An in vivo function for the transforming Myc protein: elicitation of the angiogenic phenotype.
The ability of neoplastic cells to recruit blood vasculature is crucial to their survival in the host organism. However, the evidence linking dominant oncogenes to the angiogenic switch remains incomplete. We demonstrate here that Myc, an oncoprotein implicated in many human malignancies, stimulates neovascularization. As an experimental model, we used Rat-1A fibroblasts that form vascular tumors upon transformation by Myc in immunocompromised mice. Our previous work and the use of neutralizing antibodies reveal that in these cells, the angiogenic switch is achieved via down-modulation of thrombospondin-1, a secreted inhibitor of angiogenesis, whereas the levels of vascular endothelial growth factor, a major activator of angiogenesis, remain high and unaffected by Myc. Consistent with this finding, overexpression of Myc confers upon the conditioned media the ability to promote migration of adjacent endothelial cells in vitro and corneal neovascularization in vivo. Furthermore, mobilization of estrogen-dependent Myc in vivo with the appropriate steroid provokes neovascularization of cell implants embedded in Matrigel. These data suggest that Myc is fully competent to trigger the angiogenic switch in vivo and that secondary events may not be required for neovascularization of Myc-induced tumors.
Ngo
C V
CV
Department of Pathobiology, University of Pennsylvania, Philadelphia 19104-6051, USA.
Gee
M
M
Akhtar
N
N
Yu
D
D
Volpert
O
O
Auerbach
R
R
Thomas-Tikhonenko
A
A
D000818:Animals; D002417:Cattle; D002460:Cell Line; D002461:Cell Line, Transformed; D002465:Cell Movement / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002478:Cells, Cultured; D003315:Cornea / Q000187:drug effects / Q000473:pathology; D017077:Culture Media, Conditioned / Q000737:chemistry / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D005347:Fibroblasts / Q000166:cytology / Q000637:transplantation; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D009154:Mutation; D009374:Neoplasms, Experimental / Q000235:genetics / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000235:genetics; D010641:Phenotype; D016271:Proto-Oncogene Proteins c-myc / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology
D017077:Culture Media, Conditioned; D016271:Proto-Oncogene Proteins c-myc; D013629:Tamoxifen; C016601:afimoxifene