In addition to hypoxia stimulating production of VEGF, additional factors such as estrogen along with IGF1 (insulin like growth factor 1) and IGFR (IGF1 receptor) synergistically increases the expression of VEGFs such as VEGF-A, VEGF-C and their corresponding receptors in cultured CCA cells (114). This evidence concerns the gene IGF1 and cholangiocarcinoma.