title: Dual role of pericyte α6β1-integrin in tumour blood vessels.
abstract: The α6β1-integrin is a major laminin receptor, and formation of a laminin-rich basement membrane is a key feature in tumour blood vessel stabilisation and pericyte recruitment, processes that are important in the growth and maturation of tumour blood vessels. However, the role of pericyte α6β1-integrin in angiogenesis is largely unknown. We developed mice where the α6-integrin subunit is deleted in pericytes and examined tumour angiogenesis and growth. These mice had: (1) reduced pericyte coverage of tumour blood vessels; (2) reduced tumour blood vessel stability; (3) increased blood vessel diameter; (4) enhanced blood vessel leakiness, and (5) abnormal blood vessel basement membrane architecture. Surprisingly, tumour growth, blood vessel density and metastasis were not altered. Analysis of retinas revealed that deletion of pericyte α6-integrin did not affect physiological angiogenesis. At the molecular level, we provide evidence that pericyte α6-integrin controls PDGFRβ expression and AKT-mTOR signalling. Taken together, we show that pericyte α6β1-integrin regulates tumour blood vessels by both controlling PDGFRβ and basement membrane architecture. These data establish a novel dual role for pericyte α6-integrin as modulating the blood vessel phenotype during pathological angiogenesis.
authors.affiliation: Adhesion and Angiogenesis Laboratory, Centre for Tumour Biology, Barts Cancer Institute - A CRUK Centre of Excellence, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK l.reynolds@qmul.ac.uk.
authors.forename: Louise E
authors.identifier: 0000-0001-6075-1808
authors.initials: LE
authors.lastname: Reynolds
authors.affiliation: Adhesion and Angiogenesis Laboratory, Centre for Tumour Biology, Barts Cancer Institute - A CRUK Centre of Excellence, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Gabriela
authors.initials: G
authors.lastname: D'Amico
authors.affiliation: Adhesion and Angiogenesis Laboratory, Centre for Tumour Biology, Barts Cancer Institute - A CRUK Centre of Excellence, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Tanguy
authors.initials: T
authors.lastname: Lechertier
authors.affiliation: Laboratory for Molecular Neuro-Oncology, Dept. of Neurology, University Hospital Zurich, Frauenklinikstrasse 26, Zurich CH-8091, Switzerland.
authors.forename: Alexandros
authors.initials: A
authors.lastname: Papachristodoulou
authors.affiliation: Adhesion and Angiogenesis Laboratory, Centre for Tumour Biology, Barts Cancer Institute - A CRUK Centre of Excellence, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: José M
authors.initials: JM
authors.lastname: Muñoz-Félix
authors.affiliation: IGBMC, UMR 7104, INSERM U964, Université de Strasbourg, BP. 10142, 1, Rue Laurent Fries, Illkirch Cedex 67404, France.
authors.forename: Adèle
authors.initials: A
authors.lastname: De Arcangelis
authors.affiliation: Adhesion and Angiogenesis Laboratory, Centre for Tumour Biology, Barts Cancer Institute - A CRUK Centre of Excellence, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Marianne
authors.initials: M
authors.lastname: Baker
authors.affiliation: Cancer Research UK Edinburgh Centre, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XR, UK.
authors.forename: Bryan
authors.initials: B
authors.lastname: Serrels
authors.affiliation: Adhesion and Angiogenesis Laboratory, Centre for Tumour Biology, Barts Cancer Institute - A CRUK Centre of Excellence, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Kairbaan M
authors.initials: KM
authors.lastname: Hodivala-Dilke
mesh_terms: D000818:Animals; D001485:Basement Membrane / Q000187:drug effects / Q000378:metabolism; D000077214:Becaplermin; D001808:Blood Vessels / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019426:Integrases / Q000378:metabolism; D039121:Integrin alpha6beta1 / Q000378:metabolism*; D051379:Mice; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D020286:Pericytes / Q000187:drug effects / Q000378:metabolism*; D020574:Proto-Oncogene Proteins c-sis / Q000494:pharmacology; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism
chemical_list: D039121:Integrin alpha6beta1; D020574:Proto-Oncogene Proteins c-sis; D000077214:Becaplermin; D020797:Receptor, Platelet-Derived Growth Factor beta; C045073:Cre recombinase; D019426:Integrases
keywords: Angiogenesis; Integrin; Pericyte; Tumour growth