Thymidine Phosphorylase in Cancer; Enemy or Friend?

Abstract

Thymidine phosphorylase (TP) is a nucleoside metabolism enzyme that plays an important role in the pyrimidine pathway.TP catalyzes the conversion of thymidine to thymine and 2-deoxy-α-D-ribose-1-phosphate (dRib-1-P). Although this reaction is reversible, the main metabolic function of TP is catabolic. TP is identical to the angiogenic factor platelet-derived endothelial-cell growth factor (PD-ECGF). TP is overexpressed in several human cancers in response to cellular stressful conditions like hypoxia, acidosis, chemotherapy and radiotherapy. TP has been shown to promote tumor angiogenesis, invasion, metastasis, evasion of the immune-response and resistance to apoptosis. Some of the biological effects of TP are dependent on its enzymatic activity, while others are mediated through cytokines like interleukin 10 (IL-10), basic fibroblast growth factor (bFGF) and tumour necrosis factor α (TNFα). Interestingly, TP also plays a role in cancer treatment through its role in the conversion of the oral fluoropyrimidine capecitabine into its active form 5-FU. TP is a predictive marker for fluoropyrimidine response. Given its various biological functions in cancer progression, TP is a promising target in cancer treatment. Further translational research is required in this area.

Keywords: Angiogenesis; Hallmarks of cancer; Predictive biomarkers; Thymidine phosphorylase.

Fig. 1

Enzymatic reactions catalysed by TP. TP catalyses the reversible conversion of thymidine (TdR) to thymine and 2-deoxy-α-D-ribose-1-phosphate (dRib-1-P), and the phosphorolysis of deoxyuridine to uracil and 2-deoxy-α-D-ribose-1-phosphate. Although this reaction is reversible the main function of TP is catabolic

Fig. 2

TP is overexpressed in response to cellular stress conditions like hypoxia, low PH and exposure to chemotherapy; TP then exerts its different biological effects. TP = Thymidine Phosphorylase. TNFα = Tumor necrosis factor α. HIF2α = Hypoxia inducible factor 2α. IFN = Interferon. MMP = Matrix metalloprotease. EC = Endothelial cells. FAK = Focal adhesion kinase. bFGF = b fibroblast growth factor. IL = Interleukin. BNIP3 = BCL2/adenovirus E1B 19 kDa protein-interacting protein. BAX = Bcl-2-associated X protein