Tumor vessel normalization by chloroquine independent of autophagy

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

doi:10.1016/j.ccr.2014.06.025

Tumor vessel normalization by chloroquine independent of autophagy

Cancer Cell. 2014 Aug 11;26(2):190-206. doi: 10.1016/j.ccr.2014.06.025.

Authors

Hannelore Maes¹, Anna Kuchnio², Aleksandar Peric³, Stijn Moens², Kris Nys¹, Katrien De Bock², Annelies Quaegebeur², Sandra Schoors², Maria Georgiadou², Jasper Wouters⁴, Stefan Vinckier², Hugo Vankelecom⁵, Marjan Garmyn⁶, Anne-Clémence Vion⁷, Freddy Radtke⁸, Chantal Boulanger⁷, Holger Gerhardt⁹, Elisabetta Dejana¹⁰, Mieke Dewerchin², Bart Ghesquière², Wim Annaert³, Patrizia Agostinis¹¹, Peter Carmeliet²

Affiliations

¹ Department Cellular and Molecular Medicine, Laboratory of Cell Death and Therapy, KU Leuven, B-3000 Leuven, Belgium.
² Department of Oncology, Laboratory of Angiogenesis and Neurovascular Link, KU Leuven, B-3000 Leuven, Belgium; Vesalius Research Center, Laboratory of Angiogenesis and Neurovascular Link, VIB, B-3000 Leuven, Belgium.
³ Department of Human Genetics and VIB-Center for the Biology of Disease, Laboratory for Membrane Trafficking, B-3000 Leuven, Leuven 3000, Belgium.
⁴ Department of Imaging & Pathology, Translational Cell and Tissue Research, KU Leuven, B-3000 Leuven, Belgium; Department of Development and Regeneration, Embryo and Stem Cells Unit, KU Leuven, B-3000 Leuven, Belgium.
⁵ Department of Development and Regeneration, Embryo and Stem Cells Unit, KU Leuven, B-3000 Leuven, Belgium.
⁶ Department of Oncology, Laboratory Dermatology, KU Leuven, B-3000 Leuven, Belgium.
⁷ Cardiovascular Research Center, INSERM UMR-970, Paris Cedex 15, France.
⁸ Ecole Polytechnique Fédérale de Lausanne, School of Life Science, 1015 Lausanne, Switzerland; Swiss Institute for Experimental Cancer Research, 1015 Lausanne, Switzerland.
⁹ Vascular Biology Laboratory, London Research Institute, Cancer Research UK, London WC2A 3LY, UK; Department of Oncology, Vascular Patterning Laboratory, KU Leuven, B-3000 Leuven, Belgium; Vesalius Research Center, Vascular Patterning Laboratory, VIB, B-3000 Leuven, Belgium.
¹⁰ Vascular Biology Program, IFOM, FIRC Institute of Molecular Oncology Foundation, 20139 Milan, Italy.
¹¹ Department Cellular and Molecular Medicine, Laboratory of Cell Death and Therapy, KU Leuven, B-3000 Leuven, Belgium. Electronic address: [email protected].

PMID: 25117709
DOI: 10.1016/j.ccr.2014.06.025

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Angiogenesis Inhibitors / pharmacology*
Angiogenesis Inhibitors / therapeutic use
Animals
Autophagy*
Autophagy-Related Protein 5
Camptothecin / pharmacology
Cell Line, Tumor
Cell Proliferation / drug effects
Chloroquine / pharmacology*
Chloroquine / therapeutic use
Drug Synergism
Endothelial Cells / drug effects
Endothelial Cells / physiology
Endothelium, Vascular / drug effects
Endothelium, Vascular / pathology
Humans
Melanoma, Experimental / blood supply
Melanoma, Experimental / drug therapy*
Melanoma, Experimental / pathology
Mice
Mice, Inbred C57BL
Mice, Nude
Microtubule-Associated Proteins / metabolism
Neoplasm Invasiveness
Neovascularization, Pathologic / metabolism
Neovascularization, Pathologic / prevention & control*
Receptor, Notch1 / metabolism
Skin Neoplasms / blood supply
Skin Neoplasms / drug therapy*
Skin Neoplasms / pathology
Tumor Burden / drug effects
Xenograft Model Antitumor Assays

Substances

Angiogenesis Inhibitors
Atg5 protein, mouse
Autophagy-Related Protein 5
Microtubule-Associated Proteins
Notch1 protein, mouse
Receptor, Notch1
Chloroquine
Camptothecin