Abstract
The significance of angiogenesis in cancer biology and therapy is well established. In this study, we used the prototypical RIP-Tag model of multistage pancreatic islet tumorigenesis to show that the nuclear receptor COUP-TFII is essential to regulate the balance between pro- and anti-angiogenic molecules that influence the angiogenic switch in cancer. Conditional ablation of COUP-TFII in the tumor microenvironment severely compromised neoangiogenesis and lymphangiogenesis during pancreatic tumor progression and metastasis. We found that COUP-TFII plays a cell-autonomous role in endothelial cells to control blood vessel sprouting by regulating cell proliferation and migration. Mechanistic investigations revealed that COUP-TFII suppressed vascular endothelial growth factor (VEGF)/VEGF receptor-2 (VEGFR-2) signaling by transcriptionally repressing the expression of VEGFR-1, thereby curtailing a central angiogenic driver of vascular growth. Taken together, our results implicate COUP-TFII as a critical factor in tumor angiogenesis through regulation of VEGF/VEGFR-2 signaling, suggesting COUP-TFII as a candidate target for antiangiogenic therapy.
©2010 AACR.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Blotting, Western
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COUP Transcription Factor II / antagonists & inhibitors
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COUP Transcription Factor II / physiology*
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Cell Adhesion
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Cell Movement
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Cell Proliferation
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Cells, Cultured
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Chromatin Immunoprecipitation
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Endothelium, Lymphatic / cytology
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Endothelium, Lymphatic / metabolism
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Endothelium, Vascular / cytology
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Endothelium, Vascular / metabolism
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Female
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GTPase-Activating Proteins / physiology
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Humans
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Immunoenzyme Techniques
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Infant, Newborn
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Integrases / metabolism
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Lymphatic Metastasis
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Male
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Mice
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Mice, Transgenic
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Neovascularization, Pathologic / pathology*
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Pancreatic Neoplasms / blood supply
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Pancreatic Neoplasms / pathology*
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Pancreatic Neoplasms / prevention & control
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Proteins / physiology
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RNA, Messenger / genetics
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RNA, Small Interfering / pharmacology
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RNA, Untranslated
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction*
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Umbilical Veins / cytology
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Umbilical Veins / metabolism
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Vascular Endothelial Growth Factor A / physiology*
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Vascular Endothelial Growth Factor Receptor-1 / genetics
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Vascular Endothelial Growth Factor Receptor-1 / metabolism
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Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors
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Vascular Endothelial Growth Factor Receptor-2 / genetics*
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Vascular Endothelial Growth Factor Receptor-2 / metabolism
Substances
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COUP Transcription Factor II
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GTPase-Activating Proteins
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Gt(ROSA)26Sor non-coding RNA, mouse
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Nr2f2 protein, mouse
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Proteins
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RNA, Messenger
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RNA, Small Interfering
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RNA, Untranslated
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Ralbp1 protein, mouse
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Vascular Endothelial Growth Factor A
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vascular endothelial growth factor A, mouse
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Vascular Endothelial Growth Factor Receptor-1
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Vascular Endothelial Growth Factor Receptor-2
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Cre recombinase
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Integrases