation, reduced expression of αSMA and periostin, and reduced myosin II activity. Loss of PHD2 in CAFs phenocopies the effects of hypoxia, which can be prevented by simultaneous depletion of HIF‐1α. Treatment with the PHD inhibitor DMOG in an orthotopic breast cancer model significantly decreases spontaneous metastases to the lungs and liver, associated with decreased tumour stiffness and fibroblast activation. PHD2 depletion in CAFs co‐injected with tumour cells similarly prevents CAF‐induced metastasis to lungs and liver. Our data argue that reversion of CAFs towards a less active state is possible and could have important clinical implications.