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

BMC Clinical Pathology

Yvonne Wettergren¹  Peter Falk¹  Bengt Gustavsson¹  Kristoffer Derwinger¹  Elinor Bexe Lindskog¹ 

[1] Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg 416 85, Sweden

关键词: Biological markers;    Serum;    Chemotherapy;    PD-ECGF;    Colorectal neoplasms;   

Others  :  834732
DOI  :  10.1186/1472-6890-14-25

 received in 2013-09-20, accepted in 2014-05-28,  发布年份 2014

【 摘 要 】

Background

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.

Methods

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.).

Results

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.

Conclusions

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.

【 授权许可】

   
2014 Bexe Lindskog et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

【 参考文献 】

• [1]Bronckaers A, Gago F, Balzarini J, Liekens S: The dual role of thymidine phosphorylase in cancer development and chemotherapy. Med Res Rev 2009, 29:903-953.
• [2]Miwa M, Ura M, Nishida M, Sawada N, Ishikawa T, Mori K, Shimma N, Umeda I, Ishitsuka H: Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue. Eur J Cancer 1998, 34:1274-1281.
• [3]Takebayashi Y, Yamada K, Miyadera K, Sumizawa T, Furukawa T, Kinoshita F, Aoki D, Okumura H, Yamada Y, Akiyama S, Aikou T: The activity and expression of thymidine phosphorylase in human solid tumours. Eur J Cancer 1996, 32A:1227-1232.
• [4]Nozawa T, Enomoto T, Koshida Y, Sato Y, Kuranami M: Specific enhanced expression of platelet-derived endothelial cell growth factor in submucosa of human colorectal cancer. Dis Colon Rectum 2004, 47:2093-2100.
• [5]Amatori F, Di Paolo A, Del Tacca M, Fontanini G, Vannozzi F, Boldrini L, Bocci G, Lastella M, Danesi R: Thymidylate synthase, dihydropyrimidine dehydrogenase and thymidine phosphorylase expression in colorectal cancer and normal mucosa in patients. Pharmacogenet Genomics 2006, 16:809-816.
• [6]Matsuura T, Kuratate I, Teramachi K, Osaki M, Fukuda Y, Ito H: Thymidine phosphorylase expression is associated with both increase of intratumoral microvessels and decrease of apoptosis in human colorectal carcinomas. Cancer Res 1999, 59:5037-5040.
• [7]Sengupta S, Sellers LA, Matheson HB, Fan TP: Thymidine phosphorylase induces angiogenesis in vivo and in vitro: an evaluation of possible mechanisms. Br J Pharmacol 2003, 139:219-231.
• [8]Matsumura M, Chiba Y, Lu C, Amaya H, Shimomatsuya T, Horiuchi T, Muraoka R, Tanigawa N: Platelet-derived endothelial cell growth factor/thymidine phosphorylase expression correlated with tumor angiogenesis and macrophage infiltration in colorectal cancer. Cancer Lett 1998, 128:55-63.
• [9]Takebayashi Y, Akiyama S, Akiba S, Yamada K, Miyadera K, Sumizawa T, Yamada Y, Murata F, Aikou T: Clinicopathologic and prognostic significance of an angiogenic factor, thymidine phosphorylase, in human colorectal carcinoma. J Natl Cancer Inst 1996, 88:1110-1117.
• [10]Kitazono M, Takebayashi Y, Ishitsuka K, Takao S, Tani A, Furukawa T, Miyadera K, Yamada Y, Aikou T, Akiyama S: Prevention of hypoxia-induced apoptosis by the angiogenic factor thymidine phosphorylase. Biochem Biophys Res Commun 1998, 253:797-803.
• [11]Mimori K, Matsuyama A, Yoshinaga K, Yamashita K, Masuda T, Inoue H, Ueo H, Mori M: Localization of thymidine phosphorylase expression in colorectal carcinoma tissues by in situ RT-PCR assay. Oncology 2002, 62:327-332.
• [12]Gustavsson B, Kaiser C, Carlsson G, Wettergren Y, Odin E, Lindskog EB, Niyikiza C, Ma D: Molecular determinants of efficacy for 5-FU-based treatments in advanced colorectal cancer: mRNA expression for 18 chemotherapy-related genes. Int J Cancer 2009, 124:1220-1226.
• [13]Kumamoto K, Kuwabara K, Tajima Y, Amano K, Hatano S, Ohsawa T, Okada N, Ishibashi K, Haga N, Ishida H: Thymidylate synthase and thymidine phosphorylase mRNA expression in primary lesions using laser capture microdissection is useful for prediction of the efficacy of FOLFOX treatment in colorectal cancer patients with liver metastasis. Oncol Lett 2012, 3:983-989.
• [14]Metzger R, Danenberg K, Leichman CG, Salonga D, Schwartz EL, Wadler S, Lenz HJ, Groshen S, Leichman L, Danenberg PV: High basal level gene expression of thymidine phosphorylase (platelet-derived endothelial cell growth factor) in colorectal tumors is associated with nonresponse to 5-fluorouracil. Clin Cancer Res 1998, 4:2371-2376.
• [15]Sadahiro S, Suzuki T, Tanaka A, Okada K, Nagase H, Uchida J: Association of right-sided tumors with high thymidine phosphorylase gene expression levels and the response to oral uracil and tegafur/leucovorin chemotherapy among patients with colorectal cancer. Cancer Chemother Pharmacol 2012, 70:285-291.
• [16]Tang X, Mo C, Wang Y, Wei D, Xiao H: Anti-tumour strategies aiming to target tumour-associated macrophages. Immunology 2013, 138:93-104.
• [17]Pauly JL, Schuller MG, Zelcer AA, Kirss TA, Gore SS, Germain MJ: Identification and comparative analysis of thymidine phosphorylase in the plasma of healthy subjects and cancer patients. J Natl Cancer Inst 1977, 58:1587-1590.
• [18]Shimada H, Takeda A, Shiratori T, Nabeya Y, Okazumi S, Matsubara H, Funami Y, Hayashi H, Gunji Y, Kobayashi S, Suzuki T, Ochiai T: Prognostic significance of serum thymidine phosphorylase concentration in esophageal squamous cell carcinoma. Cancer 2002, 94:1947-1954.
• [19]Fujimoto J, Sakaguchi H, Aoki I, Tamaya T: The value of platelet-derived endothelial cell growth factor as a novel predictor of advancement of uterine cervical cancers. Cancer Res 2000, 60:3662-3665.
• [20]Haraguchi M, Komuta K, Ueda T, Akashi A, Minami S, Furui J, Kanematsu T: Prognostic significance of the serum thymidine phosphorylase levels in venous blood drainage specimens in patients with colorectal cancer. Hepatogastroenterology 2008, 55:418-421.
• [21]Miller AB, Hoogstraten B, Staquet M, Winkler A: Reporting results of cancer treatment. Cancer 1981, 47:207-214.
• [22]Derwinger K, Lindskog EB, Palmqvist E, Wettergren Y: Changes in thymidine phosphorylase gene expression related to treatment of rectal cancer. Anticancer Res 2013, 33:2447-2451.
• [23]Lowry OH, Rosebrough NJ, Farr AL, Randall RJ: Protein measurement with the Folin phenol reagent. J Biol Chem 1951, 193:265-275.
• [24]van Halteren HK, Peters HM, van Krieken JH, Coebergh JW, Roumen RM, van der Worp E, Wagener JT, Vreugdenhil G: Tumor growth pattern and thymidine phosphorylase expression are related with the risk of hematogenous metastasis in patients with Astler Coller B1/B2 colorectal carcinoma. Cancer 2001, 91:1752-1757.
• [25]Lindskog EB, Wettergren Y, Odin E, Gustavsson B, Derwinger K: Thymidine phosphorylase gene expression in stage III colorectal cancer. Clin Med Insights Oncol 2012, 6:347-353.
• [26]Ciaparrone M, Quirino M, Schinzari G, Zannoni G, Corsi DC, Vecchio FM, Cassano A, La Torre G, Barone C: Predictive role of thymidylate synthase, dihydropyrimidine dehydrogenase and thymidine phosphorylase expression in colorectal cancer patients receiving adjuvant 5-fluorouracil. Oncology 2006, 70:366-377.
• [27]Tsuji T, Sawai T, Yamashita H, Takeshita H, Nakagoe T, Shindou H, Fukuoka H, Yoshinaga M, Hidaka S, Yasutake T, Nagayasu T, Tagawa Y: Platelet-derived endothelial cell growth factor expression is an independent prognostic factor in colorectal cancer patients after curative surgery. Eur J Surg Oncol 2004, 30:296-302.
• [28]Shabo I, Svanvik J: Expression of macrophage antigens by tumor cells. Adv Exp Med Biol 2011, 714:141-150.
• [29]Schwartz EL, Baptiste N, Wadler S, Makower D: Thymidine phosphorylase mediates the sensitivity of human colon carcinoma cells to 5-fluorouracil. J Biol Chem 1995, 270:19073-19077.
• [30]Matsushita S, Ikeda R, Nishizawa Y, Che XF, Furukawa T, Miyadera K, Tabata S, Ushiyama M, Tajitsu Y, Yamamoto M, Takeda Y, Mihami K, Mataki H, Kanzaki T, Yamada K, Kanekura T, Akiyama S: The role of thymidine phosphorylase in the induction of early growth response protein-1 and thrombospondin-1 by 5-fluorouracil in human cancer carcinoma cells. Int J Oncol 2010, 36:1193-1200.
• [31]Kato Y, Matsukawa S, Muraoka R, Tanigawa N: Enhancement of drug sensitivity and a bystander effect in PC-9 cells transfected with a platelet-derived endothelial cell growth factor thymidine phosphorylase cDNA. Br J Cancer 1997, 75:506-511.
• [32]Yanagisawa Y, Maruta F, Iinuma N, Ishizone S, Koide N, Nakayama J, Miyagawa S: Modified irinotecan/5FU/leucovorin therapy in advanced colorectal cancer and predicting therapeutic efficacy by expression of tumor-related enzymes. Scand J Gastroenterol 2007, 42:477-484.
• [33]Kuramochi H, Hayashi K, Uchida K, Miyakura S, Shimizu D, Vallbohmer D, Park S, Danenberg KD, Takasaki K, Danenberg PV: 5-fluorouracil-related gene expression levels in primary colorectal cancer and corresponding liver metastasis. Int J Cancer 2006, 119:522-526.
• [34]Uchida K, Danenberg PV, Danenberg KD, Grem JL: Thymidylate synthase, dihydropyrimidine dehydrogenase, ERCC1, and thymidine phosphorylase gene expression in primary and metastatic gastrointestinal adenocarcinoma tissue in patients treated on a phase I trial of oxaliplatin and capecitabine. BMC Cancer 2008, 8:386. BioMed Central Full Text