Department of Biochemistry and Molecular Biology, George Washington University, School of Medicine, Washington, DC, USA.
IUBMB Life. 2012 Aug;64(8):676-83. doi: 10.1002/iub.1057. Epub 2012 Jun 20.
The role of NO and cGMP signaling in tumor biology has been extensively studied during the past three decades. However, whether the pathway is beneficial or detrimental in cancer is still open to question. We suggest several reasons for this ambiguity: first, although NO participates in normal signaling (e.g., vasodilation and neurotransmission), NO is also a cytotoxic or apoptotic molecule when produced at high concentrations by inducible nitric-oxide synthase (iNOS or NOS-2). In addition, the cGMP-dependent (NO/sGC/cGMP pathway) and cGMP-independent (NO oxidative pathway) components may vary among different tissues and cell types. Furthermore, solid tumors contain two compartments: the parenchyma (neoplastic cells) and the stroma (nonmalignant supporting tissues including connective tissue, blood vessels, and inflammatory cells) with different NO biology. Thus, the NO/sGC/cGMP signaling molecules in tumors as well as the surrounding tissue must be further characterized before targeting this signaling pathway for tumor therapy. In this review, we focus on the NOS-2 expression in tumor and surrounding cells and summarized research outcome in terms of cancer therapy. We propose that a normal function of the sGC-cGMP signaling axis may be important for the prevention and/or treatment of malignant tumors. Inhibiting NOS-2 overexpression and the tumor inflammatory microenvironment, combined with normalization of the sGC/cGMP signaling may be a favorable alternative to chemotherapy and radiotherapy for malignant tumors.
在过去的三十年中，NO 和 cGMP 信号通路在肿瘤生物学中的作用已经得到了广泛的研究。然而，该通路在癌症中是有益还是有害仍然存在争议。我们提出了以下几个原因：首先，尽管 NO 参与正常信号转导（如血管扩张和神经递质传递），但当诱导型一氧化氮合酶（iNOS 或 NOS-2）产生高浓度的 NO 时，NO 也是一种细胞毒性或凋亡分子。此外，cGMP 依赖性（NO/sGC/cGMP 通路）和 cGMP 非依赖性（NO 氧化途径）成分可能因不同组织和细胞类型而异。此外，实体瘤包含两个隔室：实质（肿瘤细胞）和基质（非恶性支持组织，包括结缔组织、血管和炎症细胞），其 NO 生物学特性不同。因此，在针对肿瘤治疗靶向该信号通路之前，必须进一步表征肿瘤及其周围组织中的 NO/sGC/cGMP 信号分子。在这篇综述中，我们重点关注 NOS-2 在肿瘤和周围细胞中的表达，并根据癌症治疗的研究结果进行总结。我们提出，sGC-cGMP 信号轴的正常功能可能对预防和/或治疗恶性肿瘤很重要。抑制 NOS-2 过表达和肿瘤炎症微环境，结合 sGC/cGMP 信号的正常化，可能是恶性肿瘤化疗和放疗的有利替代方法。
