Department of Chemical & Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA.
Breast & Ovarian Cancer Program, Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, 21287, USA.
Target Oncol. 2018 Apr;13(2):157-173. doi: 10.1007/s11523-018-0555-4.
Metastasis is the leading cause of cancer-related deaths. Recent research has implicated tumor inflammation as a promoter of metastasis. Myeloid, lymphoid, and mesenchymal cells in the tumor microenvironment promote inflammatory signaling amongst each other and together with cancer cells to modulate sustained inflammation, which may enhance cancer invasiveness. Tumor hypoxia, a state of reduced available oxygen present in the majority of solid tumors, acts as a prognostic factor for a worse outcome and is known to have a role in tumor inflammation through the regulation of inflammatory mediator signals in both cancer and neighboring cells in the microenvironment. Multiple methods to target tumor hypoxia have been developed and tested in clinical trials, and still more are emerging as the impacts of hypoxia become better understood. These strategies include mechanistic inhibition of the hypoxia inducible factor signaling pathway and hypoxia activated pro-drugs, leading to both anti-tumor and anti-inflammatory effects. This prompts a need for further research on the prevention of hypoxia-mediated inflammation in cancer. Hypoxia-targeting strategies seem to have the most potential for therapeutic benefit when combined with traditional chemotherapy agents. This paper will serve to summarize the role of the inflammatory response in metastasis, to discuss how hypoxia can enable or enhance inflammatory signaling, and to review established and emerging strategies to target the hypoxia-inflammation-metastasis axis.
转移是癌症相关死亡的主要原因。最近的研究表明，肿瘤炎症是转移的促进因素。肿瘤微环境中的髓样细胞、淋巴样细胞和成纤维细胞相互促进炎症信号，并与癌细胞一起调节持续的炎症，这可能增强癌症的侵袭性。肿瘤缺氧是大多数实体瘤中存在的氧气供应减少的状态，它是预后不良的一个预测因素，并且已知通过调节微环境中癌细胞和邻近细胞中的炎症介质信号，在肿瘤炎症中起作用。已经开发并在临床试验中测试了多种针对肿瘤缺氧的方法，并且随着对缺氧影响的理解的加深，更多的方法正在出现。这些策略包括缺氧诱导因子信号通路的机制抑制和缺氧激活前药，从而产生抗肿瘤和抗炎作用。这促使人们需要进一步研究癌症中缺氧介导的炎症的预防。当与传统化疗药物联合使用时，缺氧靶向策略似乎具有最大的治疗获益潜力。本文将总结炎症反应在转移中的作用，讨论缺氧如何能够激活或增强炎症信号，并综述现有的和新兴的靶向缺氧-炎症-转移轴的策略。
