Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

  1. Sims, D. E. Diversity within pericytes. Clin. Exp. Pharmacol. Physiol. 27, 842–846 (2000).

    Article  CAS  Google Scholar 

  2. Gerhardt, H. & Betsholtz, C. Endothelial-pericyte interactions in angiogenesis. Cell Tissue Res. 314, 15–23 (2003).

    Article  Google Scholar 

  3. Cleaver, O. & Melton, D. A. Endothelial signaling during development. Nature Med. 9, 661–668 (2003).

    Article  CAS  Google Scholar 

  4. Hirschi, K. K. & D'Amore, P. A. Pericytes in the microvasculature. Cardiovasc. Res. 32, 687–698 (1996).

    Article  CAS  Google Scholar 

  5. Bergers, G. & Benjamin, L. E. Tumorigenesis and the angiogenic switch. Nature Rev. Cancer 3, 401–410 (2003).

    Article  CAS  Google Scholar 

  6. Yancopoulos, G. D. et al. Vascular-specific growth factors and blood vessel formation. Nature 407, 242–248 (2000).

    Article  CAS  Google Scholar 

  7. Betsholtz, C., Lindblom, P. & Gerhardt, H. Role of pericytes in vascular morphogenesis. EXS 94, 115–125 (2005).

    Google Scholar 

  8. Ozerdem, U. & Stallcup, W. B. Early contribution of pericytes to angiogenic sprouting and tube formation. Angiogenesis 6, 241–249 (2003).

    Article  CAS  Google Scholar 

  9. Hirschi, K. K., Rohovsky, S. A. & D'Amore, P. A. PDGF, TGF-β, and heterotypic cell-cell interactions mediate endothelial cell-induced recruitment of 10T1/2 cells and their differentiation to a smooth muscle fate. J. Cell Biol. 141, 805–814 (1998).

    Article  CAS  Google Scholar 

  10. Hellstrom, M., Kalen, M., Lindahl, P., Abramsson, A. & Betsholtz, C. Role of PDGF-B and PDGFR-β in recruitment of vascular smooth muscle cells and pericytes during embryonic blood vessel formation in the mouse. Development 126, 3047–3055 (1999).

    CAS  PubMed  Google Scholar 

  11. Betsholtz, C., Karlsson, L. & Lindahl, P. Developmental roles of platelet-derived growth factors. Bioessays 23, 494–507 (2001).

    Article  CAS  Google Scholar 

  12. Leveen, P. et al. Mice deficient for PDGF B show renal, cardiovascular, and hematological abnormalities. Genes Dev. 8, 1875–1887 (1994).

    Article  CAS  Google Scholar 

  13. Lindahl, P., Johansson, B., Leveen, P. & Betsholtz, C. Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science 126, 3047–3055 (1997).

    Google Scholar 

  14. Hellstrom, M. et al. Lack of pericytes leads to endothelial hyperplasia and abnormal vascular morphogenesis. J. Cell Biol. 153, 543–553 (2001).

    Article  CAS  Google Scholar 

  15. Enge, M. et al. Endothelium-specific platelet-derived growth factor-B ablation mimics diabetic retinopathy. EMBO J. 21, 4307–4316 (2002).

    Article  CAS  Google Scholar 

  16. Hirschi, K. K., Rohovsky, S. A., Beck, L. H., Smith, S. R. & D'Amore, P. A. Endothelial cells modulate the proliferation of mural cell precursors via platelet-derived growth factor-BB and heterotypic cell contact. Circ. Res. 84, 298–305 (1999).

    Article  CAS  Google Scholar 

  17. Fukushi, J., Makagiansar, I. T. & Stallcup, W. B. NG2 proteoglycan promotes endothelial cell motility and angiogenesis via engagement of galectin-3 and α3β1 integrin. Mol. Biol. Cell 15, 3580–3590 (2004).

    Article  CAS  Google Scholar 

  18. Benjamin, L., Hemo, I. & Keshet, E. A plasticity window for blood vessel remodelling is defined by pericyte coverage of the preformed endothelial network and is regulated by PDGF-B and VEGF. Development 125, 1591–1598 (1998).

    CAS  PubMed  Google Scholar 

  19. Morikawa, S. et al. Abnormalities in pericytes on blood vessels and endothelial sprouts in tumors. Am. J. Pathol. 160, 985–1000 (2002).

    Article  Google Scholar 

  20. Bergers, G., Song, S., Meyer-Morse, N., Bergsland, E. & Hanahan, D. Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J. Clin. Invest. 111, 1287–1295 (2003).

    Article  CAS  Google Scholar 

  21. Reinmuth, N. et al. Induction of VEGF in perivascular cells defines a potential paracrine mechanism for endothelial cell survival. Faseb. J. 15, 1239–1241 (2001).

    Article  CAS  Google Scholar 

  22. Shaheen, R. M. et al. Tyrosine kinase inhibition of multiple angiogenic growth factor receptors improves survival in mice bearing colon cancer liver metastases by inhibition of endothelial cell survival mechanisms. Cancer Res. 61, 1464–1468 (2001).

    CAS  PubMed  Google Scholar 

  23. Heldin, C. H. & Westermark, B. Mechanism of action and in vivo role of platelet-derived growth factor. Physiol. Rev. 79, 1283–1316 (1999).

    Article  CAS  Google Scholar 

  24. Betsholtz, C. Insight into the physiological functions of PDGF through genetic studies in mice. Cytokine Growth Factor Rev. 15, 215–218 (2004).

    Article  CAS  Google Scholar 

  25. Parangi, S. et al. Antiangiogenic therapy of transgenic mice impairs de novo tumor growth. Proc. Natl Acad. Sci. USA 93, 2002–2007 (1996).

    Article  CAS  Google Scholar 

  26. Bergers, G., Hanahan, D. & Coussens, L. M. Angiogenesis and apoptosis are cellular parameters of neoplastic progression in transgenic mouse models of tumorigenesis. Int. J. Dev. Biol. 42, 995–1002 (1998).

    CAS  PubMed  Google Scholar 

  27. Bondjers, C. et al. Transcription profiling of platelet-derived growth factor-B-deficient mouse embryos identifies RGS5 as a novel marker for pericytes and vascular smooth muscle cells. Am. J. Pathol. 162, 721–729 (2003).

    Article  CAS  Google Scholar 

  28. Cho, H., Kozasa, T., Bondjers, C., Betsholtz, C. & Kehrl, J. H. Pericyte-specific expression of Rgs5: implications for PDGF and EDG receptor signaling during vascular maturation. Faseb. J. 17, 440–442 (2003).

    Article  CAS  Google Scholar 

  29. Kanamori, M., Vanden Berg, S. R., Bergers, G., Berger, M. S. & Pieper, R. O. Integrin β3 overexpression suppresses tumor growth in a human model of gliomagenesis: implications for the role of β3 overexpression in glioblastoma multiforme. Cancer Res. 64, 2751–2758 (2004).

    Article  CAS  Google Scholar 

  30. Nishishita, T. & Lin, P. C. Angiopoietin 1, PDGF-B, and TGF-β gene regulation in endothelial cell and smooth muscle cell interaction. J. Cell. Biochem. 91, 584–593 (2004).

    Article  CAS  Google Scholar 

  31. Darland, D. C. & D'Amore, P. A. Cell-cell interactions in vascular development. Curr. Top. Dev. Biol. 52, 107–149 (2001).

    Article  CAS  Google Scholar 

  32. Chen, S. & Lechleider, R. J. Transforming growth factor-β-induced differentiation of smooth muscle from a neural crest stem cell line. Circ. Res. 94, 1195–1202 (2004).

    Article  CAS  Google Scholar 

  33. Rajantie, I. et al. Adult bone marrow-derived cells recruited during angiogenesis comprise precursors for periendothelial vascular mural cells. Blood 104, 2084–2086 (2004).

    Article  CAS  Google Scholar 

  34. Ding, R., Darland, D. C., Parmacek, M. S. & D'Amore, P. A. Endothelial-mesenchymal interactions in vitro reveal molecular mechanisms of smooth muscle/pericyte differentiation. Stem Cells Dev. 13, 509–520 (2004).

    Article  CAS  Google Scholar 

  35. Abramsson, A. et al. Analysis of mural cell recruitment to tumor vessels. Circulation 105, 112–117 (2002).

    Article  CAS  Google Scholar 

  36. Lyden, D. et al. Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nature Med. 7, 1194–1201 (2001).

    Article  CAS  Google Scholar 

  37. Rabbany, S. Y., Heissig, B., Hattori, K. & Rafii, S. Molecular pathways regulating mobilization of marrow-derived stem cells for tissue revascularization. Trends Mol. Med. 9, 109–117 (2003).

    Article  CAS  Google Scholar 

  38. Benjamin, L. E., Golijanin, D., Itin, A., Pode, D. & Keshet, E. Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal [see comments]. J. Clin. Invest. 103, 159–165 (1999).

    Article  CAS  Google Scholar 

  39. Pietras, K. & Hanahan, D. A multitargeted, metronomic, and maximum-tolerated dose “chemo-switch” regimen is antiangiogenic, producing objective responses and survival benefit in a mouse model of cancer. J. Clin. Oncol. 23, 939–952 (2004).

    Article  Google Scholar 

  40. Ozerdem, U., Grako, K. A., Dahlin-Huppe, K., Monosov, E. & Stallcup, W. B. NG2 proteoglycan is expressed exclusively by mural cells during vascular morphogenesis. Dev. Dyn. 222, 218–227 (2001).

    Article  CAS  Google Scholar 

  41. Naik, P., Karrim, J. & Hanahan, D. The rise and fall of apoptosis during multistage tumorigenesis: down-modulation contributes to progression from angiogenic progenitors. Genes Dev. 10, 2105–2116 (1996).

    Article  CAS  Google Scholar 

  42. Ades, E. W. et al. HMEC-1: establishment of an immortalized human microvascular endothelial cell line. J. Invest. Dermatol. 99, 683–690 (1992).

    Article  CAS  Google Scholar 

  43. Radvanyi, F., Christgau, S., Baekkeskov, S., Jolicoeur, C. & Hanahan, D. Pancreatic β cells cultured from individual preneoplastic foci in a multistage tumorigenesis pathway: a potentially general technique for isolating physiologically representative cell lines. Mol. Cell. Biol. 13, 4223–4232 (1993).

    Article  CAS  Google Scholar 

Download references

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.

Author information

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

Authors
  1. Steven Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andrew J. Ewald
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. William Stallcup
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zena Werb
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gabriele Bergers
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gabriele Bergers.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary figures S1, S2 and S3 (PDF 544 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb1288

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing