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Loss of vascular endothelial growth factor A activity in murine epidermal keratinocytes delays wound healing and inhibits tumor formation

(2004) CANCER RESEARCH. 64(10). p.3508-3516
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Abstract
The angiogenic cytokine vascular endothelial growth factor (VEGF)-A plays a central role in both wound healing and tumor growth. In the skin, epidermal keratinocytes are a major source of this growth factor. To study the contribution of keratinocyte-derived VEGF-A to these angiogenesis-dependent processes, we generated mice in which this cytokine was inactivated specifically in keratin 5-expressing tissues. The mutant mice were macroscopically normal, and the skin capillary system was well established, demonstrating that keratinocyte-derived VEGF-A is not essential for angiogenesis in the skin during embryonic development. However, healing of full-thickness wounds in adult animals was appreciably delayed compared with controls, with retarded crust shedding and the appearance of a blood vessel-free zone underneath the newly formed epidermis. When 9,12-dimethyl 1,2-benzanthracene was applied as both tumor initiator and promoter, a total of 143 papillomas developed in 20 of 23 (87%) of control mice. In contrast, only three papillomas arose in 2 of 17 (12%) of the mutant mice, whereas the rest merely displayed epidermal thickening and parakeratosis. Mutant mice also developed only 2 squamous cell carcinomas, whereas 11 carcinomas were found in seven of the control animals. These data demonstrate that whereas keratinocyte-derived VEGF-A is dispensable for skin vascularization under physiological conditions, it plays an important albeit nonessential role during epidermal wound healing and is crucial for the development of 9,12-dimethyl 1,2-benzanthracene-induced epithelial skin tumors.
Keywords
TRANSGENIC MICE, ANGIOGENESIS, MOUSE SKIN, PERMEABILITY FACTOR, VEGF, EXPRESSION, RECEPTORS, GENE, CARCINOGENESIS, OVEREXPRESSION

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Chicago
Rossiter, H, C Barresi, J Pammer, M Rendl, Jody Haigh, EF Wagner, and E Tschachler. 2004. “Loss of Vascular Endothelial Growth Factor A Activity in Murine Epidermal Keratinocytes Delays Wound Healing and Inhibits Tumor Formation.” Cancer Research 64 (10): 3508–3516.
APA
Rossiter, H., Barresi, C., Pammer, J., Rendl, M., Haigh, J., Wagner, E., & Tschachler, E. (2004). Loss of vascular endothelial growth factor A activity in murine epidermal keratinocytes delays wound healing and inhibits tumor formation. CANCER RESEARCH, 64(10), 3508–3516.
Vancouver
1.
Rossiter H, Barresi C, Pammer J, Rendl M, Haigh J, Wagner E, et al. Loss of vascular endothelial growth factor A activity in murine epidermal keratinocytes delays wound healing and inhibits tumor formation. CANCER RESEARCH. 2004;64(10):3508–16.
MLA
Rossiter, H, C Barresi, J Pammer, et al. “Loss of Vascular Endothelial Growth Factor A Activity in Murine Epidermal Keratinocytes Delays Wound Healing and Inhibits Tumor Formation.” CANCER RESEARCH 64.10 (2004): 3508–3516. Print.
@article{1202201,
  abstract     = {The angiogenic cytokine vascular endothelial growth factor (VEGF)-A plays a central role in both wound healing and tumor growth. In the skin, epidermal keratinocytes are a major source of this growth factor. To study the contribution of keratinocyte-derived VEGF-A to these angiogenesis-dependent processes, we generated mice in which this cytokine was inactivated specifically in keratin 5-expressing tissues. The mutant mice were macroscopically normal, and the skin capillary system was well established, demonstrating that keratinocyte-derived VEGF-A is not essential for angiogenesis in the skin during embryonic development. However, healing of full-thickness wounds in adult animals was appreciably delayed compared with controls, with retarded crust shedding and the appearance of a blood vessel-free zone underneath the newly formed epidermis. When 9,12-dimethyl 1,2-benzanthracene was applied as both tumor initiator and promoter, a total of 143 papillomas developed in 20 of 23 (87\%) of control mice. In contrast, only three papillomas arose in 2 of 17 (12\%) of the mutant mice, whereas the rest merely displayed epidermal thickening and parakeratosis. Mutant mice also developed only 2 squamous cell carcinomas, whereas 11 carcinomas were found in seven of the control animals. These data demonstrate that whereas keratinocyte-derived VEGF-A is dispensable for skin vascularization under physiological conditions, it plays an important albeit nonessential role during epidermal wound healing and is crucial for the development of 9,12-dimethyl 1,2-benzanthracene-induced epithelial skin tumors.},
  author       = {Rossiter, H and Barresi, C and Pammer, J and Rendl, M and Haigh, Jody and Wagner, EF and Tschachler, E},
  issn         = {0008-5472},
  journal      = {CANCER RESEARCH},
  keyword      = {TRANSGENIC MICE,ANGIOGENESIS,MOUSE SKIN,PERMEABILITY FACTOR,VEGF,EXPRESSION,RECEPTORS,GENE,CARCINOGENESIS,OVEREXPRESSION},
  language     = {eng},
  number       = {10},
  pages        = {3508--3516},
  title        = {Loss of vascular endothelial growth factor A activity in murine epidermal keratinocytes delays wound healing and inhibits tumor formation},
  volume       = {64},
  year         = {2004},
}

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