Modulation and exploitation of the tumor microenvironment to improve anticancer therapies : focus on endothelial nitric oxide synthase and caveolin-1
(2008)
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- Abstract
- The tumor vasculature displays architectural and functional abnormalities. Tumor blood perfusion is therefore perturbed and, as a result, oxygen supply and elimination of metabolic wastes are largely inefficient. Low pO2 (partial oxygen pressure) and low pH therefore generally characterize the microenvironment of many tumors. These features are known to impede the efficacy of conventional anticancer therapies. Lack of O2 reduces the efficacy of radiotherapy and abnormal tumor perfusion alters the tumor delivery of chemotherapeutic agents or vectors used for gene therapy. NO plays key roles in regulating vessel tone and O2 consumption in tumors. Modulation of its production may therefore contribute to overcome part of the above-mentioned resistance to antitumor strategies. In the first part of our work, we showed that a systemic administration of nitrite, which is reconverted into NO in acidic and hypoxic conditions (i.e., the conditions encountered in tumor microenvironment), induces a tumor-specific increase in oxygenation and consequently radiosensitizes tumors. We also documented that low dose irradiation favors local NO production, which in turn increases tumor perfusion and oxygenation. We further demonstrated that such effect could be exploited to promote the delivery of therapeutic gene-containing cationic lipids. A plasmid encoding a dominant-negative form of Akt was evaluated in vivo and shown to exert synergistic anti-tumor effects with radiotherapy. In the second part of our work, we provided evidence that long-term exposure to nitrite, under relative hypoxic conditions, displays pro-angiogenic properties that are particularly pronounced in the absence of caveolin-1 expression. Similarly, we found that while VEGF/NO signaling was impaired in response to caveolin downregulation, the pro-angiogenic effects of bFGF were increased in caveolin-deficient endothelial cells. A decrease in caveolin expression was concomitantly reported by us and others in the vasculature of different tumors, giving credential to a role of endogenous nitrite in the development of the tumor neovasculature and of the bFGF pathway as a key alternative mode of angiogenic progression in tumors. In conclusion, our work shows that some aspects of the tumor microenvironment (in particular those related to NO production and caveolin expression) may be either modulated or even exploited to develop strategies aiming to improve the efficacy of antitumor therapy including radio- and gene therapy.
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Frérart, F. (2008). Modulation and exploitation of the tumor microenvironment to improve anticancer therapies : focus on endothelial nitric oxide synthase and caveolin-1. https://hdl.handle.net/2078.5/112058