Summary
Recently, the serum level of interleukin (IL)-6 has been shown to correlate with disease progression and prognosis of cancer patients. However, the available information about the source and the pathophysiological regulation of IL-6 in cancer cells is limited. Thus, in this study, we tried to identify the source and the clinical roles of serum IL-6 in patients with oesophageal squamous cell carcinoma (ESCC), and then further to characterize the biological regulation of IL-6 in ESCC cell lines. Sera and tissue specimens from 80 consecutive patients with ESCC were collected between 1993 and 1997. Additionally, three ESCC cell lines were used for in vitro study. The concentration of serum IL-6 was measured by enzyme-linked immunosorbent assay (ELISA), and correlated the survival time with measured IL-6 level. Expressions of IL-6, IL-6Rα (IL-6 receptor alpha) and gp130 in pathological sections and cell lines were characterized by immunological staining. Detection of IL-6 mRNA was determined by in situ hybridization (ISH) and reverse transcription-polymerase chain reaction (RT-PCR). Up-regulation of IL-6 by n-sodium butyrate (n-BT) was studied in ESCC cell lines. The levels of serum IL-6 in patients with ESCC were significantly higher than those in the healthy controls. Serum levels of IL-6 were also shown to correlate with disease progression and survival. However, sCD8 levels and lymphocyte counts in the peripheral blood were not parallel to the changed pattern of serum IL-6. In pathological sections and ESCC cell lines, message of IL-6 was identified by ISH in cancer cells. Expression of IL-6 mRNA was further confirmed with RT-PCR in ESCC cell lines. Although IL-6 was detected in some ESCC cell lines, IL-6 gene expression and protein production could be induced or enhanced by n-BT treatment in all three cell lines. The serum levels of IL-6 are frequently elevated at diagnosis of ESCC, and are associated with poor prognosis. IL-6 that could be produced by cancer cells is up-regulated by n-BT.
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References
Baba, M., Hasegawa, H., Nakayabu, M., Shimizu, N., Suzuki, S., Kamada, N. & Tani, K. (1995). Establishment and characteristics of a gastric cancer cell line (HuGC-OOHIRA) producing high levels of G-CSF, GM-CSF, and IL-6: the presence of autocrine growth control by G-CSF. Am J Hematol 49: 207–215.
Blay, J. Y., Negrier, S., Combaret, V., Attali, S., Goillot, E., Merrouche, Y., Mercatello, A., Ravault, A., Tourani, J. M. & Moskovtchenko, J. F. (1992). Serum level of interleukin 6 as a prognostic factor in metastatic renal cell carcinoma. Cancer Res 52: 3317–3322.
Castell, J. V., Gomez-Lechon, M. J., David, M., Horano, T., Kishimoto, T. & Heinrich, P. C. (1990). Acute phase responses of human hepatocytes: regulation of acute phase protein synthesis by IL-6. Hepatology 12: 1179–1186.
Chiu, C. F., Chow, K. C., Lin, F. M., Lin, C. K., Liu, S. M. & Chen, K. Y. (1997). Expression of DNA topoisomerase IIα and multidrug resistance p-glycoprotein in acute leukemia. Chin Med J (Taipei) 60: 184–190.
Chow, K. C. & Chen, K. Y. (1995). The role of Epstein–Barr virus infection and the immunocompetence of patients with nasopharyngeal cancers. Therapeutic Radiol Oncol 2: 243–260.
Chow, K. C., Nacilla, J. Q., Witzig, T. E. & Li, C. Y. (1992). Is persistent polyclonal B lymphocytosis caused by Epstein–Barr virus? A study with polymerase chain reaction and in situ hybridization. Am J Hematol 41: 270–275.
Chow, K. C., Zhang, J. H., Chou, S. L., Tseng, W. S. & Chen, K. Y. (1997). The application of virus in the diagnosis and therapy of tumor. Therapeutic Radiol Oncol 4: 155–178.
Eustace, D., Han, X., Gooding, R., Rowbottom, A., Riches, P. & Heyderman, E. (1993). Interleukin 6 (IL-6) functions as an autocrine growth factor in cervical carcinoma in vitro. Gyneccol Oncol 50: 151–159.
Gauldie, J., Richards, C., Harnish, D., Lansdorp, P. & Baumann, H. (1987). Interferon β 2/BSF2 shares identity with monocyte derived hepatocyte stimulating factor and regulates the major acute phase protein in liver cells. Proc Natl Acad Sci USA 84: 7251–7255.
Inoue, M., Minami, M., Fujii, Y., Matsuda, H., Shirakura, R. & Kido, T. (1997). Granulocyte colony-stimulating factor and interleukin-6-producing lung cancer cell line, LCAM. J Surg Oncol 64: 347–350.
Kabir, S. & Daar, G. A. (1995). Serum levels of interleukin-1, interleukin-6 and tumour necrosis factor-alpha in patients with gastric carcinoma. Cancer Lett 95: 207–212.
Kaplan, E. L. & Meier, P. (1958). Nonparametric estimation from incomplete observations. Am Stat Assoc J 53: 457–481.
Katlic, M. R., Wilkins, E. W. & Grillo, H. C. (1990). Three decades of treatment of oesophageal squamous carcinoma at the Massachusetts General Hospital. J Thorac Cardiovasc Surg 99: 929–938.
Kawano, M., Hirano, T., Matsuda, T., Taga, T., Horii, Y., Iwato, K., Asaoku, H., Tang, B., Tanabe, O. & Tanaka, H. (1988). Autocrine generation and requirement of BSF-2/IL-6 for human multiple myeloma. Nature 332: 83–85.
Kishimoto, T. (1990). The biology of interleukin 6. Blood 74: 1–10.
Lee, J. D., Sievers, T. M., Skotzko, M., Chandler, C. F., Morton, D. L., McBride, W. H. & Economou, J. S. (1992). Interleukin 6 production by human melanoma cell lines. Lymphokine Cytokine Res 11: 161–166.
Liu, C. C., Fahn, H. J., Li, W. Y., Wu, Y. C., Huang, M. H. & Wang, L. S. (1998). Lymph node metastasis in squamous cell carcinoma of the intrathoracic esophagus. Chin Med J (Taipei) 61: 77–84.
Miki, S., Iwano, M., Miki, Y., Yamamoto, M., Tang, B., Yokokawa, K., Sonoda, T., Hirano, T. & Kishimoto, T. (1989). Interleukin 6 (IL-6) functions as an in vitro autocrine growth factor in renal cell carcinomas. FEBS Lett 250: 607–610.
Ni, K. & O’Neill, H. C. (1992). Proliferation of the BCL1 B cell lymphoma induced by IL-4 and IL-5 is dependent on IL-6 and GM-CSF. Immunol Cell Biol 70: 315–321.
Obata, N. H., Tamakoshi, K., Shibata, K., Kikkawa, F. & Tomoda, Y. (1997). Effects of interleukin-6 on in vitro cell attachment, migration and invasion of human ovarian carcinoma. Anticancer Res 17: 337–342.
Oka, M., Yamamoto, K., Takahashi, M., Hakozaki, M., Abe, T., Iizuka, N., Hazama, S., Hirazawa, K., Hayashi, H., Tangoku, A., Hirose, K., Ishihara, T. & Suzuki, T. (1996). Relationship between serum levels of interleukin 6, various disease parameters, and malnutrition in patients with oesophageal carcinoma. Cancer Res 56: 2776–2780.
Peto, R. & Pike, M. C. (1973). Conservatism of the approximation Σ (O–E)2/E in the log-rank test for survival data or incidence data. Biometrics 29: 579–584.
Ray, A., Tatter, S. B., May, L. T. & Sehgal, P. B. (1988). Activation of the human ‘β2-interferon/hepatocyte-stimulating factor/interleukin 6’ promoter by cytokines, viruses, and second messenger agonists. Proc Natl Acad Sci USA 85: 6701–6705.
Reichner, J. S., Mulligan, J. A., Palla, M. E., Hixson, D. C., Albina, J. E. & Bland, K. (1996). Interleukin-6 production by rat hepatocellular carcinoma cells is associated with metastatic potential but not with tumorigenicity. Arch Surg 131: 360–365.
Scambia, G., Testa, U., Benedetti Panici, P., Foti, E., Martucci, R., Gadducci, A., Perillo, A., Facchini, V., Peschle, C. & Mancuso, S. (1995). Prognostic significance of interleukin 6 serum levels in patients with ovarian cancer. Br J Cancer 71: 354–356.
Seymour, J. F., Talpaz, M., Hagemeister, F. B., Cabanillas, F. & Kurzrock, R. (1997). Clinical correlates of elevated serum levels of interleukin 6 in patients with untreated Hodgkin’s disease. Am J Med 102: 21–28.
Stein, T. P., Koerner, B., Schluter, M. D., Leskiw, M. J., Gaprindachvilli, T., Richards, E. W., Cope, F. O. & Condolucci, D. (1997). Weight loss, the gut and the inflammatory response in Aids patients. Cytokine 9: 143–147.
Strassmann, G., Fong, M., Kenney, J. S. & Jacob, C. O. (1992a). Evidence for the involvement of interleukin 6 in experimental cancer cachexia. J Clin Invest 89: 1681–1684.
Strassmann, G., Jacob, C. O., Evans, R., Beall, D. & Fong, M. (1992b). Mechanism of experimental cancer cachexia. Interaction between mononuclear phagocytes and colon-26 carcinoma and its relevance to IL-6-mediated cancer cachexia. J Immunol 148: 3674–3678.
Stephanou, A., Knight, R. A., Annicchiarico-Petruzzelli, M., Finazzi-Agro, A., Lightmann, S. L. & Melino, G. (1992). Interleukin-1 beta and interleukin-6 mRNA are expressed in human glioblastoma and neuroblastoma cells respectively. Funct Neurol 7: 129–133.
Tabibzadeh, S. S., Poubouridis, D., May, L. T. & Sehgal, P. B. (1989). Interleukin 6 immunoactivity in human tumors. Am J Pathol 135: 427–433.
Taga, T., Hibi, M., Hirata, Y., Yamasaki, K., Yasukawa, K., Matsuda, T., Hirano, T. & Kishimoto, T. (1989). Interleukin-6 triggers the association of its receptor with a possible signal transducer, gp130. Cell 58: 573–581.
Takeuchi, E., Ito, M., Mori, M., Yamaguchi, T., Nakagawa, M., Yokota, S., Nishikawa, H., Sakuma-Mochizuki, J., Hayashi, S. & Ogura, T. (1996). Lung cancer producing interleukin-6. Intern Med 35: 212–214.
Takizawa, H., Ohtoshi, T., Ohta, K., Yamashita, N., Hirohata, S., Hirai, K., Hiramatsu, K. & Ito, K. (1993). Growth inhibition of human lung cancer cell lines by interleukin 6 in vitro: a possible role in tumor growth via an autocrine mechanism. Cancer Res 53: 4175–4181.
Tamura, S., Fujimoto-Ouchi, K., Mori, K., Endo, M., Matsumoto, T., Eden, H., Tanaka, Y., Ishitsuka, H., Tokita, H. & Yamaguchi, K. (1995). Involvement of human interleukin 6 in experimental cachexia induced by a human uterine carcinoma xenograft. Clin Cancer Res 1: 1353–1358.
Tanner, J. & Tosato, G. (1991). Impairment of natural killer functions by interleukin 6 increases lymphoblastoid cell tumorigenicity in athymic mice. J Clin Invest 88: 239–247.
VanMeir, E., Sawamura, Y., Diserens, A. C., Hamou, M. F. & de Tribolet, N. (1990). Human glioblastoma cells release interleukin 6 in vitro and in vivo. Cancer Res 50: 6683–6688.
Walker, P. R., Saas, P. & Dietrich, P. V. (1997). Role of Fas ligand (CD95L) in immune ESCCape. J Immunol 158: 4521–4524.
Wang, G. G., Witek-Giannotti, J., Hewick, R. M., Clark, S. C. & Ogawa, M. (1988). Interleukin 6: identification as a hematopoietic colony-stimulating factor. Behring Inst Mitt 83: 40–47.
Wang, L. S., Huang, M. H., Huang, B. S. & Chien, K. Y. (1992). Gastric substitution for resectable carcinoma of the esophagus. An analysis of 368 cases. Ann Thorac Surg 53: 289–294.
Wang, L. S., Chi, K. H., Hu, M. H., Fahn, H. J. & Huang, M. H. (1996). Management for patients with advanced T4 epidermoid carcinoma of the esophagus. J Surg Oncol 62: 22–29.
Wang, L. S., Lin, H. Y., Chang, C. J., Fahn, H. J., Huang, M. H. & Lin, C. F. (1998). Effects of en bloc esophagectomy on nutritional and immune status in patients with esophageal carcinoma. J Surg Oncology 67: 90–98.
Watson, J. M., Sensintaffar, J. L., Berek, J. S. & Martinez-Maza, O. (1990). Constitutive production of interleukin 6 in viro: a possible role in tumor growth via an autocrine mechanism. Cancer Res 50: 6959–6965.
Wojciechowska-Lacka, A., Matecka-Nowak, M., Adamiak, E., Lacki, J. K. & Cerkaska-Gluszak, B. (1996). Serum levels of interleukin-10 and interleukin-6 in patients with lung cancer. Neoplasma 43: 155–158.
Wu, C. W., Wang, S. R., Chao, M. F., Wu, T. C., Lui, W. Y., P’eng, F. K. & Chi, C. W. (1996). Serum interleukin-6 levels reflect disease status of gastric cancer. Am J Gastroenterol 91: 1417–1422.
Wu, Y. K., Chen, P. T., Fang, J. & Lin, S. S. (1980). Surgical treatment of oesophageal carcinoma. Am J Surg 139: 805–809.
Yamasaki, K., Taga, T., Hirata, Y., Yawata, H., Kawanishi, Y., Seed, B., Taniguchi, T., Hirano, T. & Kishimoto, T. (1988). Cloning and expression of the human interleukin-6 (BFS-2/IFNB2) receptor. Science 241: 825–828.
Yamashita, S., Ogawa, M., Abe, T., Yamashita, J., Sakamoto, K., Niwa, H. & Yamamura, K. (1994). Group II phospholipase A2 in invasive gastric cancer cell line is induced by interleukin 6. Biochem Biophys Res Commun 198: 878–884.
Yanagawa, H., Sone, S., Takahashi, Y., Haku, T., Yano, S., Shinohara, T. & Ogura, T. (1995). Serum levels of interleukin 6 in patients with lung cancer. Br J Cancer 71: 1095–1098.
Zhang, Y., Lin, J. X. & Vilcek, J. (1988). Synthesis of interleukin 6 (interferon-β2/B cell stimulatory factor 2) in human fibroblasts is triggered by an increase in intracellular cyclic AMP. J Biol Chem 263: 6177–6182.
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Wang, LS., Chow, KC. & Wu, CW. Expression and up-regulation of interleukin-6 in oesophageal carcinoma cells by n-sodium butyrate. Br J Cancer 80, 1617–1622 (1999). https://doi.org/10.1038/sj.bjc.6690571
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DOI: https://doi.org/10.1038/sj.bjc.6690571
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