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.
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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.
The authors declare that they have no competing financial interests.
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)
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Staller, P., Sulitkova, J., Lisztwan, J. et al. Chemokine receptor CXCR4 downregulated by von Hippel–Lindau tumour suppressor pVHL. Nature 425, 307–311 (2003). https://doi.org/10.1038/nature01874
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