Thymidine phosphorylase expression is associated with time to progression in patients with metastatic colorectal cancer

Abstract

Background5-Fluorouracil (5-FU) is the cornerstone of chemotherapeutic treatment for patients with colorectal cancer. The enzyme thymidine phosphorylase (TP) catalyzes the conversion of 5-FU to its active metabolite, 5-fluoro-2’-deoxyuridine. TP is expressed in tumour epithelial cells and stromal cells, particularly in tumour-associated macrophages. These macrophages may affect sensitivity to chemotherapy. Previously, we identified TP as a predictive factor in microdissected tumour samples of patients with advanced colorectal cancer. In the present study, we analysed TP expression in tissues and associated stromal cells from patients with advanced colorectal cancer and associated TP levels to tumour response and time-to-event variables during first-line chemotherapy treatment. We also investigated the association between serum TP levels at the time of surgery and gene expression in primary tumour tissues.MethodsThis study included 125 patients with metastatic colorectal cancer treated with first-line 5-FU-based chemotherapy. To quantify TP gene expression levels in tumour tissues, real-time polymerase chain reaction was performed using the 7500 Fast Real-Time PCR system (Applied Biosystems, Foster City, CA, USA). TP protein concentration in matched serum samples was determined using an enzyme-linked immunosorbent assay system (USCN Life Science Inc.).ResultsThe tumour response rate was 31%, and 30% of patients exhibited stable disease. No associations between TP expression level and age or gender were observed. Levels of TP mRNA in mucosa and tumours were positively correlated (r = 0.41, p < 0.01). No correlation between TP expression and tumour response rate was observed. Time to progression was significantly longer in patients with high TP expression (p < 0.01). Serum TP protein levels were not associated with tumour response or time-to-event variables and did not correlate with gene expression in tumour tissues.ConclusionsHigh TP gene expression in non-microdissected tumour tissues of patients with advanced colorectal cancer correlates with longer time to progression, which could be related to treatment. These results are in contrast to previous studies where microdissected tumour cells were analysed and may be due to the presence of adjacent stromal cells. Serum TP protein expression does not correlate to TP gene expression in tissues of patients with advanced colorectal cancer.

Thymidine phosphorylase expression and prognosis in colorectal cancer treated with 5‑fluorouracil‑based chemotherapy: A meta‑analysis

“…However, five of these 20 studies did not offer eligible data and it was no possible to obtain exact survival information from these five articles. After completing the selection process, data from a total of 15 studies ( 4 , 5 , 24 – 29 , 35 – 41 ) involving 1225 patients ( Fig. 1 ) were systematically analyzed.…”

“…Of the 15 studies, 9 ( 4 , 24 , 25 , 27 , 36 – 39 , 41 ) were conducted in Asia and seven were from Japan. A total of 10 ( 4 , 5 , 25 , 26 , 28 , 35 , 37 – 39 , 41 ) were retrospective studies, one ( 29 ) was a prospective study and the other four ( 24 , 27 , 35 , 40 ) were not stated. Although the chemotherapy regimen varied in all 15 articles, they all used 5-FU-based drugs.…”

“…As it has been demonstrated that TP has a complicated role in CRC development and 5-FU treatment, whether TP may predict the prognosis of patients with CRC treated with 5-FU-based chemotherapy remains uncertain. Various studies ( 4 , 5 , 24 , 25 ) have investigated the association between the levels of TP and survival in CRC patients; however, a certain conclusion regarding this has not been drawn. Although the majority have reported poorer overall survival (OS) and progression-free survival (PFS) in patients with tumors expressing high TP levels, there are also reports that have demonstrated no association between them, resulting in greatly different estimates of the prognostic value of TP expression between studies ( 26 – 29 ).…”

Pharmacologic resistance in colorectal cancer: a review

“…Low TP expression, measured in one study by reverse transcriptase polymerase chain reaction (RT-PCR) and in another by immunohistochemistry (IHC) and tissue microarrays, correlated with improved treatment outcomes, in terms of overall survival (OS), in patients with mCRC treated with adjuvant 5-FU [Soong et al 2008;Salonga et al 2000]. A more recent study analyzed tumor tissue from mCRC by RT-PCR and found longer time to progression with high TP expression [Lindskog et al 2014]. Further well-designed trials are needed to establish a definitive link between TP expression and resistance to FP therapy.…”

Identification of valid endogenous control genes for determining gene expression in C6 glioma cell line treated with conditioned medium from adipose-derived stem cell

“…Gene expression analysis using quantitative real-time reversetranscription PCR (RT-qPCR) has been shown to be a promising tool to study molecular markers related with cell malignancy, chemoresistance and response to treatment [25][26][27][28][29] besides being a fast, sensitive, reproducible and specific method to analyze gene expression [30]. The normalization of this method is an important step to control the experimental errors introduced during the process, such as variability of RNA, variability of extraction protocols, RNA purity, inefficiency of reverse transcription, inaccurate quantification of RNA sample and errors of pipetting [31,32].…”