Intracrine vascular endothelial growth factor signaling in survival and chemoresistance of human colorectal cancer cells

• Published in: Oncogene Vol. 30; no. 10; pp. 1205 - 1212
• Main Authors: Samuel, S, Fan, F, Dang, L H, Xia, L, Gaur, P, Ellis, L M
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10.03.2011; Nature Publishing Group
• Subjects: 5-Fluorouracil; 631/67/1059/99; 692/699/67/1059/2326; 692/699/67/1504/1885; Ageing, cell death; Angiogenesis; Animals; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Apoptosis - physiology; Autocrine signalling; Biological and medical sciences; Blotting, Western; Cancer cells; Caspase-3; Cell Biology; Cell Line, Tumor; Cell physiology; Cell Proliferation - drug effects; Cell Separation; Cell survival; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Chemoresistance; Clonal deletion; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Cytotoxicity; Drug resistance; Drug Resistance, Neoplasm - genetics; Drug therapy; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Fundamental and applied biological sciences. Psychology; Gastroenterology. Liver. Pancreas. Abdomen; Gene deletion; Gene expression; Gene Knockdown Techniques; Genotype & phenotype; Human Genetics; Humans; Immunohistochemistry; Internal Medicine; Male; Medical sciences; Medicine; Medicine & Public Health; Mice; Mice, Nude; Molecular and cellular biology; Oncology; original-article; Physiological aspects; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - analysis; RNA, Small Interfering; Signal transduction; Signal Transduction - drug effects; Signal Transduction - physiology; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Survivin; Tumors; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism; United States; apoptosis; colorectal cancer; chemosensitivity; VEGF; autocrine; intracrine; Human; Rectal disease; Colorectal cancer; Malignant tumor; Carcinogenesis; Survival; Colonic disease; Vascular endothelium growth factor; Chemosensitivity; Digestive diseases; Intestinal disease; Cancer; Apoptosis
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2010.496

Although the effects of vascular endothelial growth factor (VEGF) on angiogenesis and vascular function are well known, the effects of VEGF on tumor cell function remain to be elucidated. We studied phenotypic changes in human colorectal cancer (CRC) cells with homozygous deletion of VEGF alleles to determine the potential direct role of VEGF on tumor cell function. Loss of VEGF expression led to significantly decreased cell growth and increased spontaneous apoptosis in CRC cells ( P <0.01). Loss of VEGF also increased the in vitro sensitivity of cells to the cytotoxic effects of the chemotherapeutic drug 5-fluorouracil, as shown by increased apoptosis ( P <0.05). These effects were mediated via upregulation of the proapoptotic mediators caspase-3, cleaved PARP and Bax and downregulation of the pro-survival mediator survivin. Our findings suggest a novel and distinct function of VEGF in mediating autocrine/intracrine CRC cell survival.