Tumor Vessel Normalization by Chloroquine Independent of Autophagy

被引：359

作者：

Maes, Hannelore ^{[1
]}

Kuchnio, Anna ^{[2
,3
]}

Peric, Aleksandar ^{[4
,5
]}

Moens, Stijn ^{[2
,3
]}

Nys, Kris ^{[1
]}

De Bock, Katrien ^{[2
,3
]}

Quaegebeur, Annelies ^{[2
,3
]}

Schoors, Sandra ^{[2
,3
]}

Georgiadou, Maria ^{[2
,3
]}

Wouters, Jasper ^{[6
,7
]}

Vinckier, Stefan ^{[2
,3
]}

Vankelecom, Hugo ^{[7
]}

Garmyn, Marjan ^{[8
]}

Vion, Anne-Clemence ^{[9
]}

Radtke, Freddy ^{[10
,11
]}

Boulanger, Chantal ^{[9
]}

Gerhardt, Holger ^{[12
,13
,14
]}

Dejana, Elisabetta ^{[15
]}

Dewerchin, Mieke ^{[2
,3
]}

Ghesquiere, Bart ^{[2
,3
]}

Annaert, Wim ^{[4
,5
]}

Agostinis, Patrizia ^{[1
]}

Carmeliet, Peter ^{[2
,3
]}

机构：

[1] Katholieke Univ Leuven, Dept Cellular & Mol Med, Lab Cell Death & Therapy, B-3000 Leuven, Belgium

[2] Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Neurovasc Link, B-3000 Leuven, Belgium

[3] VIB, Vesalius Res Ctr, Lab Angiogenesis & Neurovasc Link, B-3000 Leuven, Belgium

[4] Dept Human Genet, B-3000 Leuven, Belgium

[5] VIB, Ctr Biol Dis, Lab Membrane Trafficking, B-3000 Leuven, Belgium

[6] Katholieke Univ Leuven, Dept Imaging & Pathol, B-3000 Leuven, Belgium

[7] Katholieke Univ Leuven, Dept Dev & Regenerat, Embryo & Stem Cells Unit, B-3000 Leuven, Belgium

[8] Katholieke Univ Leuven, Dept Oncol, Dermatol Lab, B-3000 Leuven, Belgium

[9] INSERM, Cardiovasc Res Ctr, UMR 970, Paris 15, France

[10] Ecole Polytech Fed Lausanne, Sch Life Sci, CH-1015 Lausanne, Switzerland

[11] Swiss Inst Expt Canc Res, CH-1015 Lausanne, Switzerland

[12] Canc Res UK, London Res Inst, Vasc Biol Lab, London WC2A 3LY, England

[13] Katholieke Univ Leuven, Dept Oncol, Vasc Patterning Lab, B-3000 Leuven, Belgium

[14] VIB, Vesalius Res Ctr, Vasc Patterning Lab, B-3000 Leuven, Belgium

[15] FIRC Inst Mol Oncol Fdn, IFOM, Vasc Biol Program, I-20139 Milan, Italy

来源：

CANCER CELL | 2014年 / 26卷 / 02期

基金：

欧洲研究理事会;

关键词：

NOTCH; ANGIOGENESIS; METASTASIS; INHIBITION; THERAPY; DISEASE; CANCER; MICE;

D O I：

10.1016/j.ccr.2014.06.025

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：190 / 206

页数：17

共 34 条

[1] Notch signaling: simplicity in design, versatility in function [J].

Andersson, Emma R. ;

Sandberg, Rickard ;

Lendahl, Urban .

DEVELOPMENT, 2011, 138 (17) :3593-3612

[2] Endocytic routes to Notch activation [J].

Baron, Martin .

SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY, 2012, 23 (04) :437-442

[3] Notch-dependent VEGFR3 upregulation allows angiogenesis without VEGF-VEGFR2 signalling [J].

Benedito, Rui ;

Rocha, Susana F. ;

Woeste, Marina ;

Zamykal, Martin ;

Radtke, Freddy ;

Casanovas, Oriol ;

Duarte, Antonio ;

Pytowski, Bronislaw ;

Adams, Ralf H. .

NATURE, 2012, 484 (7392) :110-+

[4] Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases [J].

Carmeliet, Peter ;

Jain, Rakesh K. .

NATURE REVIEWS DRUG DISCOVERY, 2011, 10 (06) :417-427

[5] Gene-Targeting of Phd2 Improves Tumor Response to Chemotherapy and Prevents Side-Toxicity [J].

de Oliveira, Rodrigo Leite ;

Deschoemaeker, Sofie ;

Henze, Anne-Theres ;

Debackere, Koen ;

Finisguerra, Veronica ;

Takeda, Yukiji ;

Roncal, Carmen ;

Dettori, Daniela ;

Tack, Evelyne ;

Jonsson, Yannick ;

Veschini, Lorenzo ;

Peeters, Annelies ;

Anisimov, Andrey ;

Hofmann, Matthias ;

Alitalo, Kari ;

Baes, Myriam ;

D'hooge, Jan ;

Carmeliet, Peter ;

Mazzone, Massimiliano .

CANCER CELL, 2012, 22 (02) :263-277

[6] Novel Research Horizons for Presenilins and γ-Secretases in Cell Biology and Disease [J].

De Strooper, Bart ;

Annaert, Wim .

ANNUAL REVIEW OF CELL AND DEVELOPMENTAL BIOLOGY, VOL 26, 2010, 26 :235-260

[7] Disruption of Notch1 Induces Vascular Remodeling, Intussusceptive Angiogenesis, and Angiosarcomas in Livers of Mice [J].

Dill, Michael T. ;

Rothweiler, Sonja ;

Djonov, Valentin ;

Hlushchuk, Ruslan ;

Tornillo, Luigi ;

Terracciano, Luigi ;

Meili-Butz, Silvia ;

Radtke, Freddy ;

Heim, Markus H. ;

Semela, David .

GASTROENTEROLOGY, 2012, 142 (04) :967-U464

[8] VEGF signaling inside vascular endothelial cells and beyond [J].

Eichmann, Anne ;

Simons, Michael .

CURRENT OPINION IN CELL BIOLOGY, 2012, 24 (02) :188-193

[9] Notch Signaling: The Core Pathway and Its Posttranslational Regulation [J].

Fortini, Mark E. .

DEVELOPMENTAL CELL, 2009, 16 (05) :633-647

[10] Induction of autophagy during extracellular matrix detachment promotes cell survival [J].

Fung, Christopher ;

Lock, Rebecca ;

Gao, Sizhen ;

Salas, Eduardo ;

Debnath, Jayanta .

MOLECULAR BIOLOGY OF THE CELL, 2008, 19 (03) :797-806

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