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

Tumor vessel normalization by chloroquine independent of autophagy.

Author information

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: patrizia.agostinis@med.kuleuven.be.

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.

PMID:
25117709
DOI:
10.1016/j.ccr.2014.06.025
[Indexed for MEDLINE]
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