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Migration: VEGF suppresses invasion

Nature Reviews Cancer 12, 9 (01 September 2012) | doi:10.1038/nrc3345

Inhibition of vascular endothelial growth factor (VEGF) provides some initial benefit for patients with glioblastoma, but most tumours progress while on this therapy: Gabriele Bergers and colleagues asked why.

Lara Crow/NPG

Previous treatment studies in mouse models of glioblastoma have shown that VEGF inhibition can cause tumours to grow more invasively, with cells migrating along blood vessels. This pattern is also seen in ∼30% of relapsing human glioblastomas that are treated with the VEGF-blocking antibody bevacizumab. Bergers and colleagues had noted that VEGF is able to limit the migration of glioblastoma cells towards hepatocyte growth factor (HGF), a ligand for the pro-invasive receptor MET. To investigate this in vivo, they orthotopically injected mice with transformed mouse astrocytoma cells that lacked VEGF expression (VEGF-knockout (VEGFKO) cells), or that had normal levels of VEGF (glioblastoma-WT) or that overexpressed exogenous VEGF (VEGFKO–VEGF). As expected, the VEGFKO cells grew invasively along blood vessels, whereas the glioblastoma-WT cells produced angiogenic tumours with locally invasive cells. The VEGFKO–VEGF cells produced tightly packed tumours with smooth borders, suggesting few invasive cells. Although the levels of MET expression did not differ among these tumours, levels of phosphorylated MET were substantially different, with the highest levels evident in the VEGFKO cells. Similar high levels of phosphorylated MET were evident in biopsy samples from patients with glioblastoma who had relapsed while on bevacizumab therapy. So, what is the mechanism? Treatment of VEGFKO cells with HGF resulted in the phosphorylation of MET, and this was reduced by the addition of VEGF. The authors established that human and mouse glioblastoma cells express VEGF receptor 1 (VEGFR1) and VEGFR2, and neutralizing antibodies to these receptors indicated that the effect of VEGF on MET occurs via VEGFR2. Indeed, short hairpin RNAs (shRNAs) targeting Vegfr2 negated the effect of VEGF on MET phosphorylation. Immunoprecipitation in human glioblastoma cells revealed an interaction between MET and VEGFR2 that required the last 450 amino acids of the carboxy-terminal domain of VEGFR2. This interaction occurs independently of ligand, but proximal ligation studies indicated that stimulation with both HGF and VEGF might result in the binding of other proteins to a MET–VEGFR2 complex. Further analyses indicated that VEGF increases the recruitment of protein tyrosine phosphatase 1B (PTP1B) to the VEGFR2–MET complex, resulting in the dephosphorylation of MET.

patients with glioblastoma who express both MET and VEGFR2 on their tumour cells might benefit from treatments that block both VEGF and HGF signalling

Does this pathway have relevance in vivo? Mice injected with VEGFKO cells transduced with shRNAs to target Met developed tumours with reduced invasive growth. Part of this reduction is attributable to blocking a mesenchymal phenotype that becomes evident once MET is phosphorylated in the absence of VEGF. Indeed, mesenchymal markers were found in invasive glioblastoma cells in biopsy samples from patients with glioblastoma who relapsed on bevacizumab treatment.

These studies indicate that patients with glioblastoma who express both MET and VEGFR2 on their tumour cells might benefit from treatments that block both VEGF and HGF signalling. Similar findings have recently been published for neuroendocrine pancreatic cancer, indicating that this pathway is not unique to glioblastoma.

Nicola McCarthy

ORIGINAL RESEARCH PAPER

  1. Lu, K. V. et al. VEGF inhibits tumour cell invasion and mesenchymal transition through a MET/VEGFR2 complex. Cancer Cell 22, 21–35 (2012)
    Article | Article | PubMed | CAS |

FURTHER READING

  1. Sennino, B. et al. Supression of tumour invasion and metastasis by concurrent inhibition of c-Met and VEGF signaling in pancreatic neuroendocrine tumours. Cancer Disc. 2, 270–287 (2012)
    Article | Article | CAS |

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