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Prognostic factors of oesophageal squamous cell carcinoma from the perspective of molecular biology

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Summary

Recent developments in molecular biology have revealed that several oncogenes, suppressor genes and adhesion molecules are involved in the development of oesophageal cancer; however, the role of these genes is still unknown. To evaluate which molecular biological factors are related to patients’ prognosis and recurrence, we checked p53, p16, p21/Waf1, cyclin D1, Ki-67, epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), Mdm2, Bcl2, E-cadherin and MRP1/CD9 by means of immunohistochemical analysis in 116 cases of oesophageal cancer (R0). We also checked the regrowth capability of the primary cultures of the resected tumours and the effect of post-operative treatment. Although univariate analysis revealed that pN (pTNM), pT (pTNM), sex, cyclin D1, Ki-67, VEGF, E-cadherin and cell regrowth capability were prognostic factors, multivariate analysis revealed that pN (risk ratio (RR) 3.17), sex (RR 8.13), cell regrowth capability (RR 3.03) and E-cadherin (RR 0.30) were prognostic factors. Interestingly, step-wise analysis revealed that the following five factors were prognostic factors: pN (RR 5.74), sex (RR 3.14), cyclin D1 (RR 2.29), E-cadherin (RR 0.26) and cell regrowth capability (RR 1.94). Logistic regression analysis revealed that the risk factors of haematogenous recurrence were pN (odds ratio (OR) 8.97), cyclin D1 (OR 4.52) and EGFR (OR 0.18). On the other hand, the risk factor of lymph node recurrence was pN (OR 5.16). With regard to the effect of post-operative treatment, post-operative radiotherapy was a favourable risk factor (RR 0.43) and reduced the haematogenous recurrence (OR 0.18). Our data indicate that combination analysis using pN, sex, cyclin D1, E-cadherin, EGFR and cell regrowth capability may be useful for the prediction of patient survival and recurrence.

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  • 16 November 2011

    This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication

References

  • Akiyama, H., Tsurumaru, M., Udagawa, H. & Kajiyama, Y. (1994). Radical lymph node dissection for cancer of the thoracic esophagus. Ann Surg 220: 364–373.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Akselen, L. A. & Varhaug, J. E. (1995). Oncoproteins and tumour progression in papillary thyroid carcinoma. Cancer 76: 1643–1654.

    Article  Google Scholar 

  • Bukholm, I. K., Nesland, J. M., Karesen, R., Jacobsen, U. & Borresen-Dale, A. L. (1997). Interaction between bcl-2 and p21 (WAF1/CIP1) in breast carcinomas with wild-type p53. Int J Cancer 73: 38–41.

    CAS  Article  PubMed  Google Scholar 

  • Casey, G., Lopez, M. E., Ramos, J. C., Plummer, S. J., Arboleda, M. J., Shaughnessy, M., Karlan, B. & Slamon, D. J. (1996). DNA sequence analysis of exon 2 through 11 and immunohistochemical staining are required to detect all known p53 alterations in human malignancies. Oncogene 13: 1971–1981.

    CAS  PubMed  Google Scholar 

  • Coggi, G., Bosari, S., Roncalli, M., Graziani, D., Bossi, P., Viale, G., Buffa, R., Ferrero, S., Piazza, M., Blandamura, S., Segalin, A., Bonavina, L. & Peracchia, A. (1997). P53 protein accumulation and p53 gene mutation in esophageal carcinoma. Cancer 79: 425–432.

    CAS  Article  PubMed  Google Scholar 

  • Cox, D. R. (1972). Regression models and life tables. J R Stat Soc (B) 34: 187–220.

    Google Scholar 

  • Higashiyama, M., Doi, O., Kodama, K., Yokouchi, H., Kasugai, T., Ishiguro, S., Takami, K., Nakayama, T. & Nishisho, I. (1997). MDM2 gene amplification and expression in non-small-cell lung cancer: immunohistochemical expression of its protein is a favorable prognostic marker in patients without p53 protein accumulation. Br J Cancer 75: 1302–1308.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Imamura, M., Shimada, Y., Kanda, Y., Miyahara, T., Hashimoto, M., Tobe, T., Arai, T. & Hatano, Y. (1992). Hemodynamic changes after resection of thoracic duct for en bloc resection of esophageal cancer. Surg Today 22: 226–232.

    CAS  Article  PubMed  Google Scholar 

  • Inoue, K., Ozeki, Y., Suganuma, T., Sugiura, Y. & Tanaka, S. (1997). Vascular endothelial growth factor expression in primary esophageal squamous cell carcinoma. Cancer 79: 206–213.

    CAS  Article  PubMed  Google Scholar 

  • Ishikawa, T., Furihata, M., Ohtsuki, Y., Murakami, H., Inoue, A. & Ogoshi, S. (1998). Cyclin D1 overexpression related to retinoblastoma protein expression as a prognostic marker in human oesophageal squamous cell carcinoma. Br J Cancer 77: 92–97.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Itakura, Y., Sasano, H., Shiga, C., Furukawa, Y., Shiga, K., Mori, S. & Nagura, H. (1994). Epidermal growth factor receptor overexpression in esophageal carcinoma. Cancer 74: 795–804.

    CAS  Article  PubMed  Google Scholar 

  • Jiang, W., Kahn, S. M., Tomiyta, N., Tomita, N., Zhang, Y. J., Lu, S. H. & Weinstein, I. B. (1992). Amplification and expression of the human cyclinD gene in esophageal cancer. Cancer Res 52: 2980–2983.

    CAS  PubMed  Google Scholar 

  • Kadowaki, T., Shiozaki, H., Inoue, M., Tamura, S., Oka, H., Doki, Y., Iihara, K., Matsui, S., Iwazawa, T., Nagafuchi, A., Tsuikita, S. & Mori, T. (1994). E-cadherin and α-catenin expression in human esophageal cancer. Cancer Res 54: 291–296.

    CAS  PubMed  Google Scholar 

  • Kanda, Y., Nishiyama, Y., Shimada, Y., Imamura, M., Nomura, H. & Hiai, H., Fukumoto (1994). Analysis of gene amplification and overexpression in human esophageal-carcinoma cell lines. Int J Cancer 58: 291–297.

    CAS  Article  PubMed  Google Scholar 

  • Komiya, T., Hosono, Y., Hirashima, T., Masuda, N., Yasumitsu, T., Nakagawa, K., Kikui, M., Ohno, A., Fukuoka, M. & Kawase, I. (1997). p21 expression as a predictor for favourable prognosis in squamous cell carcinoma of the lung. Clin Cancer Res 3: 1831–1835.

    CAS  PubMed  Google Scholar 

  • Maex, J. (1994). How cells cycle toward cancer. Science 263: 319–321.

    Article  Google Scholar 

  • Maruyama, K., Watanabe, H., Shiozaki, H., Takayama, T., Gofuku, J., Yano, H., Inoue, M., Tamura, S., Raz, A. & Monden, M. (1995). Expression of autocrine motility factor receptor in human oesophageal squamous cell carcinoma. Int J Cancer 64: 316–321.

    CAS  Article  PubMed  Google Scholar 

  • Matsubara, T., Kasai, T., Ishiguro, M. & Nakajima, T. (1994). Better grading system for evaluating the degree of lymph node invasion in cancer of the thoracic esophagus. Surg Today 24: 500–505.

    CAS  Article  PubMed  Google Scholar 

  • Matsushime, H., Roussel, M. F., Ashimun, R. A. & Sherr, C. J. (1991). Colony-stimulating factor 1 regulates novel cyclins during the G1 phase of the cell cycle. Cell 65: 701–713.

    CAS  Article  PubMed  Google Scholar 

  • Miyake, M., Nakano, K., Itoi, S., Koh, T. & Taki, T. (1996). Motility-rerated protein-1 (MRP-1/CD9) reduction as a factor of poor prognosis in breast cancer. Cancer Res 56: 1244–1249.

    CAS  PubMed  Google Scholar 

  • Miyata, M., Shiozaki, H., Iihara, K., Shimaya, K., Oka, H., Kadowaki, T., Inoue, M., Tamura, S., Takeichi, M. & Mori, T. (1994). Relationship between E-cadherin expression and lymph node metastasis in human esophageal cancer. Int J Oncol 4: 61–65.

    CAS  PubMed  Google Scholar 

  • Mukaida, H., Toi, M., Hirai, T., Yamashita, Y. & Toge, T. (1991). Clinical significance of the expression of epidermal growth factor and its receptor in esophageal cancer. Cancer 68: 142–148.

    CAS  Article  PubMed  Google Scholar 

  • Naitoh, H., Shibata, J., Kawaguchi, A., Kodama, M. & Hattori, T. (1995). Overexpression and localization of cyclin D1 mRNA and antigen in esophageal cancer. Am J Pathol 146: 1161–1169.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Nakagawa, H., Zukerberg, L., Togawa, K., Meltzer, S. J., Nishihara, T. & Rustgi, A. K. (1995). Human cyclin D1 oncogene and esophageal squamous cell carcinoma. Cancer 76: 541–549.

    CAS  Article  PubMed  Google Scholar 

  • Nishimura, Y., Ono, K., Imamura, M., Hiraoka, M., Takahashi, M., Abe, M., Ohishi, K., Yanagibashi, K. & Tobe, T. (1989). Postoperative radiation therapy for esophageal cancer. Radiation Medicine 7: 88–94.

    CAS  PubMed  Google Scholar 

  • Ohbu, M., Saegusa, M., Kobayashi, N., Tsukamoto, H., Mieno, H., Kakita, A. & Okayasu, I. (1997). Expression of bcl-2 protein in oesophageal squamous cell carcinomas and its association with lymph node metastasis. Cancer 79: 1287–1293.

    CAS  Article  PubMed  Google Scholar 

  • Ohtsubo, M., Gamou, S. & Shimizu, N. (1998). Antisense oligonucleotide of WAF1 gene prevents EGF-induced cell-cycle arrest in A431 cells. Oncogene 16: 797–802.

    CAS  Article  PubMed  Google Scholar 

  • Ozawa, S., Ueda, M., Ando, N., Shimizu, N. & Abe, O. (1988). Prognostic significance of epidermal growth factor receptor in esophageal squamous cell carcinomas. Cancer 63: 2169–2173.

    Article  Google Scholar 

  • Paavonen, K., Horelli, K. N., Chilov, D., Kukk-E, Pennanen, S., Kallioniemi, O. P., Pajusola, K., Olofsson, B., Eriksson, U., Joukov, V., Palotie, A. & Alitalo, K. (1996). Novel human vascular endothelial growth factor genes VEGFb and VEGFc localize to chromosome 11q13 and 4q34, respectively. Circulation 93: 1079–1082.

    CAS  Article  PubMed  Google Scholar 

  • Ruol, A., Segalin, A., Panozzo, M., Stephens, J. K., Dalla, P. P., Skinner, D. B., Peracchia, A. & Little, A. G. (1990). Flow cytometric DNA analysis of squamous cell carcinoma of the esophagus. Cancer 65: 1185–1188.

    CAS  Article  PubMed  Google Scholar 

  • Sabin, L. H. & Wittekind, C. H. (1997). TNM Classification of Malignant Tumours, 5th edn. Wiley-Liss: New York

    Google Scholar 

  • Sarbia, M., Porschen, R., Borchard, F., Horstmann, O., Willers, R. & Gabbert, H. E. (1994). p53 protein expression and prognosis in squamous cell carcinoma of the oesophagus. Cancer 74: 2218–2223.

    CAS  Article  PubMed  Google Scholar 

  • Sarbia, M., Brittinger, F., Porshen, R., Verreet, P., Dutkowski, P., Willers, R. & Gabbert, H. E. (1996). Bcl2 expression and prognosis in squamous cell carcinomas of the oesophagus. Int J Cancer 69: 324–328.

    CAS  Article  PubMed  Google Scholar 

  • Shibagaki, I., Shimada, Y., Wagata, T., Ikenaga, M., Imamura, M. & Ishizaki, K. (1994). Allelotype analysis of oesophageal squamous cell carcinoma. Cancer Res 54: 2996–3000.

    CAS  PubMed  Google Scholar 

  • Shibagaki, I., Tanaka, H., Shimada, Y., Wagata, T., Ikenaga, M., Imamura, M. & Ishizaki, K. (1995). p53 mutation, murine double minute 2 amplification, and human papillomavirus infection are frequently involved but not associated with each other in oesophageal squamous cell carcinoma. Clin Cancer Res 1: 769–773.

    CAS  PubMed  Google Scholar 

  • Shimada, Y. & Imamura, M. (1993). Prognostic significance of cell culture in carcinoma of the oesophagus. Br J Surg 80: 605–607.

    CAS  Article  PubMed  Google Scholar 

  • Shimada, Y., Kanda, Y., Wagata, T., Shibagaki, I., Toda, S., Yamazoe, Y., Maetani, S. & Imamura, M. (1994). Predictive factors in the recurrence of esophageal carcinoma after curative esophagectomy. Jpn J Gastroenterol Surg 27: 2273–2278.

    Article  Google Scholar 

  • Shimada, Y., Kanda, Y., Shibagaki, I., Kato, M., Watanabe, G., Tanaka, H., Kano, M. & Imamura, M. (1996). The prognostic value of monolayer culture patterning in primary cell culture of oesophageal cancer. Br J Surg 83: 1148–1151.

    CAS  Article  PubMed  Google Scholar 

  • Shimada, Y., Imamura, M., Shibagaki, I., Tanaka, H., Miyahara, T., Kato, M. & Ishizaki, K. (1997). Genetic alterations in patients with esophageal cancer with short- and long-term survival rates after curative esophagectomy. Ann Surg 226: 162–168.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Shinozaki, H., Ozawa, S., Ando, N., Tsuruta, H., Terada, M., Ueda, M. & Kitajima, M. (1996). Cyclin D1 amplification as a new predictive classification for squamous cell carcinoma of the esophagus adding gene information. Clin Cancer Res 2: 1155–1161.

    CAS  PubMed  Google Scholar 

  • Shiozaki, H., Kadowaki, T., Doki, Y., Inoue, M., Tamura, S., Oka-H, Iwazawa, T., Matsui, S., Shimaya, K., Takeichi, M. & Monden, M. (1995). Effect of epidermal growth factor on cadherin-mediated adhesion in a human oesophageal cancer cell line. Br J Cancer 71: 250–258.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Sugimachi, K., Matsuoka, H., Matsufuji, H., Maekawa, S., Kai, H. & Okudaira, Y. (1987). Survival rates of women with carcinoma of the esophagus exceed those of men. Surg Gynecol Obstet 164: 541–544.

    CAS  PubMed  Google Scholar 

  • Takeuchi, H., Ozawa, S., Ando, N., Shih, C. H., Koyanagi, K., Ueda, M. & Kitajima, M. (1997). Altered p16/MTS1/CDKN2 and cyclin D1/PRAD1 gene expression is associated with the prognosis of squamous cell carcinoma of the esophagus. Clin Cancer Res 3: 2229–2236.

    CAS  PubMed  Google Scholar 

  • Tamura, S., Shiozaki, H., Miyata, M., Kadowaki, T., Inoue, M., Matsui, S., Iwazawa, T., Takayama, T., Takeichi, M. & Monden, M. (1996). Decreased E-cadherin expression is associated with haematogenous recurrence and poor prognosis in patients with squamous cell carcinoma of the oesophagus. Br J Surg 83: 1608–1614.

    CAS  Article  PubMed  Google Scholar 

  • Uchida, S., Shimada, Y., Watanabe, G., Tanaka, H., Shibagaki, I., Miyahara, T., Ishigami, S., Arii, S. & Imamura, M. (1998). In oesophageal squamous carcinoma vascular endothelial growth factor is associated with p53 mutation, advanced stage and poor prognosis. Br J Cancer 77: 1704–1709.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Ueo, H., Matsuoka, H., Sugimachi, K., Kuwano, H., Mori, M. & Akiyoshi, T. (1990). Inhibitory effects of estrogen on the growth of a human esophageal carcinoma cell line. Cancer Res 50: 7212–7215.

    CAS  PubMed  Google Scholar 

  • Utsumi, Y., Nakamura, T., Nagasue, N., Kubota, H. & Morikawa, S. (1989). Role of estrogen receptors in the growth of human esophageal carcinoma. Cancer 64: 88–93.

    CAS  Article  PubMed  Google Scholar 

  • VanAndel, J. G., Dees, J. & Dijkhuis, C. M. (1979). Carcinoma of the esophagus. Ann Surg 190: 684–689.

    CAS  Article  Google Scholar 

  • Wagata, T., Ishizaki, K., Imamura, M., Shimada, Y., Ikenaga, M. & Tobe, T. (1991). Deletion of 17p and amplification of the int-2 gene in esophageal carcinomas. Cancer Res 51: 2113–2117.

    CAS  PubMed  Google Scholar 

  • Wagata, T., Shibagaki, I., Imamura¡, M., Shimada, Y., Toguchida, J., Yandell, D. W., Ikenaga, M., Tobe, T. & Ishizaki, K. (1993). Loss of 17p, mutation of p53 gene, and overexpression of p53 protein in esophageal squamous cell carcinomas. Cancer Res 53: 846–850.

    CAS  PubMed  Google Scholar 

  • Wang, D. Y., Xiang, Y. Y., Tanaka, M., Li-XR, Li-JL, Shen, Q., Sugimura, H. & Kino, I. (1994). High prevalence of p53 protein overexpression in patients with esophageal cancer in Linxian, China and its relationship to progression and prognosis. Cancer 74: 3089–3096.

    CAS  Article  PubMed  Google Scholar 

  • Yano, H., Shiozaki, H., Kobayashi, K., Yano, T., Tahara, H., Tamura, S. & Mori, T. (1991). Immunohistologic detection of the epidermal growth factor in human esophageal squamous cell carcinoma. Cancer 67: 91–98.

    CAS  Article  PubMed  Google Scholar 

  • Youssef, E. M., Matsuda, T., Takada, N., Osugi, H., Higashino, M., Kinoshita, H., Watanabe, T., Katsura, Y., Wanibuchi, H. & Fukushima, S. (1995). Prognostic significance of the MIB-1 proliferation index for patients with squamous cell carcinoma of the esophagus. Cancer 76: 358–366.

    CAS  Article  PubMed  Google Scholar 

  • Zhou, P., Jiang, W., Zhang, Y., Kahn, S. M., Schieren, I., Santella, R. M. & Weinstein, I. B. (1995). Antisense to cyclin D1 inhibits growth and reverses the transformed phenotype of human esophageal cancer cells. Oncogene 11: 571–580.

    CAS  PubMed  Google Scholar 

  • Zhou, P., Jiang, W., Weghorst, C. M. & Weinstein, I. B. (1996). Overexpression of cyclin D1 enhances gene amplification. Cancer Res 56: 36–39.

    CAS  PubMed  Google Scholar 

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Shimada, Y., Imamura, M., Watanabe, G. et al. Prognostic factors of oesophageal squamous cell carcinoma from the perspective of molecular biology. Br J Cancer 80, 1281–1288 (1999). https://doi.org/10.1038/sj.bjc.6990499

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Keywords

  • oesophageal cancer
  • molecular marker
  • biological marker
  • cyclin D1
  • E-cadherin

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