Clinicopathologic and Prognostic Significance of an Angiogenic Factor, Thymidine Phosphorylase, in Human Colorectal Carcinoma

Abstract

Inhibition of dThdPase in human colorectal carcinomas might improve prognosis for some patients.

The Sp1 transcription factor contributes to the tumor necrosis factor-induced expression of the angiogenic factor thymidine phosphorylase in human colon carcinoma cells

“…Thus the similarity in the transcription regulation of both TP and VEGF provides a molecular explanation for their coexpression in tumor tissue and its clinical consequences. In other instances in which both TP and VEGF levels were measured in the same specimen, however, TP was found to be an independent prognostic factor compared to VEGF, and it may be the primary contributor to angiogenesis in tumors which have low levels of VEGF (Takebayashi et al, 1996;Takahashi et al, 1996). This suggests that TP and VEGF expression need not always be coordinated, and other factors contribute to their levels of expression.…”

“…It is an angiogenic factor that was found to be chemotactic for endothelial cells in vitro and to induce neovascularization in several in vivo assays (Miyazono et al, 1987;Ishikawa et al, 1989;Sumizawa et al, 1993;Finnis et al, 1993). Studies have shown that TP expression was frequently elevated in human solid tumors, including colorectal cancers, where its expression was correlated with increased tumor microvessel density, increased tumor invasion and metastasis, and shorter patient survival time (Takebayashi et al, 1996). A more careful investigation of TP expression in colorectal and other cancers by immunohistochemistry revealed that TP was frequently highly expressed in the non-malignant infiltrating cells in the tumor, in some cases, in the absence of expression in the tumor neoplastic epithelium cells (Takahashi et al, 1996;Koukourakis et al, 1998;Lee et al, 1999;Engels et al, 1997;Takahashi et al, 1998;Shimaoka et al, 2000;van Triest et al, 2000).…”

Thymidine Phosphorylase and 2-Deoxyribose Stimulate Human Endothelial Cell Migration by Specific Activation of the Integrins α5β1 and αVβ3

“…Significantly less is known about the corresponding actions of TP, despite evidence that it is overexpressed in a large percentage and wide range of human solid tumors (22)(23)(24)(25)(26). Recent studies suggest that there are similarities in the transcriptional regulation of TP and VEGF, and there is a tendency for VEGF and TP to be co-expressed in some human cancers (34)(35)(36).…”

“…Recent studies suggest that there are similarities in the transcriptional regulation of TP and VEGF, and there is a tendency for VEGF and TP to be co-expressed in some human cancers (34)(35)(36). In other instances in which both TP and VEGF levels were measured in the same specimen, however, TP was found to be an independent prognostic factor distinct from VEGF, and it may be the primary contributor to angiogenesis in tumors that have low levels of VEGF (23,24). Our studies of the combined effect of TP and VEGF on HUVEC migration found that their effects were additive but only up to the maximal effect of each individual agent, suggesting that at some point in their transduction of signals, the two utilize the same or similar pathways.…”

“…TP is chemotactic for endothelial cells and has angiogenic activity in several in vivo assays, although it did not directly stimulate endothelial cell proliferation (16 -20). Studies have established a role for TP in experimental and clinical tumor angiogenesis, including transfection studies in which the TP gene increased the vascularization and growth of tumors growing in nude mice (20,21), and immunohistochemical studies of primary human solid tumors, in which TP was often found to be elevated in the tumors when compared with the corresponding nonneoplastic regions of the same organs (22)(23)(24)(25)(26). The mechanism by which TP mediates angiogenesis is unknown; we have used endothelial cell migration as an in vitro model to address this question.…”