Abstract IA5: The role of nitric oxide in the tumor microenvironment
Authors: Fukumura Dai 
Published: June 2012

Abstract
Tumor blood vessels exhibit abnormal organization, structure, and function characterized by heterogeneous and at times compromised blood flow, and hyperpermeability. Furthermore, intra-tumoral lymphatics are not functional even if they exist and peritumoral lymphatics are dysfunctional. Collectively, these abnormalities result in a hostile tumor microenvironment, which hinders the delivery and efficacy of therapeutic agents, and also promotes a more malignant phenotype. Nitric oxide (NO), a mediator of diverse physiological and pathological processes, may contribute towards these deleterious processes.
NO and NO synthases (NOS) are ubiquitous in malignant tumors and have been shown to exert both pro- and anti-tumor activities depending on their localization and activity. In tumor blood vessels, NO, as endotheliumderived relaxing factor, dilates blood vessels and thus serves to maintain blood flow. NO can mediate the angiogenic process either directly, or both up- or downstream of various other angiogenic factors. Furthermore, NO mediates vessel remodeling and maturation via its effect on perivascular cell recruitment. We have found that endothelial NOS (eNOS)-derived NO is critical for angiogenesis and vessel maturation. Conversely, NO produced from non-endothelial sources (for example tumor cells) interferes with vessel maturation and hence contributes to the abnormal functioning of blood vessels.
Similarly, NO influences the formation and function of lymphatic vessels. In particular, NO mediates the proliferation of lymphatic endothelial cells, in vivo lymphangiogenesis, and lymphatic metastasis – all of which are enhanced by vascular endothelial growth factor-C. We have found that eNOS-derived NO produced in lymphatic endothelial cells promotes efferent lymphatic flow by regulating lymphatic contraction. On the other hand, interstitial NO produced by inducible NOS (iNOS) in inflammatory cells or tumor cells inhibits the function of these lymphatics.
Collectively, these studies suggest that NO can regulate the tumor vasculature both positively and negatively, and that its precise localization is an important determinant of its role. Based on these findings, we hypothesized that the modulation of tissue NO location would normalize tumor vessels and improve the efficacy of concomitantly administered cytotoxic therapy. To test this hypothesis, we blocked tumor-derived NO production from glioma (neuronal NOS) and breast cancer (iNOS) cells both pharmacologically and genetically. In vivo imaging showed that after inhibition of tumor cell NOS, NO was seen primarily in a vascular location (eNOS-derived). This redistribution of tissue NO gradients were associated with an improved structure and function of tumor blood vessels. We observed a reduction in hypoxia suggesting improved overall function of vessel networks, and a consequent enhancement of radiotherapy efficacy in both orthotopic tumor models. Taken together, our data suggest that aberrant production of NO from tumor cells interferes with vessel maturation, and that the restoration of tissue NO distribution by selective NOS modulation improves tumor vascular function, facilitating the effects of concomitantly administered cytotoxic therapies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr IA5.