New Insight into Mechanism of VEGF Inhibitors

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angiogenesisVascular endothelial growth factor (VEGF) is an important signalling molecule which contributes to angiogenesis. Since angiogenesis is believed to be essential for the growth and metastasis of tumours, blocking the VEGF pathway is considered to be a viable antitumor strategy and both antibodies to VEGF and small molecule inhibitors of VEGF-stimulated tyrosine kinases are used as chemotherapy. Now, a study carried out by researchers at the University of California suggests that dense networks of blood vessels formed during angiogenesis could impede rather than promote the growth of tumours. Inflammatory cells, which infiltrate many tumours, provide a source of VEGF and the team created a strain of mice in which most of the inflammatory cells lacked the gene for VEGF. These mice were then crossed with a strain of mice which reliably develop mammary tumours. Although blood supply to the tumours in the VEGF-deficient mice was reduced, the blood vessels looked more normally organised and less leaky than in the non-engineered mice.

All of the mice developed tumours by 20 weeks of age, but the mice with low levels of VEGF had larger growths that were more likely to have progressed to a later stage of cancer. Although the tumours grew faster in the VEGF-deficient mice, importantly, they were also more susceptible to two different chemotherapy drugs. The study suggests a reason why blocking the effect of VEGF is less effective as monotherapy for cancer than when used in combination with traditional chemotherapy drugs: reduced levels of VEGF lead to more normal blood vessels that are better able to deliver the drugs to the tumour. The findings are published in the 9 November online edition of the journal, Nature.

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