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PDGFRβ+ perivascular progenitor cells in tumours regulate pericyte differentiation and vascular survival

Nature Cell Biology volume 7, pages 870–879 (2005)Cite this article

Abstract

The microvasculature consists of endothelial cells and their surrounding pericytes. Few studies on the regulatory mechanisms of tumour angiogenesis have focused on pericytes. Here we report the identification of tumour-derived PDGFRβ+ (platelet-derived growth factor receptor β) progenitor perivascular cells (PPCs) that have the ability to differentiate into pericytes and regulate vessel stability and vascular survival in tumours. A subset of PDGFRβ+ PPCs is recruited from bone marrow to perivascular sites in tumours. Specific inhibition of PDGFRβ signalling eliminates PDGFRβ+ PPCs and mature pericytes around tumour vessels, leading to vascular hyperdilation and endothelial cell apoptosis in pancreatic islet tumours of transgenic Rip1Tag2 mice.

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Figure 1: PDGFRβ+ cells are perivascular cells (PDGFRβ+ PVC) but are distinct from mature pericytes in tumours.
Figure 2: PDGFRβ+ cells differentiate into mature pericytes in vitro.
Figure 3: PDGFRβ+ cells and endothelial cells in co-culture form pericyte-covered vascular tubes.
Figure 4: Tumour-associated PDGFRβ+ PPCs originate from bone-marrow-derived haematopoietic Sca1+ cells.
Figure 5: Inhibition of PDGFRβ signalling depletes pericytes and increases endothelial cell apoptosis.
Figure 6: PDGFRβ+ cells support vascular tube stability and survival.

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Acknowledgements

We thank N. Boudreau for valuable discussions and advice, D. Hanahan for RipTag2-Rag1ko/ko mice, N. Korets for excellent technical assistance, A. McMillan for statistical analysis, and S. Reynolds for help with the manuscript preparation. This work was supported by grants from the National Institutes of Health (R01 CA109390, R01 CA99948, RO1 CA95287, P01 CA72006), by an NIH Institutional NRSA fellowship to A.J.E. (5T32HL007731), by a grant from the American Cancer Society, and by start-up funds to G.B. from the Department of Neurological Surgery at UCSF.

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Authors and Affiliations

  1. Departments of Neurological Surgery, UCSF Comprehensive Cancer Center, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, 94143, CA, USA

    Steven Song & Gabriele Bergers

  2. Anatomy,UCSF Comprehensive Cancer Center, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, 94143, CA, USA

    Andrew J. Ewald & Zena Werb

  3. Brain Tumor Research Center, UCSF Comprehensive Cancer Center, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, 94143, CA, USA

    Steven Song & Gabriele Bergers

  4. UCSF Comprehensive Cancer Center, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, 94143, CA, USA

    Zena Werb & Gabriele Bergers

  5. Cancer Research Center, Burnham Institute, 10901 North Torrey Pines Road, 92037, CA, La Jolla, USA

    William Stallcup

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Correspondence to Gabriele Bergers.

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Song, S., Ewald, A., Stallcup, W. et al. PDGFRβ+ perivascular progenitor cells in tumours regulate pericyte differentiation and vascular survival. Nat Cell Biol 7, 870–879 (2005). https://doi.org/10.1038/ncb1288

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