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Vascular normalization in Rgs5-deficient tumours promotes immune destruction

Nature volume 453, pages 410–414 (2008)Cite this article

Abstract

The vasculature of solid tumours is morphologically aberrant and characterized by dilated and fragile vessels, intensive vessel sprouting and loss of hierarchical architecture1. Constant vessel remodelling leads to spontaneous haemorrhages2 and increased interstitial fluid pressure in the tumour environment3,4. Tumour-related angiogenesis supports tumour growth and is also a major obstacle for successful immune therapy as it prevents migration of immune effector cells into established tumour parenchyma2,5,6. The molecular mechanisms for these angiogenic alterations are largely unknown. Here we identify regulator of G-protein signalling 5 (Rgs5) as a master gene responsible for the abnormal tumour vascular morphology in mice. Loss of Rgs5 results in pericyte maturation, vascular normalization and consequent marked reductions in tumour hypoxia and vessel leakiness. These vascular and intratumoral changes enhance influx of immune effector cells into tumour parenchyma and markedly prolong survival of tumour-bearing mice. This is the first demonstration, to our knowledge, of reduced tumour angiogenesis and improved immune therapeutic outcome on loss of a vascular gene function and establishes a previously unrecognized role of G-protein signalling in tumour angiogenesis.

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Figure 1: Establishment of Rgs5 -/- mice.
Figure 2: Vascular normalization in Rgs5 -deficient tumours.
Figure 3: Improved oxygenation and reduced vessel leakiness in Rgs5 -/- tumours.
Figure 4: Immune-mediated tumour rejection after vascular normalization.

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Acknowledgements

We thank G. Küblbeck, A. Klevenz, G. Hollman and S. Schmidt for technical support in establishing Rgs5-knockout mice, K. Bieber for assessing brain ischaemia, B. Misselwitz for providing the contrast agent Gadomer, and H. Ee and G. Bergers for critical reading of the manuscript. This study was supported by a National Health and Medical Research Council of Australia Project Grant, start-up funds from the Western Australian Institute for Medical Research and University of Western Australia (to R.G.), the Deutsche Forschungsgemeinschaft, and the EU projects MUGEN and CancerImmunoTherapy. Microscopy was carried out using facilities at the Centre for Microscopy and Microanalysis/Biomedical Image and Analysis Facility, The University of Western Australia, which are supported by University, State and Federal Government funding.

Author Contributions J.H. and M.M. performed animal experiments and histology, and analysed data; M.J. and F.K. performed MRI analyses; P.R. performed confocal microscopy studies; H.H.M and T.R. coordinated and analysed brain infarct experiments; S.K. and H.-J.G. performed electron microscopy; G.J.H. and B.A. contributed to the design of Rgs5-knockout studies; and R.G. designed and performed experiments, coordinated all studies and wrote the manuscript.

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Authors and Affiliations

  1. Western Australian Institute for Medical Research, UWA Centre for Medical Research, Perth, Western Australia 6000, Australia,

    Juliana Hamzah, Mitali Manzur & Ruth Ganss

  2. Department of Medical Physics in Radiology,, Juniorgroup Molecular Imaging,

    Manfred Jugold & Fabian Kiessling

  3. Department of Cellular and Molecular Pathology, and,

    Sylvia Kaden & Hermann-Josef Gröne

  4. Department of Molecular Immunology, German Cancer Research Center, 69120 Heidelberg, Germany,

    Günter J. Hämmerling & Bernd Arnold

  5. Centre for Microscopy, Characterisation and Analysis, The University of Western Australia, Perth, Western Australia 6000, Australia,

    Paul Rigby

  6. Institute of Physiology and Pathophysiology, University of Heidelberg, 69120 Heidelberg, Germany

    Hugo H. Marti & Tamer Rabie

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  1. Juliana Hamzah
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Correspondence to Ruth Ganss.

Supplementary information

Supplementary information

This file contains Supplementary Figures 1-6 with Legends and Supplementary Table 1. This file was updated on 16 May 2008 to include Supplementary Table 1 which was inadvertently omitted in production. (PDF 905 kb)

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Hamzah, J., Jugold, M., Kiessling, F. et al. Vascular normalization in Rgs5-deficient tumours promotes immune destruction. Nature 453, 410–414 (2008). https://doi.org/10.1038/nature06868

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