The establishment of individualized chemotherapy for colorectal carcinoma based on the expression of genes involved in chemotherapeutic sensitivity or prognosis is necessary. To achieve this, the expression profiles of genes within tumors and their relationship to clinicopathological factors must be elucidated. Here, we selected 10 genes (TS, DPD, TP, FPGS, GGH, DHFR, ERCC1, TOPO-1, VEGF, and EGFR), examined differences in their mRNA expression between the upper and lower thirds of tumors by laser-captured microdissection and real-time RT-PCR (the Danenberg tumor profile), and analyzed the relationships between their expression profiles and clinicopathological factors. Interestingly, the mRNA expression of DPD, TP, and VEGF was significantly higher in the lower third than in the upper third of tumors ( , , and , resp.). Furthermore, increased ERCC1 mRNA expression in the lower third of tumors correlated with recurrence ( ), and VEGF mRNA expression was significantly higher in cases with recurrence than in cases without recurrence, both in the upper and lower thirds of tumors ( and , resp.). These results implied that heterogeneity in DPD, TP, and VEGF expression may exist in colorectal carcinoma and that ERCC-1 and VEGF may be markers predicting recurrence after curative operation. 1. Introduction 5-Fluorouracil (5-FU) and its relatives are mainstays in the chemotherapeutic treatment of colorectal carcinoma [1, 2]. Recently, several newly discovered drugs, including molecular targeted agents, have facilitated the progression and diversifications of chemotherapies. Furthermore, many studies have reported that a variety of candidates can be used to predict chemotherapeutic sensitivity or prognosis [3], and the establishment of individualized chemotherapy based on the expression profiles of these genes is necessary for promoting the efficacy of chemotherapeutic agents in both nonresponders and responders. To achieve this, differences in gene expression profiles and distributions throughout the tumor must be analyzed, and relationships between the distribution and extent of gene expression and clinicopathological factors must be elucidated. Among the many candidates reported thus far, we selected 10 genes that have been extensively analyzed as possible factors related to chemosensitivity and/or prognosis in colorectal carcinoma. Six genes (thymidylate synthetase TS, dihydropyrimidine dehydrogenase DPD, thymidine phosphorylase TP, folylpolyglutamate synthetase FPGS, gamma-glutamyl hydrolase GGH, and dihydrofolate reductase DHFR) are known to be involved in
References
[1]
A. Avallone, E. Di Gennaro, F. Bruzzese et al., “Synergistic antitumour effect of raltitrexed and 5-fluorouracil plus folinic acid combination in human cancer cells,” Anti-Cancer Drugs, vol. 18, no. 7, pp. 781–791, 2007.
[2]
P. Correale, S. Messinese, M. Caraglia et al., “A novel biweekly multidrug regimen of gemcitabine, oxaliplatin, 5-fluorouracil (5-FU), and folinic acid (FA) in pretreated patients with advanced colorectal carcinoma,” British Journal of Cancer, vol. 90, no. 9, pp. 1710–1714, 2004.
[3]
S. Fogli and M. Caraglia, “Genotype-based therapeutic approach for colorectal cancer: state of the art and future perspectives,” Expert Opinion on Pharmacotherapy, vol. 10, no. 7, pp. 1095–1108, 2009.
[4]
K. U. Hartmann and C. Heidelberger, “Studies on fluorinated pyrimidines—13. Inhibition of thymidylate synthetase,” The Journal of Biological Chemistry, vol. 236, pp. 3006–3013, 1961.
[5]
R. J. Langenbach, P. V. Danenberg, and C. Heidelberger, “Thymidylate synthetase: mechanism of inhibition by 5-fluoro- -deoxyuridylate,” Biochemical and Biophysical Research Communications, vol. 48, no. 6, pp. 1565–1571, 1972.
[6]
Z. H. Lu, R. Zhang, and R. B. Diasio, “Purification and characterization of dihydropyrimidine dehydrogenase from human liver,” Journal of Biological Chemistry, vol. 267, no. 24, pp. 17102–17109, 1992.
[7]
W. Ichikawa, H. Uetake, Y. Shirota et al., “Combination of dihydropyrimidine dehydrogenase and thymidylate synthase gene expressions in primary tumors as predictive parameters for the efficacy of fluoropyrimidine-based chemotherapy for metastatic colorectal cancer,” Clinical Cancer Research, vol. 9, no. 2, pp. 786–791, 2003.
[8]
M. E. Nita, O. Tominaga, H. Nagawa, T. Tsuruo, and T. Muto, “Dihydropyrimidine dehydrogenase but not thymidylate synthase expression is associated with resistance to 5-fluorouracil in colorectal cancer,” Hepato-Gastroenterology, vol. 45, no. 24, pp. 2117–2122, 1998.
[9]
T. Kobunai, A. Ooyama, S. Sasaki et al., “Changes to the dihydropyrimidine dehydrogenase gene copy number influence the susceptibility of cancers to 5-FU-based drugs: data mining of the NCI-DTP data sets and validation with human tumour xenografts,” European Journal of Cancer, vol. 43, no. 4, pp. 791–798, 2007.
[10]
R. Metzger, K. Danenberg, C. G. Leichman et al., “High basal level gene expression of thymidine phosphorylase (platelet- derived endothelial cell growth factor) in colorectal tumors is associated with nonresponse to 5-fluorouracil,” Clinical Cancer Research, vol. 4, no. 10, pp. 2371–2376, 1998.
[11]
B. S. Askari and M. Krajinovic, “Dihydrofolate reductase gene variations in susceptibility to disease and treatment outcomes,” Current Genomics, vol. 11, no. 8, pp. 578–583, 2010.
[12]
Y. Shirota, J. Stoehlmacher, J. Brabender et al., “ERCC1 and thymidylate synthase mRNA levels predict survival for colorectal cancer patients receiving combination oxaliplatin and fluorouracil chemotherapy,” Journal of Clinical Oncology, vol. 19, no. 23, pp. 4298–4304, 2001.
[13]
J. Folkman and Y. Shing, “Angiogenesis,” Journal of Biological Chemistry, vol. 267, no. 16, pp. 10931–10934, 1992.
[14]
J. Folkman, “What is the evidence that tumors are angiogenesis dependent?” Journal of the National Cancer Institute, vol. 82, no. 1, pp. 4–6, 1990.
[15]
H. S. Hochster, L. L. Hart, R. K. Ramanathan, et al., “Safety and efficacy of oxaliplatin and fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer: results of the TREE Study,” Journal of Clinical Oncology, vol. 26, no. 21, pp. 3523–3529, 2008.
[16]
H. Hurwitz, L. Fehrenbacher, W. Novotny et al., “Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer,” New England Journal of Medicine, vol. 350, no. 23, pp. 2335–2342, 2004.
[17]
A. F. Hashim, A. A. Al-Janabi, L. H. Mahdi, K. M. Al-Toriahi, and A. A. Yasseen, “Vascular endothelial growth factor (VEGF) receptor expression correlates with histologic grade and stage of colorectal cancer,” Libyan Journal of Medicine, vol. 5, no. 10, article 5059, 2010.
[18]
A. Furudoi, S. Tanaka, K. Haruma et al., “Clinical significance of vascular endothelial growth factor C expression and angiogenesis at the deepest invasive site of advanced colorectal carcinoma,” Oncology, vol. 62, no. 2, pp. 157–166, 2002.
[19]
I. Hyodo, T. Doi, H. Endo et al., “Clinical significance of plasma vascular endothelial growth factor in gastrointestinal cancer,” European Journal of Cancer, vol. 34, no. 13, pp. 2041–2045, 1998.
[20]
H. Takiuchi, I. Hirata, S. I. Kawabe, Y. Egashira, and K. I. Katsu, “Immunohistochemical expression of vascular endothelial growth factor can predict response to 5-fluorouracil and cisplatin in patients with gastric adenocarcinoma,” Oncology Reports, vol. 7, no. 4, pp. 841–846, 2000.
[21]
D. E. Neal, C. Marsh, and M. K. Bennett, “Epidermal-growth-factor receptors in human bladder cancer: comparison of invasive and superficial tumours,” Lancet, vol. 1, no. 8425, pp. 366–368, 1985.
[22]
R. V. N. Lord, D. Salonga, K. D. Danenberg et al., “Telomerase reverse transcriptase expression is increased early in the Barrett's metaplasia, dysplasia, adenocarcinoma sequence,” Journal of Gastrointestinal Surgery, vol. 4, no. 2, pp. 135–142, 2000.
[23]
J. Matsubara, T. Nishina, Y. Yamada et al., “Impacts of excision repair cross-complementing gene 1 (ERCC1), dihydropyrimidine dehydrogenase, and epidermal growth factor receptor on the outcomes of patients with advanced gastric cancer,” British Journal of Cancer, vol. 98, no. 4, pp. 832–839, 2008.
[24]
W. Ichikawa, T. Takahashi, K. Suto et al., “Thymidylate synthase and dihydropyrimidine dehydrogenase gene expression in relation to differentiation of gastric cancer,” International Journal of Cancer, vol. 112, no. 6, pp. 967–973, 2004.
[25]
Y. Fukui, T. Oka, S. Nagayama, P. V. Danenberg, K. D. Danenberg, and M. Fukushima, “Thymidylate synthase, dihydropyrimidine dehydrogenase, orotate phosphoribosyltransferase mRNA and protein expressionlevels in solid tumors in large scale population analysis,” International Journal of Molecular Medicine, vol. 22, no. 6, pp. 709–716, 2008.
