title: Tumor vessel normalization by chloroquine independent of autophagy.
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.
authors.affiliation: Department Cellular and Molecular Medicine, Laboratory of Cell Death and Therapy, KU Leuven, B-3000 Leuven, Belgium.
authors.forename: Hannelore
authors.initials: H
authors.lastname: Maes
authors.affiliation: 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.
authors.forename: Anna
authors.initials: A
authors.lastname: Kuchnio
authors.affiliation: Department of Human Genetics and VIB-Center for the Biology of Disease, Laboratory for Membrane Trafficking, B-3000 Leuven, Leuven 3000, Belgium.
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Peric
authors.affiliation: 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.
authors.forename: Stijn
authors.initials: S
authors.lastname: Moens
authors.affiliation: Department Cellular and Molecular Medicine, Laboratory of Cell Death and Therapy, KU Leuven, B-3000 Leuven, Belgium.
authors.forename: Kris
authors.initials: K
authors.lastname: Nys
authors.affiliation: 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.
authors.forename: Katrien
authors.initials: K
authors.lastname: De Bock
authors.affiliation: 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.
authors.forename: Annelies
authors.initials: A
authors.lastname: Quaegebeur
authors.affiliation: 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.
authors.forename: Sandra
authors.initials: S
authors.lastname: Schoors
authors.affiliation: 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.
authors.forename: Maria
authors.initials: M
authors.lastname: Georgiadou
authors.affiliation: 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.
authors.forename: Jasper
authors.initials: J
authors.lastname: Wouters
authors.affiliation: 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.
authors.forename: Stefan
authors.initials: S
authors.lastname: Vinckier
authors.affiliation: Department of Development and Regeneration, Embryo and Stem Cells Unit, KU Leuven, B-3000 Leuven, Belgium.
authors.forename: Hugo
authors.initials: H
authors.lastname: Vankelecom
authors.affiliation: Department of Oncology, Laboratory Dermatology, KU Leuven, B-3000 Leuven, Belgium.
authors.forename: Marjan
authors.initials: M
authors.lastname: Garmyn
authors.affiliation: Cardiovascular Research Center, INSERM UMR-970, Paris Cedex 15, France.
authors.forename: Anne-Clémence
authors.initials: AC
authors.lastname: Vion
authors.affiliation: Ecole Polytechnique Fédérale de Lausanne, School of Life Science, 1015 Lausanne, Switzerland; Swiss Institute for Experimental Cancer Research, 1015 Lausanne, Switzerland.
authors.forename: Freddy
authors.initials: F
authors.lastname: Radtke
authors.affiliation: Cardiovascular Research Center, INSERM UMR-970, Paris Cedex 15, France.
authors.forename: Chantal
authors.initials: C
authors.lastname: Boulanger
authors.affiliation: 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.
authors.forename: Holger
authors.initials: H
authors.lastname: Gerhardt
authors.affiliation: Vascular Biology Program, IFOM, FIRC Institute of Molecular Oncology Foundation, 20139 Milan, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Dejana
authors.affiliation: 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.
authors.forename: Mieke
authors.initials: M
authors.lastname: Dewerchin
authors.affiliation: 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.
authors.forename: Bart
authors.initials: B
authors.lastname: Ghesquière
authors.affiliation: Department of Human Genetics and VIB-Center for the Biology of Disease, Laboratory for Membrane Trafficking, B-3000 Leuven, Leuven 3000, Belgium.
authors.forename: Wim
authors.initials: W
authors.lastname: Annaert
authors.affiliation: Department Cellular and Molecular Medicine, Laboratory of Cell Death and Therapy, KU Leuven, B-3000 Leuven, Belgium. Electronic address: patrizia.agostinis@med.kuleuven.be.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Agostinis
authors.affiliation: 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.
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001343:Autophagy; D000071187:Autophagy-Related Protein 5; D002166:Camptothecin / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology* / Q000627:therapeutic use; D004357:Drug Synergism; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology; D006801:Humans; D008546:Melanoma, Experimental / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000517:prevention & control*; D051881:Receptor, Notch1 / Q000378:metabolism; D012878:Skin Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D008869:Microtubule-Associated Proteins; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D002738:Chloroquine; D002166:Camptothecin