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Perivascular nitric oxide gradients normalize tumor vasculature


Normalization of tumor vasculature is an emerging strategy to improve cytotoxic therapies. Here we show that eliminating nitric oxide (NO) production from tumor cells via neuronal NO synthase silencing or inhibition establishes perivascular gradients of NO in human glioma xenografts in mice and normalizes the tumor vasculature, resulting in improved tumor oxygenation and response to radiation treatment. Creation of perivascular NO gradients may be an effective strategy for normalizing abnormal vasculature.

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Figure 1: Effects of NOS1 silencing in U87MG cells on NO distribution, vessel morphology and function in tumors.
Figure 2: Effects of nNOS silencing in U87MG cells on tumor tissue oxygenation and the efficacy of fractionated radiation therapy.


  1. Fukumura, D. & Jain, R.K. Microvasc. Res. 74, 72–84 (2007).

    CAS  Article  Google Scholar 

  2. Jain, R.K. Science 307, 58–62 (2005).

    CAS  Article  Google Scholar 

  3. Fukumura, D., Kashiwagi, S. & Jain, R.K. Nat. Rev. Cancer 6, 521–534 (2006).

    CAS  Article  Google Scholar 

  4. Kashiwagi, S. et al. J. Clin. Invest. 115, 1816–1827 (2005).

    CAS  Article  Google Scholar 

  5. Yu, J. et al. Proc. Natl. Acad. Sci. USA 102, 10999–11004 (2005).

    CAS  Article  Google Scholar 

  6. Gerhardt, H. & Betsholtz, C. Cell Tissue Res. 314, 15–23 (2003).

    Article  Google Scholar 

  7. Abramsson, A., Lindblom, P. & Betsholtz, C. J. Clin. Invest. 112, 1142–1151 (2003).

    CAS  Article  Google Scholar 

  8. van der Zee, R. et al. Circulation 95, 1030–1037 (1997).

    CAS  Article  Google Scholar 

  9. Babaei, S. et al. Am. J. Pathol. 162, 1927–1936 (2003).

    CAS  Article  Google Scholar 

  10. Igarashi, J., Bernier, S.G. & Michel, T. J. Biol. Chem. 276, 12420–12426 (2001).

    CAS  Article  Google Scholar 

  11. Dulak, J. et al. Arterioscler. Thromb. Vasc. Biol. 20, 659–666 (2000).

    CAS  Article  Google Scholar 

  12. Ziche, M. et al. Circ. Res. 80, 845–852 (1997).

    CAS  Article  Google Scholar 

  13. Hall, E.J. & Giaccia, A.J. Radiobiology for the Radiobiologist 85–105 (Lippincott, Williams & Wilkins, Philadelphia, 2006).

  14. Mitchell, J.B. Cancer Res. 53, 5845–5848 (1993).

    CAS  PubMed  Google Scholar 

  15. Pou, S., Pou, W.S., Bredt, D.S., Snyder, S.H. & Rosen, G.M. J. Biol. Chem. 267, 24173–24176 (1992).

    CAS  PubMed  Google Scholar 

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We thank H.D. Suit and K.D. Held for their insightful suggestions; L.L. Munn, D. Fuja and C.D. Ley for their assistance in image analysis; D. Laccore for her assistance in hypoxia detection; S.S. Chae for his assistance in western blot analysis; P. Huang for his direction of the gnotobiotic animal facility; and M. Fortier, J. Kahn, M. Riley, S. Roberge, E. Smith and C. Smith for their excellent technical assistance. This work was supported by National Cancer Institute grants R01-CA96915 (D.F.) and P01-CA80124 (R.K.J. and D.F.).

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S.K. performed most of the experiments; K.T. and J.M. performed intravital microscopy and animal studies; L.X. contributed to mutant cell generation and molecular analysis; S.V.K. and L.E.G. contributed to radiation studies and writing; J.A.T. contributed to image analysis; W.C.S. contributed to the cavtratin study; S.K., R.K.J. and D.F. designed the study, analyzed the data and wrote the manuscript.

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Correspondence to Dai Fukumura.

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Supplementary Figs. 1–6 and Supplementary Methods (PDF 6364 kb)

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Kashiwagi, S., Tsukada, K., Xu, L. et al. Perivascular nitric oxide gradients normalize tumor vasculature. Nat Med 14, 255–257 (2008).

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