Editors' ChoiceCancer

Antiangiogenic cancer drug drives lymphangiogenic metastasis

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Science Translational Medicine  08 Feb 2017:
Vol. 9, Issue 376, eaam6060
DOI: 10.1126/scitranslmed.aam6060


Tumor blood vessel–destroying cancer drug induces development of tumor lymphatics that contribute to treatment failure.

Metastatic renal cell carcinoma (RCC), which is characterized by vascular endothelial growth factor (VEGF)–driven hypervascularization, has very poor prognosis due to radio- and chemotherapy resistance. Sunitinib is an antiangiogenic tyrosine kinase inhibitor, which exerts its activity on VEGF receptors and is used as the first line treatment for metastatic RCC. Although sunitinib provides an overall benefit to patients with advanced RCC, most patients unfortunately develop resistance to sunitinib and relapse after one year.

Accumulating evidence indicates the potential for antiangiogenic therapies to elicit metastatic phenotypes that compromise their antitumor effects. It has been proposed that therapy-induced metastasis may explain disease progression after adjuvant treatment or renewed tumor growth after treatment withdrawal. Lymphatics represent a major route of tumor invasion, and tumor expression of lymphangiogenic factor VEGFC, which acts through VEGF receptor 3, correlates with unfavorable tumor outcomes and with metastasis in some cancer types. Very little is known, however, about how cancer therapies influence VEGFC expression in tumor cells. In this study, Dufies and colleagues used patient xenografts and biopsies to identify a molecular mechanism linking sunitinib treatment to lymphangiogenesis activation in RCC through stimulation of VEGFC gene transcription and stabilization of VEGFC mRNA. The team also found that sunitinib-induced VEGFC up-regulation correlated with the development of a tumor lymphatic network, which was associated with increased metastasis and overall survival in mice as well as lymph node metastasis in patients, which predicted shorter overall survival.

These findings help explain the observations of increased metastasis and increased lymphatic vessels in many sunitinib-treated patients. They also indicate that the antiangiogenic benefits of sunitinib may be compromised by stimulation of lymphatic vessel formation, a compensatory effect promoting metastasis that may decrease treatment efficacy. It may be possible to combine VEGFC inhibitors with sunitinib to treat advanced RCC and limit the cancer's progression, but this has yet to be established.

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