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Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases

Nature Reviews Drug Discovery volume 10, pages 417–427 (2011)Cite this article

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Abstract

Despite having an abundant number of vessels, tumours are usually hypoxic and nutrient-deprived because their vessels malfunction. Such abnormal milieu can fuel disease progression and resistance to treatment. Traditional anti-angiogenesis strategies attempt to reduce the tumour vascular supply, but their success is restricted by insufficient efficacy or development of resistance. Preclinical and initial clinical evidence reveal that normalization of the vascular abnormalities is emerging as a complementary therapeutic paradigm for cancer and other vascular disorders, which affect more than half a billion people worldwide. Here, we discuss the mechanisms, benefits, limitations and possible clinical translation of vessel normalization for cancer and other angiogenic disorders.

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Figure 1: Tumour vessels are structurally and functionally abnormal.
Figure 2: Molecular changes leading to abnormal vessels.
Figure 3: Potential targets and strategies for vascular normalization.

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Acknowledgements

We would like to thank D. G. Duda, S. Goel, E. Dejana, H. Augustin and L. Claesson-Welsch for their insightful comments and L. Notebaert for help with the illustrations. The work of P.C. is supported by grant IUAP06/30 from the Federal Government Belgium; by long-term structural Methusalem funding by the Flemish Government; by grant GOA2006/11 from the Concerted Research Activities (Belgium); and by a grant from The Research Foundation — Flanders (FWO; FWO G.0673.08). The research of R.K.J. is supported by US National Institutes of Health grants P01-CA80124, R01-CA85140, R01-CA115767 and R01-CA126642; by Federal Share/NCI Proton Beam Program Income; and by a National Foundation for Cancer Research and Department of Defense Breast Cancer Research Innovator Award (W81XWH-10-1-0016).

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Authors and Affiliations

  1. Peter Carmeliet is at the Vesalius Research Center, VIB, K. U. Leuven, Campus Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium.,

    Peter Carmeliet

  2. Department of Radiation Oncology, Rakesh K. Jain is at the Edwin L. Steele Laboratory for Tumour Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.,

    Rakesh K. Jain

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  1. Peter Carmeliet
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Correspondence to Peter Carmeliet or Rakesh K. Jain.

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Competing interests

P.C. is a named inventor on patent applications claiming subject matter that is partially based on the results described in this paper, which may result in royalty payments. He is a consultant to and has received speaker fees from Hoffman-La Roche, and is a consultant for, received research grants and holds stocks from Thrombogenics. He is a member of the Science Advisory Board.

R.K.J. has received research grants from Dyax, MedImmune and Roche; has served as a consultant for AstraZeneca, Astellas, Dyax, Genzyme, Noxxon and SynDevRx; has received an honoraium for a lecture given at MPM Capital; is on the scientific advisory boards of Enlight and SynDevRx; and is on the board of trustees for H&Q Capital Management.

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Carmeliet, P., Jain, R. Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Nat Rev Drug Discov 10, 417–427 (2011). https://doi.org/10.1038/nrd3455

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