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Tumour cells expressing single VEGF isoforms display distinct growth, survival and migration characteristics

Tumour cells expressing single VEGF isoforms display distinct growth, survival and migration characteristics
Tumour cells expressing single VEGF isoforms display distinct growth, survival and migration characteristics
Vascular endothelial growth factor-A (VEGF) is produced by most cancer cells as multiple isoforms, which display distinct biological activities. VEGF plays an undisputed role in tumour growth, vascularisation and metastasis; nevertheless the functions of individual isoforms in these processes remain poorly understood. We investigated the effects of three main murine isoforms (VEGF188, 164 and 120) on tumour cell behaviour, using a panel of fibrosarcoma cells we developed that express them individually under endogenous promoter control. Fibrosarcomas expressing only VEGF188 (fs188) or wild type controls (fswt) were typically mesenchymal, formed ruffles and displayed strong matrix-binding activity. VEGF164- and VEGF120-producing cells (fs164 and fs120 respectively) were less typically mesenchymal, lacked ruffles but formed abundant cell-cell contacts. On 3D collagen, fs188 cells remained mesenchymal while fs164 and fs120 cells adopted rounded/amoeboid and a mix of rounded and elongated morphologies respectively. Consistent with their mesenchymal characteristics, fs188 cells migrated significantly faster than fs164 or fs120 cells on 2D surfaces while contractility inhibitors accelerated fs164 and fs120 cell migration. VEGF164/VEGF120 expression correlated with faster proliferation rates and lower levels of spontaneous apoptosis than VEGF188 expression. Nevertheless, VEGF188 was associated with constitutively active/phosphorylated AKT, ERK1/2 and Stat3 proteins. Differences in proliferation rates and apoptosis could be explained by defective signalling downstream of pAKT to FOXO and GSK3 in fs188 and fswt cells, which also correlated with p27/p21 cyclin-dependent kinase inhibitor over-expression. All cells expressed tyrosine kinase VEGF receptors, but these were not active/activatable suggesting that inherent differences between the cell lines are governed by endogenous VEGF isoform expression through complex interactions that are independent of tyrosine kinase receptor activation. VEGF isoforms are emerging as potential biomarkers for anti-VEGF therapies. Our results reveal novel roles of individual isoforms associated with cancer growth and metastasis and highlight the importance of understanding their diverse actions.
1932-6203
e104015
Kanthou, Chryso
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Dachs, Gabi U.
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Lefley, Diane V.
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Steele, Andrew J.
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Coralli-Foxon, Claudia
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Harris, Sheila
64c0ebdc-86fc-45b4-bb75-9946f970720b
Greco, Olga
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Dos Santos, Sofia A.
b00f590d-2aac-4270-aef0-00ee72eac4e8
Reyes-Aldasoro, Constantino C.
e213ec0e-6040-4a2c-8daf-fc7d8bedb57e
English, William R.
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Tozer, Gillian M.
c963e0e4-c1d0-43c8-a7a5-dc0a8dbe2557
Kanthou, Chryso
bdac8aa7-e27d-464d-9255-4513f2f7f623
Dachs, Gabi U.
6b227831-3df0-48cd-904c-0898d4b758dd
Lefley, Diane V.
5d1521b2-ab14-425e-b6d2-6c76c14803bb
Steele, Andrew J.
4349f6aa-2e3a-49a8-be73-7716056ae089
Coralli-Foxon, Claudia
35e473dd-29cc-4ecc-a4be-34bcae50c44b
Harris, Sheila
64c0ebdc-86fc-45b4-bb75-9946f970720b
Greco, Olga
6b753370-fbfe-4dcc-a058-c7b4d12ae871
Dos Santos, Sofia A.
b00f590d-2aac-4270-aef0-00ee72eac4e8
Reyes-Aldasoro, Constantino C.
e213ec0e-6040-4a2c-8daf-fc7d8bedb57e
English, William R.
c9dd1ac3-b511-4dbd-be0e-8d8d4e168c65
Tozer, Gillian M.
c963e0e4-c1d0-43c8-a7a5-dc0a8dbe2557

Kanthou, Chryso, Dachs, Gabi U., Lefley, Diane V., Steele, Andrew J., Coralli-Foxon, Claudia, Harris, Sheila, Greco, Olga, Dos Santos, Sofia A., Reyes-Aldasoro, Constantino C., English, William R. and Tozer, Gillian M. (2014) Tumour cells expressing single VEGF isoforms display distinct growth, survival and migration characteristics. PLoS ONE, 9 (8), e104015. (doi:10.1371/journal.pone.0104015).

Record type: Article

Abstract

Vascular endothelial growth factor-A (VEGF) is produced by most cancer cells as multiple isoforms, which display distinct biological activities. VEGF plays an undisputed role in tumour growth, vascularisation and metastasis; nevertheless the functions of individual isoforms in these processes remain poorly understood. We investigated the effects of three main murine isoforms (VEGF188, 164 and 120) on tumour cell behaviour, using a panel of fibrosarcoma cells we developed that express them individually under endogenous promoter control. Fibrosarcomas expressing only VEGF188 (fs188) or wild type controls (fswt) were typically mesenchymal, formed ruffles and displayed strong matrix-binding activity. VEGF164- and VEGF120-producing cells (fs164 and fs120 respectively) were less typically mesenchymal, lacked ruffles but formed abundant cell-cell contacts. On 3D collagen, fs188 cells remained mesenchymal while fs164 and fs120 cells adopted rounded/amoeboid and a mix of rounded and elongated morphologies respectively. Consistent with their mesenchymal characteristics, fs188 cells migrated significantly faster than fs164 or fs120 cells on 2D surfaces while contractility inhibitors accelerated fs164 and fs120 cell migration. VEGF164/VEGF120 expression correlated with faster proliferation rates and lower levels of spontaneous apoptosis than VEGF188 expression. Nevertheless, VEGF188 was associated with constitutively active/phosphorylated AKT, ERK1/2 and Stat3 proteins. Differences in proliferation rates and apoptosis could be explained by defective signalling downstream of pAKT to FOXO and GSK3 in fs188 and fswt cells, which also correlated with p27/p21 cyclin-dependent kinase inhibitor over-expression. All cells expressed tyrosine kinase VEGF receptors, but these were not active/activatable suggesting that inherent differences between the cell lines are governed by endogenous VEGF isoform expression through complex interactions that are independent of tyrosine kinase receptor activation. VEGF isoforms are emerging as potential biomarkers for anti-VEGF therapies. Our results reveal novel roles of individual isoforms associated with cancer growth and metastasis and highlight the importance of understanding their diverse actions.

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Published date: 13 August 2014
Organisations: Cancer Sciences

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Local EPrints ID: 368397
URI: http://eprints.soton.ac.uk/id/eprint/368397
ISSN: 1932-6203
PURE UUID: a2538dc4-1ea8-49b8-a112-b226f2c6df64
ORCID for Andrew J. Steele: ORCID iD orcid.org/0000-0003-0667-1596

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Date deposited: 04 Sep 2014 13:01
Last modified: 15 Mar 2024 03:39

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Contributors

Author: Chryso Kanthou
Author: Gabi U. Dachs
Author: Diane V. Lefley
Author: Claudia Coralli-Foxon
Author: Sheila Harris
Author: Olga Greco
Author: Sofia A. Dos Santos
Author: Constantino C. Reyes-Aldasoro
Author: William R. English
Author: Gillian M. Tozer

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