afimoxifene and Papilloma

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

The protooncogene c-myc regulates cell growth, differentiation, and apoptosis, and its aberrant expression is frequently observed in human cancer. However, the consequences of activating c-Myc in an adult tissue, in which these cellular processes are part of normal homeostasis, remain unknown. In order to achieve this, we have targeted expression of a switchable form of the c-Myc protein to the skin epidermis, a well characterized homeostatic tissue. We show that activation of c-MycER in adult suprabasal epidermis rapidly triggers proliferation and disrupts differentiation of postmitotic keratinocytes. Sustained activation of c-Myc is sufficient to induce papillomatosis together with angiogenesis--changes that resemble hyperplastic actinic keratosis, a commonly observed human precancerous epithelial lesion. All these premalignant changes spontaneously regress upon deactivation of c-MycER.

Topics: Animals; Cell Differentiation; Cell Division; Epidermis; Estrogen Antagonists; Gene Expression Regulation, Neoplastic; Hair Follicle; Humans; Hyperplasia; Keratinocytes; Male; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Transgenic; Neovascularization, Pathologic; Papilloma; Phenotype; Proto-Oncogene Proteins c-myc; Skin Neoplasms; Tamoxifen