FAK-heterozygous mice display enhanced tumour angiogenesis
File(s)
Author(s)
Type
Journal Article
Abstract
Genetic ablation of endothelial focal adhesion kinase (FAK) can inhibit pathological angiogenesis, suggesting that loss of endothelial FAK is sufficient to reduce neovascularization. Here we show that reduced stromal FAK expression in FAK-heterozygous mice unexpectedly enhances both B16F0 and CMT19T tumour growth and angiogenesis. We further demonstrate that cell proliferation and microvessel sprouting, but not migration, are increased in serum-stimulated FAK-heterozygous endothelial cells. FAK-heterozygous endothelial cells display an imbalance in FAK phosphorylation at pY397 and pY861 without changes in Pyk2 or Erk1/2 activity. By contrast, serum-stimulated phosphorylation of Akt is enhanced in FAK-heterozygous endothelial cells and these cells are more sensitive to Akt inhibition. Additionally, low doses of a pharmacological FAK inhibitor, although too low to affect FAK autophosphorylation in vitro, can enhance angiogenesis ex vivo and tumour growth in vivo. Our results highlight a potential novel role for FAK as a nonlinear, dose-dependent regulator of angiogenesis where heterozygous levels of FAK enhance angiogenesis.
Date Issued
2013-06-25
Online Publication Date
2019-10-07T14:55:42Z
Date Acceptance
2013-05-17
ISSN
2041-1723
Publisher
Nature Research (part of Springer Nature)
Journal / Book Title
Nature Communications
Volume
4
Copyright Statement
© 2013 Springer-Verlag. The final publication is available at Springer via https://doi.org/10.1038/ncomms3020.
Sponsor
British Heart Foundation
British Heart Foundation
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000323625700004&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Grant Number
PG/09/096/28114
RG/11/17/29256
Subjects
Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
FOCAL-ADHESION KINASE
ENDOTHELIAL-CELLS
TUBE FORMATION
GROWTH-FACTOR
CANCER-CELLS
PHOSPHORYLATION
TYROSINE-861
SRC
SURVIVAL
ADENOCARCINOMA
Animals
Cell Proliferation
Cell Separation
Cell Survival
Endothelial Cells
Focal Adhesion Kinase 1
Heterozygote
Immunohistochemistry
In Vitro Techniques
Mice
Mutant Proteins
Neoplasms
Neovascularization, Pathologic
Paxillin
Proto-Oncogene Proteins c-akt
Signal Transduction
Subcutaneous Tissue
Talin
Tumor Burden
Vinculin
Subcutaneous Tissue
Endothelial Cells
Animals
Mice
Neoplasms
Neovascularization, Pathologic
Talin
Vinculin
Tumor Burden
Cell Separation
Immunohistochemistry
Signal Transduction
Cell Proliferation
Cell Survival
Heterozygote
Mutant Proteins
Proto-Oncogene Proteins c-akt
Focal Adhesion Kinase 1
Paxillin
In Vitro Techniques
Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
FOCAL-ADHESION KINASE
ENDOTHELIAL-CELLS
TUBE FORMATION
GROWTH-FACTOR
CANCER-CELLS
PHOSPHORYLATION
TYROSINE-861
SRC
SURVIVAL
ADENOCARCINOMA
Publication Status
Published
Article Number
2020
Date Publish Online
2013-06-25