Nojiri Takashi, Arai Miki, Suzuki Yutaka, Kumazoe Motofumi, Tokudome Takeshi, Miura Koichi, Hino Jun, Hosoda Hiroshi, Miyazato Mikiya, Okumura Meinoshin, Kawaoka Shinpei, Kangawa Kenji
Department of Biochemistry, National Cerebral and Cardiovascular Center Research Institute, Suita-City, Osaka, Japan.
Department of General Thoracic Surgery, Osaka University Graduate School of Medicine, Suita-City, Osaka, Japan.
Oncotarget. 2017 May 25;8(39):65534-65547. doi: 10.18632/oncotarget.18032. eCollection 2017 Sep 12.
Cancer establishes a microenvironment called the pre-metastatic niche in distant organs where disseminated cancer cells can efficiently metastasize. Pre-metastatic niche formation requires various genetic factors. Previous studies suggest that inhibiting a single niche-factor is insufficient to completely block pre-metastatic niche formation especially in human patients. Here we show that the atrial natriuretic peptide (ANP), an endogenous hormone produced by the heart, inhibits pre-metastatic niche formation and metastasis of murine solid cancer models when pharmacologically supplied . On the basis of a wealth of comprehensive RNA-seq data, we demonstrated that ANP globally suppressed expression of cancer-induced genes including known niche-factors in the lung. The lungs of mice overexpressing GC-A, a receptor for ANP in endothelial cells, were conferred resistance against pre-metastatic niche formation. Importantly, neither ANP administration nor GC-A overexpression had a detrimental effect on lung gene expression in a cancer-free condition. The current study establishes endothelial ANP-GC-A signaling as a therapeutic target to control the pre-metastatic niche.
癌症会在远处器官建立一种称为前转移生态位的微环境，在那里播散的癌细胞能够有效地发生转移。前转移生态位的形成需要多种遗传因素。先前的研究表明，抑制单一的生态位因子不足以完全阻断前转移生态位的形成，尤其是在人类患者中。在此我们表明，心房利钠肽（ANP），一种由心脏产生的内源性激素，在药理学给药时可抑制小鼠实体癌模型的前转移生态位形成和转移。基于大量全面的RNA测序数据，我们证明ANP全面抑制癌症诱导基因的表达，包括肺中已知的生态位因子。在内皮细胞中过表达ANP受体GC-A的小鼠肺脏对前转移生态位的形成具有抗性。重要的是，在无癌状态下，给予ANP或过表达GC-A对肺基因表达均无有害影响。当前研究确立了内皮细胞ANP-GC-A信号传导作为控制前转移生态位的治疗靶点。
