Edited by Kornelia Polyak, Dana-Farber Cancer Institute, Boston, MA, and accepted by the Editorial Board December 23, 2011 (received for review January 14, 2011)
Antiangiogenic therapy has been thought to hold significant potential for the treatment of cancer. However, the efficacy of such treatments, especially in breast cancer patients, has been called into question, as recent clinical trials reveal only limited effectiveness of antiangiogenic agents in prolonging patient survival. New research using preclinical models further suggests that antiangiogenic agents actually increase invasive and metastatic properties of breast cancer cells. We demonstrate that by generating intratumoral hypoxia in human breast cancer xenografts, the antiangiogenic agents sunitinib and bevacizumab increase the population of cancer stem cells. In vitro studies revealed that hypoxia-driven stem/progenitor cell enrichment is primarily mediated by hypoxia-inducible factor 1α. We further show that the Akt/β-catenin cancer stem cell regulatory pathway is activated in breast cancer cells under hypoxic conditions in vitro and in sunitinib-treated mouse xenografts. These studies demonstrate that hypoxia-driven cancer stem cell stimulation limits the effectiveness of antiangiogenic agents, and suggest that to improve patient outcome, these agents might have to be combined with cancer stem cell-targeting drugs.
Author contributions: S.J.C. and M.S.W. designed research; S.J.C., E.G., P.K., B.N., A.N.H., and S.G.C. performed research; H.K. contributed new reagents/analytic tools; S.J.C. analyzed data; and S.J.C. and M.S.W. wrote the paper.
Conflict of interest statement: M.S.W. is a consultant for Pfizer and OncoMed Pharmaceuticals and holds equity in OncoMed Pharmaceuticals.
This article is a PNAS Direct Submission. K.P. is a guest editor invited by the Editorial Board.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1018866109/-/DCSupplemental.
