Abstract
Angiogenic defects in Id mutant mice inhibit the growth of tumor xenografts, providing a genetic model for antiangiogenic stress. Our work tests the consequences of such stress on progression of more physiological Pten+/- tumors. While tumor growth occurs despite impaired angiogenesis, disruption of vasculature by Id loss causes tumor cells to experience hypoxia and necrosis, the extent of which is tumor dependent. We show that bone-marrow-derived endothelial precursors contribute functionally to neovasculature of some but not all Pten+/- tumors, partially rescuing Id mutant phenotype. We demonstrate that loss of Id1 in tumor endothelial cells results in downregulation of several proangiogenic genes, including alpha6 and beta4 integrins, matrix metalloprotease-2, and fibroblast growth factor receptor-1. Inhibition of these factors phenocopies loss of Id in in vivo angiogenesis assays.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Bone Marrow / metabolism*
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Cell Hypoxia
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Cells, Cultured
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Endothelial Cells / metabolism*
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Endothelium, Vascular / physiopathology
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Female
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Fish Proteins
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Inhibitor of Differentiation Protein 1
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Inhibitor of Differentiation Proteins
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Integrin alpha6 / metabolism
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Integrin beta4 / metabolism
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Lymph Nodes / physiopathology
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Matrix Metalloproteinase 2 / metabolism
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Mice
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Mice, Knockout
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Neoplasm Proteins / metabolism
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Neoplasms, Experimental / physiopathology
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Neovascularization, Pathologic / metabolism*
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PTEN Phosphohydrolase
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Protein Tyrosine Phosphatase, Non-Receptor Type 1
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Protein Tyrosine Phosphatases / genetics
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Protein Tyrosine Phosphatases / metabolism
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Receptor Protein-Tyrosine Kinases / metabolism
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Receptor, Fibroblast Growth Factor, Type 1
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Receptors, Fibroblast Growth Factor / metabolism
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Repressor Proteins*
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Thrombospondin 1 / metabolism
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transplantation, Heterologous
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Uterine Neoplasms / physiopathology
Substances
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Fish Proteins
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Idb1 protein, mouse
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Inhibitor of Differentiation Protein 1
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Inhibitor of Differentiation Proteins
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Integrin alpha6
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Integrin beta4
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Neoplasm Proteins
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Receptors, Fibroblast Growth Factor
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Repressor Proteins
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Thrombospondin 1
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Transcription Factors
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ID3 protein, human
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Fgfr1 protein, mouse
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Receptor Protein-Tyrosine Kinases
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Receptor, Fibroblast Growth Factor, Type 1
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Protein Tyrosine Phosphatase, Non-Receptor Type 1
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Protein Tyrosine Phosphatases
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PTEN Phosphohydrolase
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Pten protein, pufferfish
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Matrix Metalloproteinase 2