The Role of Thymidine Phosphorylase and Thrombospondin-1 in Angiogenesis and Progression of Intrahepatic Cholangiocarcinoma

Abstract

Thymidine phosphorylase (TP), an important regulator of angiogenesis, is correlated with progression, metastasis, and prognosis in various types of tumor. In contrast, both positive and negative effects of thrombospondin-1 (TSP-1) on angiogenesis have been reported. In the present study, we examined the expression of TP and TSP-1 in carcinoma cells in 67 primary intrahepatic cholangiocarcinomas (ICCs) immunohistochemically and its correlation with angiogenesis, clinicopathological features, and prognosis. Twenty-six (38.8%) cases were classified as exhibiting positive TP expression. TP expression showed a significant correlation with vascular invasion, lymphatic permeation, perineural invasion, and lymph node metastasis. Thirty-four (50.7%) cases were classified as exhibiting positive TSP-1 expression. TSP-1 expression was significantly correlated with only lymphatic permeation. The microvessel count in positive TP expression cases was significantly higher than that in negative cases. In contrast, the microvessel count in negative TSP-1 expression cases was significantly higher than that in positive cases. Survival in patients who were positive for both TP and TSP-1 expression was significantly poor. Our results suggest that the increased TP expression and decreased TSP-1 expression contribute to angiogenesis, but that the role of angiogenesis in ICC is not closely related to tumor aggressiveness. The TP and TSP-1 expression in ICC may enhance tumor aggressiveness.

Role of ErbB family receptor tyrosine kinases in intrahepatic cholangiocarcinoma

“…Increased VEGF expression has been reported to be associated with a significant vascularization of human intrahepatic cholangiocarcinomas, as assessed by microvessel density [135,136] . In comparison, hypovascularity of cholangiocarcinoma may be related to a downregulation of VEGF together with an up-regulation of the angiogenesis inhibitor thrombospondin-1 [136,141,142] , although further studies are needed to validate the likelihood of this being a primary mechanism underlying the limited angiogenesis observed in cases of intrahepatic cholangiocarcinoma.…”

“…Tumor microenvironment and bioavailability is also an impor tant factor in deter mining the potential therapeutic effectiveness of ErbB-targeted therapies against intrahepatic cholangiocarcinoma. For example, intrahepatic cholangiocarcinomas are often hypovascularized [136,141,142,191] , thereby limiting the possibility of ErbB-targeted agents of reaching the malignant cells in sufficient concentrations to be therapeutically effective. In addition, hypoxic tumor microenvironments inducing HIF-1α [192,193] and tumor extracellular matrix components, like laminin 5 [194] , may alter the effectiveness of ErbB directed antineoplastic therapies.…”

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

“…The role of TSP-1 in angiogenesis and tumor progression remains controversial. Both positive and negative effects of TSP-1 on tumor angiogenesis have been reported (5,14,15). In addition, research on the relationship of TSP-1 with tumor clinicopathological factors is limited.…”

EWS/FLI1 Regulates Tumor Angiogenesis in Ewing's Sarcoma via Suppression of Thrombospondins

“…3T5 cell growth assay was done by plating 5 Â 10 5 cells/10-cm tissue culture plate and counted and replated at 5 Â 10 5 cells every 3 days for a total of 12 days (24). Population doubling time was calculated as the ln(post-3-day cell count/5 Â 10 5 ) / ln (2). The given population doubling time was added to the cumulative population doubling time of the previous count.…”

“…This is primarily due to hypoxia and can be reversed by promoting neovascularization. Additionally, newly formed blood vessels allow the tumor cells to metastasize to distant sites in the body, underscoring the importance of understanding the regulation of tumor angiogenesis (2,3).…”