FAK-heterozygous mice display enhanced tumour angiogenesis

Vassiliki Kostourou; Tanguy Lechertier; Louise E Reynolds; Delphine M Lees; Marianne Baker; Dylan T Jones; Bernardo Tavora; Antoine R Ramjaun; Graeme M Birdsey; Stephen D Robinson; Madeline Parsons; Anna M Randi; Ian R Hart; Kairbaan Hodivala-Dilke

doi:10.1038/ncomms3020

FAK-heterozygous mice display enhanced tumour angiogenesis

Vassiliki Kostourou, Tanguy Lechertier, Louise E Reynolds, Delphine M Lees, Marianne Baker, Dylan T Jones, Bernardo Tavora, Antoine R Ramjaun, Graeme M Birdsey, Stephen D Robinson, Madeline Parsons, Anna M Randi, Ian R Hart, Kairbaan Hodivala-Dilke

BSRC "Alexander Fleming"

Research output: Contribution to journal › Article › peer-review

37 Citations (Scopus)

215 Downloads (Pure)

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.

Original language	English
Article number	2020
Number of pages	11
Journal	Nature Communications
Volume	4
Issue number	N/A
DOIs	https://doi.org/10.1038/ncomms3020
Publication status	Published - 2013

Keywords

Animals
Cell Proliferation
Cell Separation
Cell Survival
Endothelial Cells
Focal Adhesion Kinase 1
Heterozygote
Immunohistochemistry
Mice
Mutant Proteins
Neoplasms
Neovascularization, Pathologic
Paxillin
Proto-Oncogene Proteins c-akt
Signal Transduction
Subcutaneous Tissue
Talin
Tumor Burden
Vinculin

Access to Document

10.1038/ncomms3020

FAK-heterozygous mice display enhanced_KOSTOUROU Accepted 17May2008 GREEN AAMAccepted author manuscript, 5.52 MB

Cite this

@article{fb4c39f4c23b4219b330225ee1d03590,

title = "FAK-heterozygous mice display enhanced tumour angiogenesis",

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.",

keywords = "Animals, Cell Proliferation, Cell Separation, Cell Survival, Endothelial Cells, Focal Adhesion Kinase 1, Heterozygote, Immunohistochemistry, Mice, Mutant Proteins, Neoplasms, Neovascularization, Pathologic, Paxillin, Proto-Oncogene Proteins c-akt, Signal Transduction, Subcutaneous Tissue, Talin, Tumor Burden, Vinculin",

author = "Vassiliki Kostourou and Tanguy Lechertier and Reynolds, {Louise E} and Lees, {Delphine M} and Marianne Baker and Jones, {Dylan T} and Bernardo Tavora and Ramjaun, {Antoine R} and Birdsey, {Graeme M} and Robinson, {Stephen D} and Madeline Parsons and Randi, {Anna M} and Hart, {Ian R} and Kairbaan Hodivala-Dilke",

year = "2013",

doi = "10.1038/ncomms3020",

language = "English",

volume = "4",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "N/A",

}

TY - JOUR

T1 - FAK-heterozygous mice display enhanced tumour angiogenesis

AU - Kostourou, Vassiliki

AU - Lechertier, Tanguy

AU - Reynolds, Louise E

AU - Lees, Delphine M

AU - Baker, Marianne

AU - Jones, Dylan T

AU - Tavora, Bernardo

AU - Ramjaun, Antoine R

AU - Birdsey, Graeme M

AU - Robinson, Stephen D

AU - Parsons, Madeline

AU - Randi, Anna M

AU - Hart, Ian R

AU - Hodivala-Dilke, Kairbaan

PY - 2013

Y1 - 2013

N2 - 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.

AB - 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.

KW - Animals

KW - Cell Proliferation

KW - Cell Separation

KW - Cell Survival

KW - Endothelial Cells

KW - Focal Adhesion Kinase 1

KW - Heterozygote

KW - Immunohistochemistry

KW - Mice

KW - Mutant Proteins

KW - Neoplasms

KW - Neovascularization, Pathologic

KW - Paxillin

KW - Proto-Oncogene Proteins c-akt

KW - Signal Transduction

KW - Subcutaneous Tissue

KW - Talin

KW - Tumor Burden

KW - Vinculin

U2 - 10.1038/ncomms3020

DO - 10.1038/ncomms3020

M3 - Article

C2 - 23799510

SN - 2041-1723

VL - 4

JO - Nature Communications

JF - Nature Communications

IS - N/A

M1 - 2020

ER -

FAK-heterozygous mice display enhanced tumour angiogenesis

Abstract

Keywords

Access to Document

Fingerprint

Cite this