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Jul 9, 2012

Fighting Brain Tumors by Inhibiting MET

  • Treating glioblastoma multiforme (GBM) patients using a MET inhibitor in addition to VEGF inhibitors such as the monoclonal antibody bevacizumab may help prevent the recurrence of more invasive and surgically inoperable tumors, researchers suggest.

    In vitro and in vivo studies by a team at the UCSF Comprehensive Cancer Center have shown that VEGF negatively regulates tumor cell invasion via a pathway that suppresses HGF-dependent MET phosphorylation and hence tumor cell migration. In effect, they claim, blocking VEGF increases MET activity in GBM cells and triggers the cancer cells to undergo an epithelial-to-mesenchymal transition-like transformation and develop an invasive phenotype and genotype. The team’s studies showed that inhibition of MET in mouse models of VEGF-inhibited GBM blocked this mesenchymal transition and invasive capability and increased survival.

    Gabriele Bergers, M.D., and colleagues claim that as well as having implications for the treatment of GBM patients, their findings suggest that the combined therapeutic approach may have utility against other cancers that feature active VEGF and HGF-MET signaling pathways. Their results are reported in Cancer Cell, in a paper titled “VEGF Inhibits Tumor Cell Invasion and Mesenchymal Transition through a MET/VEGFR2 Complex.”

    The monoclonal antibody bevacizumab is approved for treating GBM in patients with recurrent disease and is being tested as frontline therapy. However, treated patients invariably develop new tumors despite continued VEGF inhibition. Up to 30% of patients given bevacizumab will eventually develop diffuse and invasive tumors that form as the result of cancer cells moving along blood vessels deep in the brain parenchyma.

    Previous work by the UCSF team had identified a link between HGF and VEGF, and suggested that VEGF reduces the ability of GBM cells to move toward HGF in vitro. Given that the HGF receptor MET is frequently deregulated in many cancers and correlates with increased tumor invasiveness, the team looked at whether VEGF might directly regulate GBM invasion through its regulation of MET.

    Their initial in vitro results showed that VEGF directly antagonized the HGF/MET signaling pathway and reduced both murine and human GBM cell migration and invasiveness via a mechanism that involved a physical interaction between MET and the VEGF receptor VEGFR2. Further assays demonstrated that VEGF enhanced recruitment of the nonreceptor protein tyrosine phosphatise 1B (PTP1B) to MET, triggering dephosphorylation of HGF-induced phosphorylated MET.

    The authors then postulated that MET inhibition might act to suppress the increase in tumor invasion triggered by blocking or knocking down VEGF. Indeed, studies in experimental mice confirmed that brain tumors formed from VEGF-knockout cancer cells that had been transfected with an anti-MET siRNA (VEGFKO-shMET1) were far less invasive than tumors growing from VEGF-knockout cells that retained MET activity (VEGFKO cells). The VEGFKO-shMET1 tumors continued to grow as a solid mass even in the latter stages, whereas the VEGFKO tumors developed an extensive perivascular invasive phenotype and, interestingly, demonstrated a higher proliferation in vivo. “These results underscore MET as a critical driver of GBM invasion and strongly encourage combined anti-VEGF and anti-MET therapy for GBM patients,” the authors write.

    Notably, in vitro assays showed that knocking down VEGF in cancer cells led to a change in their fibroblast-like morphology to one more akin that of epithelial cells undergoing mesenchymal-to-epithelial transition (EMT), and gradual upregulation of EMT markers. This change in gene-expression patterns was blocked in HGF-stimulated VEGFKO cells transfected with an MET shRNA, again supporting a key role for MET activity. And although mice carrying wild-type GBM tumors survived longer when treated with an anti-VEGF antibody, they also demonstrated increased cell invasion at the tumor periphery, and these invasive cells stained strongly for activated MET. This finding suggests that the increase in MET activity in response to VEGF ablation isn’t triggered by hypoxia resulting from reduced vessel density, as the edges of tumors aren’t hypoxic.

    Finally, the team looked at tumor specimens from GBM patients both before and after bevacizumab therapy. These results confirmed that the antibody treatment was associated with an increase in mesenchymal marker expression and phosphorylated MET-positive invasive cell clusters. “These results suggest that human GBM treated with targeted VEGF therapy may progress by switching to a more mesenchymal phenotype involving upregulation of MET activity and expression of key mesenchymal genes and markers.

    “These studies together suggest that one might be able to select GBM patients up front who may likely develop a proinvasive recurrence during bevacizumab treatment by evaluating MET and VEGFR2 expression in the tumor,” the authors conclude. “As we found VEGFR2 and MET expression on various tumor cell types besides GBM, combined VEGF and MET inhibition might also be useful in other cancer types.”


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