Stromal interaction essential for vascular endothelial growth factor A-induced tumour growth via transforming growth factor-beta signalling

A. C. Weidenaar, A. ter Elst, K. R. Kampen, Geertdina Meeuwsen-de Boer, H. J. M. de Jonge, F. J. G. Scherpen, W. F. A. den Dunnen, W. A. Kamps, E. S. J. M. de Bont*

*Corresponding author voor dit werk

OnderzoeksoutputAcademicpeer review

3 Citaten (Scopus)
174 Downloads (Pure)

Samenvatting

BACKGROUND: High vascular endothelial growth factor (VEGFA) levels at the time of diagnosis confer a worse prognosis to multiple malignancies. Our aim was to investigate the role of VEGFA in promoting tumour growth through interaction with its environment.

METHODS: HL-60 cells were transduced with VEGFA165 or control vector using retroviral constructs. Control cells (n = 7) or VEGFA165 cells (n = 7) were subcutaneously injected into NOD/SCID mice. Immunohistochemistry of markers for angiogenesis (CD31) and cell proliferation (Ki67) and gene expression profiling of tumours were performed. Paracrine effects were investigated by mouse-specific cytokine arrays.

RESULTS: In vivo we observed a twofold increase in tumour weight when VEGFA165 was overexpressed (P = 0.001), combined with increased angiogenesis (P = 0.002) and enhanced tumour cell proliferation (P = 0.001). Gene expression profiling revealed human genes involved in TGF-beta signalling differentially expressed between both tumour groups, that is, TGFBR2 and SMAD5 were lower expressed whereas the inhibitory SMAD7 was higher expressed with VEGFA165. An increased expression of mouse-derived cytokines IFNG and interleukin 7 was found in VEGFA165 tumours, both described to induce SMAD7 expression.

CONCLUSION: These results suggest a role for VEGFA-driven tumour growth by TGF-beta signalling inhibition via paracrine mechanisms in vivo, and underscore the importance of stromal interaction in the VEGFA-induced phenotype. British Journal of Cancer (2011) 105, 1856-1863. doi: 10.1038/bjc.2011.460 www.bjcancer.com Published online 1 November 2011 (C) 2011 Cancer Research UK

Originele taal-2English
Pagina's (van-tot)1856-1863
Aantal pagina's8
TijdschriftBritish Jounal of Cancer
Volume105
Nummer van het tijdschrift12
DOI's
StatusPublished - 6-dec.-2011

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