Skip to main content

Thank you for visiting 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.

  • Letter
  • Published:

Chemokine receptor CXCR4 downregulated by von Hippel–Lindau tumour suppressor pVHL


Organ-specific metastasis is governed, in part, by interactions between chemokine receptors on cancer cells and matching chemokines in target organs. For example, malignant breast cancer cells express the chemokine receptor CXCR4 and commonly metastasize to organs that are an abundant source of the CXCR4-specific ligand stromal cell-derived factor-1α (ref. 1). It is still uncertain how an evolving tumour cell is reprogrammed to express CXCR4, thus implementing the tendency to metastasize to specific organs. Here we show that the von Hippel–Lindau tumour suppressor protein pVHL negatively regulates CXCR4 expression owing to its capacity to target hypoxia-inducible factor (HIF) for degradation under normoxic conditions. This process is suppressed under hypoxic conditions, resulting in HIF-dependent CXCR4 activation. An analysis of clear cell renal carcinoma that manifests mutation of the VHL gene in most cases revealed an association of strong CXCR4 expression with poor tumour-specific survival. These results suggest a mechanism for CXCR4 activation during tumour cell evolution and imply that VHL inactivation acquired by incipient tumour cells early in tumorigenesis confers not only a selective survival advantage but also the tendency to home to selected organs.

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

Access options

Buy this article

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

Figure 1: pVHL and hypoxia regulate CXCR4 expression.
Figure 2: CXCR4 is a target gene of HIF.
Figure 3: pVHL suppresses SDF-1α-mediated chemotaxis of RCC cells.
Figure 4: CXCR4 expression in human renal cell carcinoma.

Similar content being viewed by others


  1. Müller, A. et al. Involvement of chemokine receptors in breast cancer metastasis. Nature 410, 50–56 (2001)

    Article  ADS  Google Scholar 

  2. Kaelin, W. G. Jr Molecular basis of the VHL hereditary cancer syndrome. Nature Rev. Cancer 2, 673–682 (2002)

    Article  CAS  Google Scholar 

  3. Semenza, G. L. HIF-1 and tumor progression: Pathophysiology and therapeutics. Trends Mol. Med. 8, S62–S67 (2002)

    Article  CAS  Google Scholar 

  4. Pugh, C. W. & Ratcliffe, P. J. The von Hippel–Lindau tumor suppressor, hypoxia-inducible factor-1 (HIF-1) degradation, and cancer pathogenesis. Semin. Cancer Biol. 13, 83–89 (2003)

    Article  CAS  Google Scholar 

  5. Iliopoulos, O., Levy, A. P., Jiang, C., Kaelin, W. G. Jr & Goldberg, M. A. Negative regulation of hypoxia-inducible genes by the von Hippel–Lindau protein. Proc. Natl Acad. Sci. USA 93, 10595–10599 (1996)

    Article  ADS  CAS  Google Scholar 

  6. Wiesener, M. S. et al. Constitutive activation of hypoxia-inducible genes related to overexpression of hypoxia-inducible factor-1α in clear cell renal carcinomas. Cancer Res. 61, 5215–5222 (2001)

    CAS  PubMed  Google Scholar 

  7. Mandriota, S. J. et al. HIF activation identifies early lesions in VHL kidneys: evidence for site-specific tumor suppressor function in the nephron. Cancer Cell 1, 459–468 (2002)

    Article  CAS  Google Scholar 

  8. Bleul, C. C. et al. The lymphocyte chemoattractant SDF-1 is a ligand for LESTR/fusin and blocks HIV-1 entry. Nature 382, 829–833 (1996)

    Article  ADS  CAS  Google Scholar 

  9. Oberlin, E. et al. The CXC chemokine SDF-1 is the ligand for LESTR/fusin and prevents infection by T-cell-line-adapted HIV-1. Nature 382, 833–835 (1996)

    Article  ADS  CAS  Google Scholar 

  10. Forster, R. et al. CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs. Cell 99, 23–33 (1999)

    Article  CAS  Google Scholar 

  11. Peled, A. et al. Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4. Science 283, 845–848 (1999)

    Article  ADS  CAS  Google Scholar 

  12. Chambers, A. F., Groom, A. C. & MacDonald, I. C. Dissemination and growth of cancer cells in metastatic sites. Nature Rev. Cancer 2, 563–572 (2002)

    Article  CAS  Google Scholar 

  13. Liotta, L. A. An attractive force in metastasis. Nature 410, 24–25 (2001)

    Article  ADS  CAS  Google Scholar 

  14. Clifford, S. C. et al. Contrasting effects on HIF-1α regulation by disease-causing pVHL mutations correlate with patterns of tumorigenesis in von Hippel–Lindau disease. Hum. Mol. Genet. 10, 1029–1038 (2001)

    Article  CAS  Google Scholar 

  15. Maxwell, P. H. et al. Hypoxia-inducible factor-1 modulates gene expression in solid tumors and influences both angiogenesis and tumor growth. Proc. Natl Acad. Sci. USA 94, 8104–8109 (1997)

    Article  ADS  CAS  Google Scholar 

  16. Nishita, M., Aizawa, H. & Mizuno, K. Stromal cell-derived factor 1α activates LIM kinase 1 and induces cofilin phosphorylation for T-cell chemotaxis. Mol. Cell. Biol. 22, 774–783 (2002)

    Article  CAS  Google Scholar 

  17. Arber, S. et al. Regulation of actin dynamics through phosphorylation of cofilin by LIM-kinase. Nature 393, 805–809 (1998)

    Article  ADS  CAS  Google Scholar 

  18. Aebersold, D. M. et al. Expression of hypoxia-inducible factor-1α: A novel predictive and prognostic parameter in the radiotherapy of oropharyngeal cancer. Cancer Res. 61, 2911–2916 (2001)

    CAS  PubMed  Google Scholar 

  19. Harris, A. L. Hypoxia—a key regulatory factor in tumour growth. Nature Rev. Cancer 2, 38–47 (2002)

    Article  CAS  Google Scholar 

  20. Semenza, G. Signal transduction to hypoxia-inducible factor 1. Biochem. Pharmacol. 64, 993–998 (2002)

    Article  CAS  Google Scholar 

  21. Rempel, S. A., Dudas, S., Ge, S. & Gutierrez, J. A. Identification and localization of the cytokine SDF1 and its receptor, CXC chemokine receptor 4, to regions of necrosis and angiogenesis in human glioblastoma. Clin. Cancer Res. 6, 102–111 (2000)

    CAS  PubMed  Google Scholar 

  22. Bernards, R. & Weinberg, R. A. A progression puzzle. Nature 418, 823 (2002)

    Article  ADS  CAS  Google Scholar 

  23. Hergovich, A., Lisztwan, J., Barry, R., Ballschmieter, P. & Krek, W. Regulation of microtubule stability by the von Hippel–Lindau tumour suppressor protein pVHL. Nature Cell Biol. 5, 64–70 (2003)

    Article  CAS  Google Scholar 

  24. Takahashi, Y., Takahashi, S., Shiga, Y., Yoshimi, T. & Miura, T. Hypoxic induction of prolyl 4-hydroxylase α (I) in cultured cells. J. Biol. Chem. 275, 14139–14146 (2000)

    Article  CAS  Google Scholar 

  25. Wang, G. L. & Semenza, G. L. Purification and characterization of hypoxia-inducible factor 1. J. Biol. Chem. 270, 1230–1237 (1995)

    Article  CAS  Google Scholar 

  26. Lisztwan, J. et al. Association of human CUL-1 and ubiquitin-conjugating enzyme CDC34 with the F-box protein p45(SKP2): Evidence for evolutionary conservation in the subunit composition of the CDC34-SCF pathway. EMBO J. 17, 368–383 (1998)

    Article  CAS  Google Scholar 

  27. Amara, A. et al. HIV coreceptor downregulation as antiviral principle: SDF-1α-dependent internalization of the chemokine receptor CXCR4 contributes to inhibition of HIV replication. J. Exp. Med. 186, 139–146 (1997)

    Article  CAS  Google Scholar 

  28. Moch, H. et al. High-throughput tissue microarray analysis to evaluate genes uncovered by cDNA microarray screening in renal cell carcinoma. Am. J. Pathol. 154, 981–986 (1999)

    Article  CAS  Google Scholar 

  29. Moch, H. et al. Prognostic utility of the recently recommended histologic classification and revised TNM staging system of renal cell carcinoma: A Swiss experience with 588 tumors. Cancer 89, 604–614 (2000)

    Article  CAS  Google Scholar 

  30. Pastorekova, S., Zavadova, Z., Kostal, M., Babusikova, O. & Zavada, J. A novel quasi-viral agent, MaTu, is a two-component system. Virology 187, 620–626 (1992)

    Article  CAS  Google Scholar 

Download references


We thank all members of the laboratory for discussions; K. Struckmann for providing the tumour RNA samples; G. Keller and B. Mohr for human GLUT3 and CXCR4 cDNAs, respectively; and R. Bernards, U. Muller, N. Hynes, G. Thomas and members of our laboratory for critically reading the manuscript. This work was supported by the Robert Wenner Award, the Dr Josef Steiner Foundation and the Novartis Research Foundation. H.M. is supported by a grant from the Swiss National Science Foundation. P.S. is supported by an EMBO long–term fellowship.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Wilhelm Krek.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Supplementary Figure 1: Gene expression profiles of A498(neo) versus A498(HA-pVHL30) cells (PPT 1989 kb)


Supplementary Table 2: Complete gene list of the microarray analysis of A498(neo) and A498(HA-pVHL30)-expressing cells (XLS 136 kb)


Supplementary Table 3: Expression of CXCR4, Glut-1 and CA 9 in clear cell and papillary RCC by quantitative PCR (DOC 19 kb)


Supplementary Table 4: Association of CXCR4 expression with differentiation grade and tumour stage in clear cell RCC by immunohistochemistry (DOC 19 kb)

Supplementary Figure and Table Legends (DOC 19 kb)

Supplementary Information: MIAME checklist for array analysis of A498(HA-pVHL30) vs. A489(neo) (DOC 34 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Staller, P., Sulitkova, J., Lisztwan, J. et al. Chemokine receptor CXCR4 downregulated by von Hippel–Lindau tumour suppressor pVHL. Nature 425, 307–311 (2003).

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI:


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


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