Estrogens stimulate the proliferation of human cholangiocarcinoma by inducing the expression and secretion of vascular endothelial growth factor. Academic Article uri icon


  • BACKGROUND: Estrogens may induce the proliferation of neoplastic cells by activating neo-angiogenesis. AIM: To evaluate the effect of estrogens on the expression of vascular endothelial growth factor (VEGF) and related receptors (VEGF-R) in human cholangiocarcinoma and the role played by VEGF in mediating the proliferative effects of estrogens. METHODS: Seven biopsies of intra-hepatic cholangiocarcinoma and the HuH-28 cell lines were investigated. Cell proliferation was measured by both PCNA Western blot and MTS proliferation assay. RESULTS: By immunohistochemistry, biopsies of human cholangiocarcinoma stained positively for VEGF-A and VEGF-C and related receptors. HuH-28 cells expressed VEGF-A, -C, and VEGFR-1, -2, -3 and, their protein level was enhanced by 17beta-estradiol in association with the stimulation of cell proliferation. 17beta-Estradiol-stimulated proliferation of HuH-28 cells was blocked by 70% by VEGF-TRAP, a receptor-based VEGF inhibitor. 17beta-Estradiol induced the secretion of VEGF in the supernatant of HuH-28 cells. The stimulatory effect of 17beta-estradiol on the protein expression of VEGF-A, VEGF-C and VEGFR-1, -2, -3 was blocked by antagonists of ER (Ici182,780) or insulin-like growth factor 1-receptor (alphaIR3). CONCLUSIONS: With the limitations of experiments performed in a cell line, our study indicates that VEGF plays a major role in mediating the proliferative effects of estrogens on human cholangiocarcinoma.

published proceedings

  • Dig Liver Dis

author list (cited authors)

  • Mancino, A., Mancino, M. G., Glaser, S. S., Alpini, G., Bolognese, A., Izzo, L., ... Alvaro, D.

citation count

  • 70

complete list of authors

  • Mancino, A||Mancino, MG||Glaser, SS||Alpini, G||Bolognese, A||Izzo, L||Francis, H||Onori, P||Franchitto, A||Ginanni-Corradini, S||Gaudio, E||Alvaro, D

publication date

  • January 2009