Complexity of VEGF Responses in Skin Carcinogenesis Revealed through Ex Vivo Assays Based on a VEGF-A Null Mouse Keratinocyte Cell Line

Vascular endothelial growth factor (VEGF-A) is a critical player in cutaneous angiogenesis. However, the relative contribution of VEGF-A from different sources including epithelial and mesenchymal cells has not been fully characterized during skin repair and tumorigenesis. Moreover, the actual invol...

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Bibliographic Details
Published in:Journal of investigative dermatology 2009-03, Vol.129 (3), p.730-741
Main Authors: Mirones, Isabel, Conti, Claudio J., Martínez, Jesús, Garcia, Marta, Larcher, Fernando
Format: Article
Language:English
Subjects:
Adenoviridae - genetics
Alleles
Animals
Biological and medical sciences
Calcium - metabolism
Cell Differentiation
Cell Line
Dermatology
Gene Transfer Techniques
Keratinocytes - cytology
Keratinocytes - metabolism
Medical sciences
Mice
Neoplasm Metastasis
Neovascularization, Pathologic
ras Proteins - metabolism
Skin - metabolism
Skin Neoplasms - metabolism
Vascular Endothelial Growth Factor A - metabolism
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Summary:Vascular endothelial growth factor (VEGF-A) is a critical player in cutaneous angiogenesis. However, the relative contribution of VEGF-A from different sources including epithelial and mesenchymal cells has not been fully characterized during skin repair and tumorigenesis. Moreover, the actual involvement of other vascular-specific acting molecules has remained elusive in part due to the masking and/or overlapping effects of VEGF-A. To shed light on these uncertainties we generated and characterized a clonal VEGF-null mouse keratinocyte cell line, through in vitro adenoviral gene transfer of Cre recombinase to VEGF-LoxP primary keratinocytes followed by repeated cell passaging under controlled conditions and cloning. In vitro and in vivo assays demonstrated that VEGF-null keratinocytes were nontumorigenic and expressed normal differentiation markers after calcium switch. Hras-induced tumorigenesis of immortalized VEGF-null keratinocytes upon subcutaneous injection was markedly reduced but not fully suppressed. However, the metastatic ability of Hras-transformed VEGF-null keratinocytes was abolished. These ex vivo approaches suggest the existence of VEGF-dependent and independent angiogenic stimuli in skin carcinogenesis. The VEGF-null mouse keratinocyte cell line arises as an important tool to assess the actual contribution of keratinocyte-derived VEGF with respect to other angiogenic factors in skin homeostasis and malignancy.
ISSN:0022-202X
1523-1747
DOI:10.1038/jid.2008.292