Department of Biochemistry, Center for Cellular and Molecular Therapy - CTCMol, Escola Paulista de Medicina - Universidade Federal de São Paulo - Campus São Paulo, Brazil.
Department of Microbiology, Immunology and Parasitology, Escola Paulista de Medicina - Universidade Federal de São Paulo - Campus São Paulo, Brazil.
Nitric Oxide. 2019 Aug 1;89:1-13. doi: 10.1016/j.niox.2019.04.009. Epub 2019 Apr 19.
Cancer development is closely related to chronic inflammation, which is associated with identifiable markers of tumor progression, such as uncontrolled cell proliferation, angiogenesis, genomic instability, chemotherapeutic resistance, and metastases. Redox processes mediated by reactive oxygen species (ROS) and nitric oxide (NO) within the inflammatory tumor microenvironment play an essential role in directly influencing intercellular and intracellular signaling. These reactive species originating in the cancer cell or its microenvironment, mediate the epithelial-mesenchymal transition (EMT) and the mesenchymal-epithelial transition (MET). However, intracellular interactions between NO and ROS must be controlled to prevent cell death. Melanoma, breast, and colon cancer cells have developed a mechanism to survive and adapt to oxidative and nitrosative stress. The mechanism involves a spatial-temporal fine adjustment of the intracellular concentrations of NO and ROS, thereby guaranteeing the successful development of cancer cells. Physiological concentrations of NO and supra physiological concentrations of ROS are prevalent in cancer cells at the primary site. The situation reverses in cancer cells undergoing the EMT prior to being released into the blood stream. Intracellular supra physiological concentrations of NO found in circulating cancer cells endow them with anoikis resistance. When the anoikis-resistant cancer cells arrive at a metastatic site they undergo the MET. Endogenous supra physiological concentrations of ROS and physiological NO concentrations are prevalent in these cells. Understanding tumor progression from the perspective of redox signaling permits the characterization of new markers and approaches to therapy. The synthesis and use of compounds with the capacity of modifying intracellular concentrations of NO and ROS may prove effective in disrupting a redox homeostasis operative in cancer cells.
癌症的发生与慢性炎症密切相关，后者与肿瘤进展的可识别标志物相关，如不受控制的细胞增殖、血管生成、基因组不稳定性、化疗耐药和转移。在炎症肿瘤微环境中由活性氧（ROS）和一氧化氮（NO）介导的氧化还原过程在直接影响细胞间和细胞内信号转导方面起着至关重要的作用。这些源自癌细胞或其微环境的活性物质，介导上皮-间充质转化（EMT）和间充质-上皮转化（MET）。然而，必须控制 NO 和 ROS 之间的细胞内相互作用，以防止细胞死亡。黑色素瘤、乳腺癌和结肠癌细胞已经开发出一种机制来耐受和适应氧化和硝化应激。该机制涉及 NO 和 ROS 细胞内浓度的时空精细调节，从而保证癌细胞的成功发展。生理浓度的 NO 和超生理浓度的 ROS 普遍存在于原发部位的癌细胞中。在 EMT 之前释放到血液中的癌细胞中，情况发生逆转。循环癌细胞中发现的细胞内超生理浓度的 NO 赋予它们抗失巢凋亡能力。当具有抗失巢凋亡能力的癌细胞到达转移部位时，它们会经历 MET。这些细胞中存在内源性超生理浓度的 ROS 和生理浓度的 NO。从氧化还原信号的角度理解肿瘤进展，允许对新的标志物进行表征，并探索治疗方法。合成和使用能够改变 NO 和 ROS 细胞内浓度的化合物可能在破坏癌症细胞中起作用的氧化还原平衡方面被证明是有效的。
