Lindskog Elinor Bexe, Derwinger Kristoffer, Gustavsson Bengt, Falk Peter, Wettergren Yvonne
Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg 416 85, Sweden.
BMC Clin Pathol. 2014 Jun 10;14:25. doi: 10.1186/1472-6890-14-25. eCollection 2014.
5-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.
This 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.).
The 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.
High 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.
5-氟尿嘧啶（5-FU）是结直肠癌患者化疗治疗的基石。胸苷磷酸化酶（TP）催化5-FU转化为其活性代谢产物5-氟-2'-脱氧尿苷。TP在肿瘤上皮细胞和基质细胞中表达，尤其是在肿瘤相关巨噬细胞中。这些巨噬细胞可能影响化疗敏感性。此前，我们在晚期结直肠癌患者的显微切割肿瘤样本中确定TP为一个预测因子。在本研究中，我们分析了晚期结直肠癌患者组织及相关基质细胞中的TP表达，并将TP水平与一线化疗期间的肿瘤反应和事件发生时间变量相关联。我们还研究了手术时血清TP水平与原发性肿瘤组织中基因表达之间的关联。
本研究纳入了125例接受一线基于5-FU化疗的转移性结直肠癌患者。为了量化肿瘤组织中TP基因表达水平，使用7500快速实时PCR系统（美国应用生物系统公司，福斯特城，加利福尼亚州）进行实时聚合酶链反应。使用酶联免疫吸附测定系统（武汉优尔生科技股份有限公司）测定匹配血清样本中的TP蛋白浓度。
肿瘤反应率为31%，30%的患者疾病稳定。未观察到TP表达水平与年龄或性别之间存在关联。黏膜和肿瘤中的TP mRNA水平呈正相关（r = 0.41，p < 0.01）。未观察到TP表达与肿瘤反应率之间存在相关性。TP高表达患者的疾病进展时间显著更长（p < 0.01）。血清TP蛋白水平与肿瘤反应或事件发生时间变量无关，且与肿瘤组织中的基因表达无相关性。
晚期结直肠癌患者未显微切割的肿瘤组织中TP基因高表达与更长的疾病进展时间相关，这可能与治疗有关。这些结果与之前分析显微切割肿瘤细胞的研究结果相反，可能是由于存在相邻基质细胞。晚期结直肠癌患者组织中血清TP蛋白表达与TP基因表达不相关。
