Contrasting effects of VEGF gene disruption in embryonic stem cell-derived versus oncogene-induced tumors.
Previous gene targeting studies have implicated an indispensable role of vascular endothelial growth factor (VEGF) in tumor angiogenesis, particularly in tumors of embryonal or endocrine origin. In contrast, we report here that transformation of VEGF-deficient adult fibroblasts (MDF528) with ras or neu oncogenes gives rise to highly tumorigenic and angiogenic fibrosarcomas. These aggressive VEGF-null tumors (528ras, 528neu) originated from VEGF(-/-) embryonic stem cells, which themselves were tumorigenically deficient. We also report that VEGF production by tumor stroma has a modest role in oncogene-driven tumor angiogenesis. Both ras and neu oncogenes down-regulated at least two endogenous inhibitors of angiogenesis [pigment epithelium derived factor (PEDF) and thrombospondin 1 (TSP-1)]. This is functionally important as administration of an antiangiogenic TSP-1 peptide (ABT-526) markedly inhibited growth of VEGF(-/-) tumors, with some ingress of pericytes. These results provide the first definitive genetic demonstration of the dispensability of tumor cell-derived VEGF in certain cases of 'adult' tumor angiogenesis, and thus highlight the importance of considering VEGF-independent as well as VEGF-dependent pathways when attempting to block this process pharmacologically.
Viloria-Petit
Alicia
A
Molecular and Cellular Biology Research, Sunnybrook and Women's College Health Sciences Centre, University of Toronto, Ontario M4N 3M5, Canada.
Miquerol
Lucile
L
Yu
Joanne L
JL
Gertsenstein
Marina
M
Sheehan
Capucine
C
May
Linda
L
Henkin
Jack
J
Lobe
Corrinne
C
Nagy
Andras
A
Kerbel
Robert S
RS
Rak
Janusz
J
D043925:Angiogenesis Inducing Agents / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D000818:Animals; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002472:Cell Transformation, Viral / Q000235:genetics; D002478:Cells, Cultured; D002678:Chimera; D005136:Eye Proteins; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005354:Fibrosarcoma / Q000235:genetics / Q000473:pathology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D018390:Gene Targeting; D018734:Genes, erbB-2; D011905:Genes, ras; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D008954:Models, Biological; D009154:Mutation; D009389:Neovascularization, Pathologic / Q000235:genetics; D009414:Nerve Growth Factors; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology; D011506:Proteins / Q000378:metabolism; D015843:Serpins / Q000378:metabolism; D013234:Stem Cells / Q000502:physiology*; D013724:Teratoma / Q000098:blood supply / Q000473:pathology; D019700:Thrombospondin 1 / Q000378:metabolism / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A; D000099174:Pigment Epithelium-Derived Factor
D043925:Angiogenesis Inducing Agents; D005136:Eye Proteins; D009414:Nerve Growth Factors; D010446:Peptide Fragments; D011506:Proteins; D015843:Serpins; D019700:Thrombospondin 1; D042461:Vascular Endothelial Growth Factor A; D000099174:Pigment Epithelium-Derived Factor; C477606:acetyl-sarcosyl-glycyl-valyl-isoleucyl-threonyl-norvalyl-isoleucyl-arginyl-proline ethylamide; C467480:vascular endothelial growth factor A, mouse