These authors contributed equally to this study.
Differential drug class-specific metastatic effects following treatment with a panel of angiogenesis inhibitors†
Version of Record online: 3 JUL 2012
Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
The Journal of Pathology
Volume 227, Issue 4, pages 404–416, August 2012
How to Cite
Chung, A. S., Kowanetz, M., Wu, X., Zhuang, G., Ngu, H., Finkle, D., Komuves, L., Peale, F. and Ferrara, N. (2012), Differential drug class-specific metastatic effects following treatment with a panel of angiogenesis inhibitors. J. Pathol., 227: 404–416. doi: 10.1002/path.4052
Conflict of interest: the authors are employees of Genentech Inc.
- Issue online: 10 JUL 2012
- Version of Record online: 3 JUL 2012
- Accepted manuscript online: 18 MAY 2012 09:17AM EST
- Manuscript Accepted: 10 MAY 2012
- Manuscript Revised: 4 MAY 2012
- Manuscript Received: 9 APR 2012
Inhibiting angiogenesis has become an important therapeutic strategy for cancer treatment but, like other current targeted therapies, benefits experienced for late-stage cancers can be curtailed by inherent refractoriness or by acquired drug resistance, requiring a need for better mechanistic understanding of such effects. Numerous preclinical studies have demonstrated that VEGF pathway inhibitors suppress primary tumour growth and metastasis. However, it has been recently reported that short-term VEGF and VEGFR inhibition can paradoxically accelerate tumour invasiveness and metastasis in certain models. Here we comprehensively compare the effects of both antibody and small molecule receptor tyrosine kinase (RTK) inhibitors targeting the VEGF–VEGFR pathway, using short-term therapy in various mouse models of metastasis. Our findings demonstrate that antibody inhibition of VEGF pathway molecules does not promote metastasis, in contrast to selected small molecule RTK inhibitors at elevated-therapeutic drug dosages. In particular, a multi-targeted RTK inhibitor, sunitinib, which most profoundly potentiated metastasis, also increased lung vascular permeability and promoted tumour cell extravasation. Mechanistically, sunitinib, but not anti-VEGF treatment, attenuated endothelial barrier function in culture and caused a global inhibition of protein tyrosine phosphorylation, including molecules important for maintaining endothelial cell–cell junctions. Together these findings indicate that, rather than a specific consequence of inhibiting the VEGF signalling pathway, pharmacological inhibitors of the VEGF pathway can have dose- and drug class-dependent side-effects on the host vasculature. These findings also advocate for the continued identification of mechanisms of resistance to anti-angiogenics and for therapy development to overcome it. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.