Abstract
Prostate cancer presents with a broad spectrum of biologic behavior, ranging from being an indolent, incidental finding to an aggressively invasive and metastatic disease. An improved understanding of the events involved in prostate cancer progression is critically important to its diagnosis and staging, as well as to the development of new therapies. Tumor progression, particularly in aggressive and malignant tumors, is associated with the induction of an angiogenic, gene-driven switch. In prostate cancer, one of the most powerful stimulators of angiogenesis is the vascular endothelial growth factor (VEGF). VEGF transcription can be induced by hypoxia through activation of the PI3 kinase pathway and hypoxia-inducible factor alpha. MMAC/PTEN (henceforth referred to as PTEN) is a recently identified tumor suppressor gene residing on chromosome 10q23, which is frequently inactivated in a wide range of human tumors, including advanced prostate cancer. The goal of this study was to determine whether PTEN inhibits angiogenesis by modulating VEGF activity. Our results showed that reintroduction of the PTEN gene into human prostate PC-3 and LNCaP cells decreased VEGF secretion, which was accompanied by various biologic activities, including inhibited endothelial cell growth and migration. PTEN expression also down-regulated VEGF mRNA levels, as detected by RT-PCR analysis. Concomitant with lessened VEGF expression was the reduction of VEGF promoter activity in PTEN-expressing cells. Our findings suggest that PTEN modulates angiogenesis by regulating VEGF expression.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adenocarcinoma / blood supply*
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Adenocarcinoma / metabolism
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Adenocarcinoma / pathology
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Cell Movement
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Endothelial Growth Factors / biosynthesis
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Endothelial Growth Factors / genetics
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Endothelial Growth Factors / physiology*
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Endothelium, Vascular / drug effects
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Endothelium, Vascular / physiology
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Gene Expression Regulation, Neoplastic
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Genes, Tumor Suppressor
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Humans
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Intercellular Signaling Peptides and Proteins / biosynthesis
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Intercellular Signaling Peptides and Proteins / genetics
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Intercellular Signaling Peptides and Proteins / physiology*
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Lymphokines / biosynthesis
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Lymphokines / genetics
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Lymphokines / physiology*
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Male
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Neovascularization, Pathologic / metabolism*
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PTEN Phosphohydrolase
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Phosphoric Monoester Hydrolases / genetics
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Phosphoric Monoester Hydrolases / physiology*
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Promoter Regions, Genetic
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Prostatic Neoplasms / blood supply*
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Prostatic Neoplasms / metabolism
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Prostatic Neoplasms / pathology
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Recombinant Fusion Proteins / physiology
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Reverse Transcriptase Polymerase Chain Reaction
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Transcription, Genetic
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Tumor Cells, Cultured
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / physiology*
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
Substances
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Endothelial Growth Factors
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Intercellular Signaling Peptides and Proteins
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Lymphokines
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Recombinant Fusion Proteins
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Tumor Suppressor Proteins
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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Phosphoric Monoester Hydrolases
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PTEN Phosphohydrolase
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PTEN protein, human