Angiogenesis in cholangiocellular carcinoma: Expression of vascular endothelial growth factor, angiopoietin-1/2, thrombospondin-1 and clinicopathological significance

Abstract

Abstract. Angiogenesis in cholangiocellular carcinoma (CCC) has rarely been investigated. The aim of this study was to determine the angiogenesis status of CCC and assess its relationship with angiogenic factors and clinicopathological characteristics. We examined 33 surgically resected CCC specimens. Tumor angiogenesis was assessed by microvessel density (MVD) using the anti-CD34 antibody, and the expression of VEGF, Ang-1, Ang-2, and TSP-1 was determined by immunohistochemistry. The mean (± SD) MVD was 87.2±52.6/mm 2 (range, 0-229/mm 2 ). A total of 75.6% cases were positive for VEGF expression, 36% for Ang-1, 57.6% for Ang-2 and 45.5% for TSP-1. VEGF and Ang-2 expression was associated with a significantly higher level of MVD (p=0.004 and 0.015, respectively). TSP-1 expression was associated with a significantly lower level of MVD (p=0.005) and a higher level of intrahepatic metastasis (46.7% vs. 5.

Estrogens stimulate the proliferation of human cholangiocarcinoma by inducing the expression and secretion of vascular endothelial growth factor

“…In previous studies, VEGF but not VEGF receptors were found in three different cell lines derived from extra-hepatic cholangiocarcinoma [14,21]. In human studies, IHC positivity for VEGF was demonstrated in surgical samples of intra-hepatic [13] and extra-hepatic cholangiocarcinoma [14,21].…”

“…In previous studies, VEGF but not VEGF receptors were found in three different cell lines derived from extra-hepatic cholangiocarcinoma [14,21]. In human studies, IHC positivity for VEGF was demonstrated in surgical samples of intra-hepatic [13] and extra-hepatic cholangiocarcinoma [14,21]. Specifically, more than 70% of surgical samples from intra-hepatic cholangiocarcinoma showed immunohistochemical positivity for VEGF-C, which represented an independent and important prognostic factor suspected to play an important role in the lymph node metastasis [13].…”

“…17β-Estradiol induced a significant increase in the protein expression of all the three VEGF receptors with a prominent effect on VEGFR-2 (>5-fold increase) which is a preferred receptor for both VEGF-A and VEGF-C other than being implicated in neoplastic growth [8,9,13,14,20]. The effect of 17β-estradiol was mediated by either ER or IGF1-R since it was inhibited by two specific receptor antagonists (Ici182,780 and αIR3 ).…”

“…In the present study we evaluated the involvement of VEGF and related receptors in the estrogen-indu0ced proliferation of HuH-28 cells. This topic is of current interest since VEGF and neo-angiogenesis have been demonstrated to play a major role in the growth and spreading of different cancers including cholangiocarcinoma [6,8,13,14,20]. Most importantly, anti-VEGF and anti-angiogenic strategies are currently under clinical evaluation to delay or stop cancer progression [6].…”

“…We have recently shown that intra-hepatic cholangiocarcinoma express ER-αand -β, insulin-like growth factor 1 (IGF1) and IGF1-R (receptor) and that estrogens cooperate with IGF1 and its receptor in modulating the growth of cholangiocarcinoma [12]. Recent studies suggest that, also in cholangiocarcinoma, neo-angiogenesis plays a key role in the growth and spreading of tumour mass [13][14][15].…”