Endothelin inhibits cholangiocarcinoma growth by a decrease in the vascular endothelial growth factor expression

• Published in: Liver international 2009-08, Vol.29 (7), p.1031-1042
• Main Authors: Fava, Giammarco, DeMorrow, Sharon, Gaudio, Eugenio, Franchitto, Antonio, Onori, Paolo, Carpino, Guido, Glaser, Shannon, Francis, Heather, Coufal, Monique, Marucci, Luca, Alvaro, Domenico, Marzioni, Marco, Horst, Trenton, Mancinelli, Romina, Benedetti, Antonio, Alpini, Gianfranco
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Basic Studies; Bile Duct Neoplasms - genetics; Bile Duct Neoplasms - metabolism; Bile Duct Neoplasms - pathology; Bile Ducts, Intrahepatic - metabolism; Bile Ducts, Intrahepatic - pathology; biliary cancer; Cell Line, Tumor; Cell Proliferation; Cholangiocarcinoma - genetics; Cholangiocarcinoma - metabolism; Cholangiocarcinoma - pathology; cholangiopathies; Collagen - metabolism; Down-Regulation; Endothelin-1 - metabolism; Gene Expression Regulation, Neoplastic; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; neuroendocrine hormones; proliferation; Receptor, Endothelin A - metabolism; Receptor, Endothelin B - metabolism; RNA, Messenger - metabolism; Time Factors; vascular endothelial growth factor; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism; Vascular Endothelial Growth Factor C - genetics; Vascular Endothelial Growth Factor C - metabolism; Vascular Endothelial Growth Factor Receptor-2 - metabolism; Vascular Endothelial Growth Factor Receptor-3 - metabolism
• ISSN: 1478-3223; 1478-3231
• DOI: 10.1111/j.1478-3231.2009.01997.x

Background: Endothelins (ET‐1, ET‐2, ET‐3) are peptides with vasoactive properties interacting with ETA and ETB receptors. ET‐1 inhibits secretin‐stimulated ductal secretion (hallmark of cholangiocyte growth) of cholestatic rats by interaction with ET receptors. Aim: The aims of the studies were to evaluate (i) the effect of ET‐1 on cholangiocarcinoma growth in Mz‐ChA‐1 cells and nude mice and (ii) whether ET‐1 regulation of cholangiocarcinoma growth is associated with changes in the expression of vascular endothelial growth factor‐A (VEGF‐A), VEGF‐C, VEGF receptor‐2 (VEGFR‐2) and VEGFR‐3. Methods: We determined the expression of ETA and ETB receptors on normal and malignant (Mz‐ChA‐1) cholangiocytes and human cholangiocarcinoma tissue and the effect of ET‐1 on the proliferation and expression of VEGF‐A, VEGF‐C (regulators of tumour angiogenesis) and its receptors, VEGFR‐2 and VEGFR‐3, in Mz‐ChA‐1 cells. In vivo, Mz‐ChA‐1 cells were injected into the flanks of athymic mice and injections of ET‐1 or saline into the tumours were performed daily. The effect of ET‐1 on tumour size, cell proliferation, apoptosis, collagen quantity and the expression of VEGF‐A and VEGF‐C and VEGFR‐2 and VEGFR‐3 were measured after 73 days. Results: Higher expression of ETA and ETB was observed in malignant compared with normal cholangiocytes. ET‐1 inhibited proliferation and VEGF‐A, VEGF‐C, VEGFR‐2 and VEGFR‐3 expression of Mz‐ChA‐1 cells. Chronic ET‐1 treatment decreased tumour volume, tumour cell proliferation and VEGF‐A and VEGF‐C expression but increased apoptosis and collagen tissue deposition compared with controls. Conclusions: Modulation of VEGF‐A and VEGF‐C (by ET‐1) may be important for managing cholangiocarcinoma growth.