afimoxifene and orantinib

The proto-oncogene c-myc is involved in the regulation of cell proliferation, differentiation, and apoptosis. In this study, we used an inducible transgenic mouse model in which c-Myc was targeted to the epidermis and, after activation, gave rise to hyperplastic and dysplastic skin lesions and to dermal angiogenesis, involving both vascular endothelial growth factor (VEGF) receptor-1 and VEGF receptor-2. After c-Myc activation, VEGF mRNA was expressed in postmitotic keratinocytes where it colocalized with transgene expression and areas of tissue hypoxia, suggesting a role of hypoxia in VEGF induction. In vitro, c-Myc activation alone was able to induce VEGF protein release and in conjunction with hypoxia, c-Myc activation further increased VEGF protein. Blocking VEGF signaling in vivo significantly reduced dermal angiogenesis, demonstrating the importance of VEGF as a mediating factor for the c-Myc-induced angiogenic phenotype.

Topics: Animals; Cell Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Indoles; Keratinocytes; Mice; Neovascularization, Physiologic; Oxindoles; Papilloma; Precancerous Conditions; Propionates; Proto-Oncogene Proteins c-myc; Pyrroles; RNA, Messenger; Skin; Skin Neoplasms; Tamoxifen; Transcription Factors; Transgenes; Vascular Endothelial Growth Factor A