VEGF/VPF overexpression in skin of transgenic mice induces angiogenesis, vascular hyperpermeability and accelerated tumor development

• Published in: Oncogene Vol. 17; no. 3; pp. 303 - 311
• Main Authors: LARCHER, F, MURILLAS, R, BOLONTRADE, M, CONTI, C. J, JORCANO, J. L
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 23-07-1998; Nature Publishing Group
• Subjects: Angiogenesis; Animals; Biological and medical sciences; Capillary Permeability - genetics; Carcinogenesis; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Edema; Endothelial Growth Factors - biosynthesis; Endothelial Growth Factors - genetics; Endothelial Growth Factors - physiology; Erythema; Fundamental and applied biological sciences. Psychology; Genes, ras; Genetic crosses; H-Ras protein; Hyperplasia; Keratin; Keratins - genetics; Lethality; Lymphokines - biosynthesis; Lymphokines - genetics; Lymphokines - physiology; Mice; Mice, Transgenic; Molecular and cellular biology; Neovascularization, Pathologic - genetics; Neovascularization, Physiologic - genetics; Papilloma; Papilloma - blood supply; Papilloma - chemically induced; Papilloma - genetics; Phenotypes; Precancerous Conditions - blood supply; Precancerous Conditions - chemically induced; Precancerous Conditions - genetics; Psoriasis; Receptor Protein-Tyrosine Kinases - biosynthesis; Receptors, Growth Factor - biosynthesis; Receptors, Growth Factor - genetics; Receptors, Vascular Endothelial Growth Factor; Regulatory sequences; Regulatory Sequences, Nucleic Acid; Rodents; Skin - blood supply; Skin - metabolism; Skin - pathology; Skin diseases; Skin Neoplasms - blood supply; Skin Neoplasms - genetics; Tetradecanoylphorbol Acetate; Transgenic animals; Transgenic mice; Tumorigenesis; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors; Vascularization; Wound healing; Rodentia; Transgenic animal; Gene overexpression; Gene expression; Carcinogenesis; Angiogenesis; Vertebrata; Phenotype; Mammalia; Vascular endothelium growth factor; Gene; Mouse; Tumor; Skin
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1201928

Upregulation of keratinocyte-derived VEGF-A expression has recently been established in non-neoplastic processes of skin such as wound healing, blistering diseases and psoriasis, as well as in skin neoplasia. To further characterize the effects of VEGF-A in skin in vivo, we have developed transgenic mice expressing the mouse VEGF120 under the control of a 2.4 kb 5' fragment of keratin K6 gene regulatory sequences that confers transgene inducibility upon hyperproliferative stimuli. As expected from the inducible nature of the transgene, two of the three founder mice obtained (V27 and V208), showed no apparent phenotype. However, one founder (V2), mosaic for transgene integration, developed scattered red spots throughout the skin at birth. The transgenic offspring derived from this founder developed a striking phenotype characterized by swelling and erythema, resulting in early postnatal lethality. Histological examination of the skin of these transgenics demonstrated highly increased vascularization and edema leading to disruption of skin architecture. Expression of the transgene was silent in adult animals of lines derived from founders V27 and V208. Phorbol ester-induced hyperplasia resulted in transgene induction and increased cutaneous vascularization in adult transgenic mice of these lines. Skin carcinogenesis experiments performed on hemizygous crosses of V208 mice with activated H-ras-carrying transgenic mice (TG.AC) resulted in accelerated papilloma development and increased tumor burden. Previous results from our laboratory showed that VEGF upregulation is a major angiogenic stimulus in mouse epidermal carcinogenesis. By overexpressing VEGF in the skin of transgenic mice we now move a step further toward showing that VEGF-mediated angiogenesis is a rate-limiting step in the genesis of premalignant lesions, such as mouse skin papilloma. Our transgenic mice constitute an interesting model system for in vivo study of the cutaneous angiogenic process and its relevance in tumorigenesis and other skin diseases.