JCT  Vol.6 No.5 , May 2015
Predicting Adjuvant Chemotherapy Outcome by Simultaneous Analysis of Thymidylate Synthase Expression and p53 Nuclear Accumulation in Colorectal Cancer

Studies have shown that the tumor suppressor gene p53 may regulate thymidylate synthase (TS) activity in colorectal cancer (CRC) cells, hence attributed to chemo-resistance to 5-flurouracil in CRC. In this study, a total of 299 primary CRC patients who underwent surgery alone or received an adjuvant 5-FU-based chemotherapy were retrospectively studied. TS expression and p53 nuclear accumulation on paraffin embedded primary tumor tissue arrays were immunohistochemically assessed, and their relationship to patient overall survival (OS) and disease free survival (DFS) were analyzed. No correlation was found between TS and p53 expression. p53 nuclear accumulation was significantly correlated with tumor location. In all, multivariate analysis shows that TNM stage is a good indicator of patient survival. TS or p53 is not an independent prognostic or predictive factor in the CRCs. In chemotherapy-treated group, simultaneous analysis of TS and p53 indicates patients in the p53-/TS- or p53+/TS+ group have significant better OS and DFS than the group p53-/TS+ or p53+/TS- (P < 0.01). Thus, our study suggests that simultaneous evaluation of both TS and p53 can help to predict the therapeutic effect of CRCs with 5-FU-based adjuvant chemotherapy.

Cite this paper
Yang, Z. , Huang, D. , Fang, L. , Feng, X. , Liu, H. , Wang, L. and Wang, J. (2015) Predicting Adjuvant Chemotherapy Outcome by Simultaneous Analysis of Thymidylate Synthase Expression and p53 Nuclear Accumulation in Colorectal Cancer. Journal of Cancer Therapy, 6, 446-454. doi: 10.4236/jct.2015.65048.
[1]   Jemal, A. (2011) Global Cancer Statistics (Vol. 61, Page 69, 2011). CA: A Cancer Journal for Clinicians, 61, 134-134.

[2]   Monga, D.K. and O’connell, M.J. (2006) Surgical Adjuvant Therapy for Colorectal Cancer: Current Approaches and Future Directions. Annals of Surgical Oncology, 13, 1021-1034.

[3]   Longley, D.B., Boyer, J., Allen, W.L., Latif, T., Ferguson, P.R., Maxwell, P.J., McDermott, U., Lynch, M., Harkin, D.P. and Johnston, P.G. (2002) The Role of Thymidylate Synthase Induction in Modulating p53-Regulated Gene Expression in Response to 5-Fluorouracil and Antifolates. Cancer Research, 62, 2644-2649.

[4]   Edler, D., Glimelius, B., Hallstrom, M., Jakobsen, A., Johnston, P.G., Magnusson, I., Ragnhammar, P. and Blomgren, H. (2002) Thymidylate Synthase Expression in Colorectal Cancer: A Prognostic and Predictive Marker of Benefit from Adjuvant Fluorouracil-Based Chemotherapy. Journal of Clinical Oncology, 20, 1721-1728.

[5]   Johnston, P.G., Fisher, E.R., Rockette, H.E., Fisher, B., Wolmark, N., Drake, J.C., Chabner, B.A. and Allegra, C.J. (1994) The Role of Thymidylate Synthase Expression in Prognosis and Outcome of Adjuvant Chemotherapy in Patients with Rectal Cancer. Journal of Clinical Oncology, 12, 2640-2647.

[6]   Chen, Y., Yi, C.H., Liu, L., Li, B., Wang, Y.W. and Wang, X.W. (2012) Thymidylate Synthase Expression and Prognosis in Colorectal Cancer: A Meta-Analysis of Colorectal Cancer Survival Data. The International Journal of Biological Markers, 27, 203-211.

[7]   Ohrling, K., Edler, D., Hallstrom, M., Ragnhammar, P. and Blomgren, H. (2005) Detection of Thymidylate Synthase Expression in Lymph Node Metastases of Colorectal Cancer Can Improve the Prognostic Information. Journal of Clinical Oncology, 23, 5628-5634.

[8]   Popat, S., Matakidou, A. and Houlston, R.S. (2004) Thymidylate Synthase Expression and Prognosis in Colorectal Cancer: A Systematic Review and Meta-Analysis. Journal of Clinical Oncology, 22, 529-536.

[9]   Brand, L., Munding, J., Pox, C.P., Ziebarth, W., Reiser, M., Huppe, D., Schmiegel, W., Reinacher-Schick, A. and Tannapfel, A. (2013) ss-Catenin, Cox-2 and p53 Immunostaining in Colorectal Adenomas to Predict Recurrence after Endoscopic Polypectomy. International Journal of Colorectal Disease, 28, 1091-1098.

[10]   Pancione, M., Forte, N., Campione, S., Napolitano, A., Parente, D., Sabatino, L., Febbraro, A. and Colantuoni, V (2010) The High Expression of p53 in Sporadic Colorectal Carcinoma Is Associated with Metastasis and Decreased Survival. Pathologica, 102, 51-56.

[11]   Conlin, A., Smith, G., Carey, F.A., Wolf, C.R. and Steele, R.J. (2005) The Prognostic Significance of K-Ras, p53, and APC Mutations in Colorectal Carcinoma. Gut, 54, 1283-1286.

[12]   Katkoori, V.R., Shanmugam, C., Jia, X., Vitta, S.P., Sthanam, M., Callens, T., Messiaen, L., Chen, D., Zhang, B., Bumpers, H.L., Samuel, T. and Manne, U. (2012) Prognostic Significance and Gene Expression Profiles of p53 Mutations in Microsatellite-Stable Stage III Colorectal Adenocarcinomas. PloS ONE, 7, e30020.

[13]   Lee, Y., Chen, Y., Chang, L.S. and Johnson, L.F. (1997) Inhibition of Mouse Thymidylate Synthase Promoter Activity by the Wild-Type p53 Tumor Suppressor Protein. Experimental Cell Research, 234, 270-276.

[14]   Lowe, S.W., Ruley, H.E., Jacks, T. and Housman, D.E. (1993) P53-Dependent Apoptosis Modulates the Cytotoxicity of Anticancer Agents. Cell, 74, 957-967.

[15]   Aylon, Y. and Oren, M. (2007) Living with p53, Dying of p53. Cell, 130, 597-600.

[16]   Petitjean, A., Mathe, E., Kato, S., Ishioka, C., Tavtigian, S.V., Hainaut, P. and Olivier, M. (2007) Impact of Mutant p53 Functional Properties on TP53 Mutation Patterns and Tumor Phenotype: Lessons from Recent Developments in the IARC TP53 Database. Human Mutation, 28, 622-629.

[17]   Longley, D.B., Harkin, D.P. and Johnston, P.G. (2003) 5-Fluorouracil: Mechanisms of Action and Clinical Strategies. Nature Reviews Cancer, 3, 330-338.

[18]   Bunz, F., Hwang, P.M., Torrance, C., Waldman, T., Zhang, Y., Dillehay, L., Williams, J., Lengauer, C., Kinzler, K.W. and Vogelstein, B. (1999) Disruption of p53 in Human Cancer Cells Alters the Responses to Therapeutic Agents. The Journal of Clinical Investigation, 104, 263-269.

[19]   Huh, J.W., Kim, H.R. and Kim, Y.J. (2013) Prognostic Role of p53 Messenger Ribonucleic Acid Expression in Patients after Curative Resection for Stage I to III Colorectal Cancer: Association with Colon Cancer Stem Cell Markers. Journal of the American College of Surgeons, 216, 1063-1069.

[20]   Munro, A.J., Lain, S. and Lane, D.P. (2005) P53 Abnormalities and Outcomes in Colorectal Cancer: A Systematic Review. British Journal of Cancer, 92, 434-444.

[21]   Paradiso, A., Simone, G., Petroni, S., Leone, B., Vallejo, C., Lacava, J., Romero, A., Machiavelli, M., De Lena, M., Allegra, C.J. and Johnston, P.G. (2000) Thymidilate Synthase and p53 Primary Tumour Expression as Predictive Factors for Advanced Colorectal Cancer Patients. British Journal of Cancer, 82, 560-567.

[22]   Carreras, C.W. and Santi, D.V. (1995) The Catalytic Mechanism and Structure of Thymidylate Synthase. Annual review of biochemistry, 64, 721-762.

[23]   Wilson, P.M., Danenberg, P.V., Johnston, P.G., Lenz, H.J. and Ladner, R.D. (2014) Standing the Test of Time: Targeting Thymidylate Biosynthesis in Cancer Therapy. Nature Reviews Clinical Oncology, 11, 282-298.

[24]   Danenberg, P.V., Malli, H. and Swenson, S. (1999) Thymidylate Synthase Inhibitors. Seminars in Oncology, 26, 621-631.

[25]   Rose, M.G., Farrell, M.P. and Schmitz, J.C. (2002) Thymidylate Synthase: A Critical Target for Cancer Chemotherapy. Clinical Colorectal Cancer, 1, 220-229.

[26]   Allegra, C.J., Paik, S., Colangelo, L.H., Parr, A.L., Kirsch, I., Kim, G., Klein, P., Johnston, P.G., Wolmark, N. and Wieand, H.S. (2003) Prognostic Value of Thymidylate Synthase, Ki-67, and p53 in Patients with Dukes’ B and C Colon Cancer: A National Cancer Institute-National Surgical Adjuvant Breast and Bowel Project Collaborative Study. Journal of Clinical Oncology, 21, 241-250.

[27]   Edler, D., Glimelius, B., Hallstrom, M., Jakobsen, A., Johnston, P.G., Magnusson, I., Ragnhammar, P. and Blomgren, H. (2002) Thymidylate Synthase Expression in Colorectal Cancer: A Prognostic and Predictive Marker of Benefit from Adjuvant Fluorouracil-Based Chemotherapy. Journal of Clinical Oncology, 20, 1721-1728.

[28]   Nakagawa, T., Shimada, M., Kurita, N., Iwata, T., Nishioka, M., Yoshikawa, K., Higashijima, J. and Utsunomiya, T. (2012) Thymidylate Synthase (TS) Protein Expression as a Prognostic Factor in Advanced Colorectal Cancer: A Comparison with TS mRNA Expression. Hepato-Gastroenterology, 59, 1059-1062.

[29]   Westra, J.L., Hollema, H., Schaapveld, M., Platteel, I., Oien, K.A., Keith, W.N., Mauritz, R., Peters, G.J., Buys, C.H., Hofstra, R.M. and Plukker, J.T. (2005) Predictive Value of Thymidylate Synthase and Dihydropyrimidine Dehydrogenase Protein Expression on Survival in Adjuvantly Treated Stage III Colon Cancer Patients. Annals of Oncology, 16, 1646-1653.

[30]   Chu, E., Cogliati, T., Copur, S.M., Borre, A., Voeller, D.M., Allegra, C.J. and Segal, S. (1996) Identification of in Vivo Target RNA Sequences Bound by Thymidylate Synthase. Nucleic Acids Research, 24, 3222-3228.

[31]   Chu, E., Copur, S.M., Ju, J., Chen, T.M., Khleif, S., Voeller, D.M., Mizunuma, N., Patel, M., Maley, G.F., Maley, F. and Allegra, C.J. (1999) Thymidylate Synthase Protein and p53 mRNA form an in Vivo Ribonucleoprotein Complex. Molecular and Cellular Biology, 19, 1582-1594.

[32]   Ju, J., Pedersen-Lane, J., Maley, F. and Chu, E. (1999) Regulation of p53 Expression by Thymidylate Synthase. Proceedings of the National Academy of Sciences of the United States of America, 96, 3769-3774.