METASTASIS Trigger to Roam

Many cancers are deadly because the malignant cells metastasize to distant regions of the body. Metastases to particular organs can involve the cancer cell expressing receptors for a chemokine produced by the target tissue, but the mechanisms whereby cancer cells are triggered to express such "molecular homing devices" are unclear. Hypoxia--which occurs when tumors outgrow their blood supply--provides a metastatic trigger through the transcription factor HIF (hypoxia-inducible factor). When oxygen supply is normal, the protein product of the von Hippel-Lindau tumor suppressor gene (pVHL) participates in degradation of the HIF subunit; during hypoxia, HIF levels rise, as do the levels of HIF target genes. Staller et al. used DNA microarray analysis to identify genes regulated by pVHL, which is inactivated in various cancers. When transfected into pVHL-deficient renal cell carcinoma (RCC) cells, pVHL suppressed expression of CXCR4 (a chemokine receptor associated with bone metastases in breast cancer). Functional pVHL suppressed CXCR4 mRNA expression in RCC cells and CXCR4 mRNA levels increased in response to hypoxia in pVHL-positive cell lines. Stromal cell-derived factor-1 (SDF-1, the ligand for CXCR4) activated CXCR4 signaling pathways involving LIM kinase 1 and extracellular signal-related kinases and stimulated RCC cell migration, responses that were inhibited by pVHL. The authors used quantitative reverse transcription polymerase chain reaction, as well as tissue microarray immunohistochemistry, to show that CXCR4 was overexpressed in human renal clear cell tumors. Moreover, strong CXCR4 expression correlated with poor tumor-specific survival. Bernards provides background information and discusses the implications with regard to when during cancer development tumor cells acquire the capacity to metastasize.

P. Staller, J. Sulitkova, J. Lisztwan, H. Moch, E. J. Oakeley, W. Krek, Chemokine receptor CXCR4 downregulated by von Hippel-Lindau tumour suppressor pVHL. Nature 425, 307-311 (2003). [Online Journal]

R. Bernards, Cues for migration. Nature 425, 247-248 (2003). [Online Journal]