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Tumor Vessel Normalization by Chloroquine Independent of Autophagy

2014; Cell Press; Volume: 26; Issue: 2 Linguagem: Inglês

10.1016/j.ccr.2014.06.025

1878-3686

Hannelore Maes, Anna Kuchnio, Aleksandar Perić, Stijn Moens, Kris Nys, Katrien De Bock, Annelies Quaegebeur, Sandra Schoors, Μαρία Γεωργιάδου, Jasper Wouters, Stefan Vinckier, Hugo Vankelecom, Marjan Garmyn, Anne-Clémence Vion, Freddy Radtke, Chantal M. Boulanger, Holger Gerhardt, Elisabetta Dejana, Mieke Dewerchin, Bart Ghesquière, Wim Annaert, Patrizia Agostinis, Peter Carmeliet,

Epigenetics and DNA Methylation

Chloroquine (CQ) has been evaluated as an autophagy blocker for cancer treatment, but it is unknown if it acts solely by inhibiting cancer cell autophagy. We report that CQ reduced tumor growth but improved the tumor milieu. By normalizing tumor vessel structure and function and increasing perfusion, CQ reduced hypoxia, cancer cell invasion, and metastasis, while improving chemotherapy delivery and response. Inhibiting autophagy in cancer cells or endothelial cells (ECs) failed to induce such effects. CQ’s vessel normalization activity relied mainly on alterations of endosomal Notch1 trafficking and signaling in ECs and was abrogated by Notch1 deletion in ECs in vivo. Thus, autophagy-independent vessel normalization by CQ restrains tumor invasion and metastasis while improving chemotherapy, supporting the use of CQ for anticancer treatment.