VEGF INHIBITORS AND METASTASIS

Therapies aimed at inhibiting angiogenesis by targeting the vascular endothelial growth factor A (VEGFA)-VEGFR2 (VEGF receptor 2) pathway have been beneficial in treating several types of cancers. However, the benefits are often short lived, and various adaptive mechanisms eventually lead to tumour progression. Two papers in Cancer Cell have shown that, despite positive effects on established localized tumours, inhibition of angiogenesis can result in increased tumour invasion and metastasis.

Oriol Casanovas, Douglas Hanahan and colleagues studied the response to VEGFA-VEGFR2 pathway inhibition of pancreatic neuroendocrine cancer in the RIP1-Tag2 mouse model and glioblastoma multiforme (GBM) in an orthotopic mouse model. One week of treatment of tumour-bearing immunocompromised RIP1-Tag2 mice with the anti-VEGFR2 antibody DC101 resulted in significantly more invasive tumours, an effect that was intensified by longer treatment: 6% of tumours in control mice were categorized as highly invasive compared with 54% and 62.5% in mice treated for 1 week and 4 weeks, respectively. This phenotype was not reversible, as invasiveness persisted for at least 3 weeks after treatment was stopped. Furthermore, in immunocompetent RIP1-Tag2 mice, short-term DC101 treatment significantly increased the number of mice with long-term lymph node (fourfold) and liver (twofold) metastases, and the number of liver metastases per animal. The authors noted a significant increase in hypoxia in DC101-treated tumours and metastases, suggesting one possible molecular mechanism for the increased invasion. Similar data were observed with sunitinib, a Vegfr and platelet-derived growth factor receptor (Pdgfr) kinase inhibitor currently in clinical use, when administered continuously for 5 weeks, with the interesting exception of the increased incidence of lymph node metastases. The authors speculate that this could be because sunitinib, but not DC101, also inhibits VEGFR3 in lymphatic vessels. Finally, in a model of GBM, treatment with either sunitinib or the Vegfr-selective kinase inhibitor SU10944 increased invasion, which is consistent with several recent clinical studies in GBMs.

Robert Kerbel and colleagues also found a relationship between anti-angiogenic drugs and metastasis using a different approach. In agreement with preclinical and clinical efficacy of Vegfr inhibitors, they showed that sunitinib can inhibit the growth of localized orthotopically grown tumours from 231/LM2-4^LUC+ metastatic human breast cancer cells, MeWo human melanoma cells or B16 mouse melanoma cells. However, short-term treatment of mice with sunitinib for 7 days either before or after tail vein injection of 231/LM2-4^LUC+ cells accelerated metastatic disease progression and significantly reduced median survival compared with vehicle treatment. Similar results were obtained with short-term treatment using the Vegfr inhibitors sorafenib or SU10944 prior to 231/LM2-4^LUC+ cell injection. The authors also found increased metastasis when mice were treated with short-term sunitinib before intravenous injection of MeWo cells. These data suggest that Vegfr inhibitors might precondition the host microenvironment, making it favourable for metastasis.

It is important to emphasize that both studies clearly recapitulate the clinical data that anti-angiogenic therapies can have significant, albeit transitory, effects on localized tumour growth. However, they raise interesting questions about the timing of anti-angiogenic therapy and whether combining these agents with chemotherapy or other targeted agents can counteract the observed unfavourable effects. Further studies to understand the mechanisms behind these dual effects of Vegfr inhibitors should help the development of more effective therapeutic options.

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Original Research Papers
• Pàez-Ribes, M. et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 15, 220-231 (2009)
• Ebos, J. M. L. et al. Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell 15, 232-239 (2009)

Further Reading
• Bergers G. & Hanahan D. Modes of resistance to anti-angiogenic therapy. Nature Rev. Cancer 8, 592-603 (2008)