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

Peter Staller1, Jitka Sulitkova, Joanna Lisztwan

  • 1Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland.

Nature
|September 19, 2003
PubMed

Insights

The von Hippel-Lindau protein (pVHL) controls cancer cell metastasis by regulating CXCR4 expression. VHL inactivation promotes CXCR4 activation, guiding tumor cells to specific organs.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Metastasis Research

Background:

  • Organ-specific metastasis is influenced by chemokine receptors on cancer cells and chemokines in target organs.
  • Malignant breast cancer cells express CXCR4, often metastasizing to organs rich in its ligand, stromal cell-derived factor-1alpha.
  • The mechanism by which tumors acquire CXCR4 expression for organ-specific metastasis remains unclear.

Purpose of the Study:

  • To elucidate the role of the von Hippel-Lindau tumor suppressor protein (pVHL) in regulating CXCR4 expression.
  • To investigate the link between hypoxia-inducible factor (HIF), pVHL, and CXCR4 activation in tumor cells.
  • To determine the clinical significance of VHL gene mutations and CXCR4 expression in clear cell renal carcinoma.

Main Methods:

  • Investigated the interaction between pVHL and hypoxia-inducible factor (HIF) under normoxic and hypoxic conditions.
  • Assessed the impact of pVHL's regulatory function on CXCR4 expression.
  • Analyzed VHL gene status and CXCR4 expression in clear cell renal carcinoma patient samples.

Main Results:

  • pVHL negatively regulates CXCR4 expression by targeting HIF for degradation under normoxia.
  • Hypoxic conditions inhibit pVHL, leading to HIF-dependent activation of CXCR4.
  • Strong CXCR4 expression in clear cell renal carcinoma correlates with poor tumor-specific survival, linked to VHL gene mutations.

Conclusions:

  • pVHL inactivation promotes CXCR4 activation during tumor evolution, facilitating organ-specific metastasis.
  • Early VHL inactivation in tumors provides a survival advantage and directs metastatic potential.
  • This mechanism highlights a critical pathway linking tumor suppressor function to metastatic tropism.

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