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Nutrition and Cancer

1,25-Dihydroxycholecalciferol Increases the Expression of Vascular Endothelial Growth Factor in C3H10T Mouse Embryo Fibroblasts^1,2

Interdepartmental Nutrition Program, Department of Foods and Nutrition, Purdue University, West Lafayette, IN 47907

³To whom correspondence should be addressed. E-mail: teegarden{at}cfs.purdue.edu.

Evidence suggests that biologically active vitamin D, 1,25-dihydroxycholecalciferol [1,25(OH)₂D₃], may inhibit carcinogenesis. Because angiogenesis is crucial to carcinogenesis, 1,25(OH)₂D₃ regulation of proangiogenic vascular endothelial growth factor (VEGF) secretion was investigated in cellular models for multistage carcinogenesis. Conditioned media from 1,25(OH)₂D₃-treated C3H10T mouse fibroblasts and their Harvey ras-oncogene transfected counterparts (rasneo11a cells) induced human umbilical vein endothelial cell (HUVEC) proliferation (1.3 and 0.3 times, respectively, P < 0.05), suggesting that 1,25(OH)₂D₃ altered the angiogenic phenotype of the cells. Although rasneo11a cells secreted less VEGF than C3H10T cells (97%, P < 0.005), 1,25(OH)₂D₃ induced C3H10T and rasneo11a cells to secrete 2 and 3 times, respectively, more VEGF than controls (P < 0.05). Similar effects on VEGF release occurred after 1,25(OH)₂D₃ treatment of MCF10A and MCF10Aras cells, a human breast epithelial cell model for multistage carcinogenesis. In C3H10T cells, 1,25(OH)₂D₃ activated the VEGF promoter in a dose-dependent (5–100 nmol/L) manner (maximum 60%) and all doses induced VEGF secretion (P < 0.05). 1,25(OH)₂D₃ induced VEGF mRNA expression (50%) from 2 through 24 h; VEGF release was significantly increased at 8 h and sustained for 24 h. VEGF mRNA expression and release declined as C3H10T cells grew more confluent, whereas the magnitude of 1,25(OH)₂D₃-stimulated changes in VEGF was greater in confluent (3.3 times RNA; 3.5 times release) than in subconfluent (50% RNA; 100% release) cultures (P < 0.05). Thus, 1,25(OH)₂D₃ increases VEGF secretion, and in C3H10T cells, this is likely through activation of the VEGF promoter and induction of gene expression. These data contribute to understanding the role 1,25(OH)₂D₃ plays in regulation of angiogenesis in normal compared with disease states.

KEY WORDS: • 1,25 dihydroxyvitamin D • C3H10T • ras • vascular endothelial growth factor • angiogenesis