Regulation of vascular endothelial growth factor (VEGF)-C and VEGF-D expression by the organ microenvironment in human colon carcinoma

Vascular endothelial growth factor (VEGF)-C and VEGF-D are potent lymphangiogenic factors produced by tumour and stromal cells. The purpose of this study was to investigate the expression of VEGF-C and VEGF-D in the organ microenvironment. We implanted human KM12 colon carcinoma cell lines into the subcutis and caecal wall of nude mice. The expression of VEGF-C and VEGF-D mRNAs and proteins were examined by reverse transcriptase-polymerase chain reaction and immunohistochemistry, respectively. Under culture conditions, VEGF-C mRNA was not detected in KM12 cells; however, VEGF-C expression was detected after implantation of KM12 cells into nude mice. VEGF-C and VEGF-D protein contents were higher in orthotopic (caecal wall) tumours than in ectopic (subcutis) tumours. Small vessels expressing VEGF receptor-3 were observed in the peripheral portions of caecal tumours. In metastatic liver tumours, VEGF-C and VEGF-D proteins were produced in lower amounts than those in caecal tumours. These data suggest that the expression of lymphangiogenic factors is influenced by the organ microenvironment. Therefore, experimental studies of colon cancer lymphangiogenesis should be performed with orthotopic implantation models. (C) 2004 Elsevier Ltd. All rights reserved.