c-Myc interacts with hypoxia to induce angiogenesis in vivo by a vascular endothelial growth factor-dependent mechanism.
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.
Knies-Bamforth
Ulrike E
UE
Molecular Oncology Laboratory, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
Fox
Stephen B
SB
Poulsom
Richard
R
Evan
Gerard I
GI
Harris
Adrian L
AL
D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007211:Indoles / Q000494:pharmacology; D015603:Keratinocytes / Q000378:metabolism; D051379:Mice; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D000078183:Oxindoles; D010212:Papilloma / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D011230:Precancerous Conditions / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D011422:Propionates; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism / Q000502:physiology*; D011758:Pyrroles / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012867:Skin / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D012878:Skin Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism; D019076:Transgenes; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007211:Indoles; D000078183:Oxindoles; D011422:Propionates; D016271:Proto-Oncogene Proteins c-myc; D011758:Pyrroles; D012333:RNA, Messenger; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D013629:Tamoxifen; C016601:afimoxifene; C116890:Semaxinib; C412603:orantinib