Angiogenic effect of naive and 5-fluorouracil resistant colon carcinoma on endothelial cells in vitro

Abstract

Tumour associated neovascularisation is a complex interplay between inhibitory and stimulatory angiogenic factors. Despite intense research in this field, little is known about the interaction between endothelial and chemoresistant cancer cells. For this purpose, we assessed the impact of cellular supernatants of the primary adenocarcinoma cell line CCL228, its lymph node metastasis CCL227, and four subclones resistant to different levels of 5-fluorouracil on the growth of microvascular and macrovascular endothelial cells. The growth of endothelial cells in vitro was affected to a moderate degree by supernatants from colon cancer cell lines. This effect was independent of the degree of chemoresistance. The stimulation of endothelial cells by the growth factors VEGF, bFGF, and PD-ECGF in the presence of supernatants from cancer cell lines was generally higher in macrovascular endothelial cells when compared with microvascular cells. The secretion of VEGF from colon cancer cells in vitro was inversely related to the degree of chemoresistance with the low chemoresistance phenotype producing VEGF 8.7-fold higher than the high resistance subclone. With a maximal secretion of 1500 pg VEGF/ml cell supernatant, the concentration necessary to directly stimulate the growth of endothelial cells was not achieved. In conclusion, chemoresistance affects the interaction between colon cancer cells and endothelial cells dependant on the endothelial cell type. Although the level of chemoresistance has a profound impact on the production of VEGF by cancer cells with low, intermediate or high resistance, it does not differentially affect growth stimulation or inhibition of endothelial cells in vitro.