Journal of Cancer Research and Clinical Oncology

, Volume 119, Issue 8, pp 441–449 | Cite as

Molecular and cellular features of esophageal cancer cells

  • Tetsuro Nishihira
  • Yu Hashimoto
  • Masafumi Katayama
  • Shozo Mori
  • Toshio Kuroki
Guest Editorial


More than 70 cell lines were established from esophageal cancer, including 15 TE-series cell lines established by the authors. This article reviews molecular and cellular features of esophageal cancer cells from studies using these cell lines as well as primary tumors. The subjects reviewed include primary cultures of normal epithelium of the esophagus and of esophageal tumors, their growth and differentiation properties, chromosomal aberrations, protein kinase C, growth factors and their receptors, oncogenes, and tumor-suppressor genes. Lesions of genetic loci in esophageal cancer include the absence of mutations inras genes in primary tumors, amplification and overexpression of the c-erbB gene, co-amplification ofhst-1 andint-2 genes, mutations, and allelic loss of tumor suppressor genes, p53, Rb, APC, and MCC. Future clinical improvement will be achieved on the basis of the understanding of molecular and cellular features of esophageal cancer cells.

Key words

Esophageal cancer Cell lines Oncogenes Tumorsuppressor genes Growth factors 



protein kinase C


polymerase chain reaction




Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Almoguera C, Shibata D, Forrester K, Martin J, Arnheim N, Perucho M (1988) Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell 53:549–554Google Scholar
  2. Babcock M, Marino MR, Gunning III WT, Stoner GD (1983) Clonal growth and serial propagation of rat esophageal epithelial cells. In Vitro 19:403–415Google Scholar
  3. Banks-Schlegel SP (1985) Isolation, cultivation, and characterization of normal human esophageal epithelial cells. J Tissue Culture Methods 9:95–105Google Scholar
  4. Banks-Schlegel SP, Quintero J (1986a) Growth and differentiation of human esophageal carcinoma cell lines. Cancer Res 46:250–258Google Scholar
  5. Banks-Schlegel SP, Quintero J (1986b) Human esophageal carcinoma cells have fewer, but higher affinity epidermal growth factor receptors. J Biol Chem 261:4359–4362Google Scholar
  6. Banks-Schlegel SP, Vocci MJ, Combs J, Harris CC (1985) Normal human esophageal epithelium in cell culture. In: Webber MM, Sekely LI (eds) In Vitro models for cancer research, vol I. Carcinomas of the esophagus and colon. CRC Press, Boca Raton, Fla, pp 9–38Google Scholar
  7. Bartsch H, Ohshima M, Munoz N, Pignatelli B, Friesen M, O'Neill L, Crespi M, Lu SH (1983) Assessment of endogenous nitrosation in humans in relation to the risk of cancer of the digestive tract. In: Hayes AW, Schnel RC, Miya TS (eds) Developments in the science and practice of toxicology. Elsevier, Amsterdam, pp 299–309Google Scholar
  8. Bennett WP, Hollstein MC, He A, Zhu SM, Resau JH, Trump BF, Metcalf RA, Welsh JA, Midgley C, Lane DP, Harris CC (1991) Archival analysis of p53 genetic and protein alterations in Chinese esophageal cancer. Oncogene 6:1779–1784Google Scholar
  9. Bey E, Alexander J, Whitcutt JM, Hunt JA, Gear JHS (1976) Carcinoma of the esophagus in Africans: Establishment of a continuously growing cell line from a tumor specimen. In Vitro 12:107–114Google Scholar
  10. Blount PL, Ramel S, Raskind WH, Haggitt RC, Sanchez CA, Dean PJ, Rabinovitch PS, Reid BJ (1991) 17p Allelic deletions and p53 protein overexpression in Barrett's adenocarcinoma. Cancer Res 51:5482–5486Google Scholar
  11. Bos J, Fearon E, Hamilton S, Verlann-de-Vries M, Boom J van, Vogelstein B (1987) Prevalence ofras gene mutations in human colorectal cancers. Nature 327:293–297Google Scholar
  12. Boynton RF, Huang Y, Blount PL, Reid BJ, Raskind WH, Haggitt RC, Newkirk C, Resau JH, Yin J, McDaniel T, Meltzer SJ (1991) Frequent loss of heterozygosity at the retinoblastoma locus in human esophageal cancers. Cancer Res 51:5766–5769Google Scholar
  13. Boynton RF, Blount PL, Yin J, Brown VL, Huang Y, Tong Y, McDaniel T, Newkirk C, Resau JH, Raskind WH, Haggitt RC, Reid BJ, Meltzer SJ (1992) Loss of heterozygosity involving theAPC andMCC genetic loci occurs in the majority of human esophageal cancers. Proc Natl Acad Sci USA 89:3385–3388Google Scholar
  14. Burg-Kurland GL, Purnell DM, Combs JW, Harris CC, Trump BF (1986) Monolayer culture of normal human esophageal epithelial cells. J Tissue Culture Methods 10:227–231Google Scholar
  15. Casson AG, Mukhopadhyay T, Cleary KR, Ro JY, Levin B, Roth JA (1991) p53 Gene mutations in Barrett's epithelium and esophageal cancer. Cancer Res 51:4495–4499Google Scholar
  16. Cheng SJ, Li MH (1985) A comparative study on mutagenesis of methylbenzylnitrosamine in V79 cells co-cultivated with liver or esophageal epithelial cells from chickens, rats and humans. Carcinogenesis 6:1731–1734Google Scholar
  17. Chida K, Kato N, Yamada S, Kuroki T (1988) Protein kinase C activities and bindings of phorbol ester tumor promoter in 41 cell lines. Biochem Biophys Res Commun 157:1–8Google Scholar
  18. Forrester K, Almoguera C, Han K, Grizzle W, Perucho M (1987) Detection of high incidence of K-ras oncogenes during human colon tumorigenesis. Nature 327:298–304Google Scholar
  19. Grace MP, Kim KH, True LD, Fuchs E (1985) Keratin expression in normal esophageal epithelium and squamous cell carcinoma of the esophagus. Cancer Res 45:841–846Google Scholar
  20. Hashimoto Y, Chida K, Huang M, Katayama M, Nishihira T, Kuroki T (1989) Levels of protein kinase C activity in human gastrointestinal cancers. Biochem Biophys Res Commun 163:406–411Google Scholar
  21. Hattori Y, Odagiri H, Nakatani H, Miyagawa K, Naito K, Sakamoto H, Katoh O, Yoshida T, Sugimura T, Terada M (1990) K-sam, an amplified gene in stomach cancer, is a member of the heparin-binding growth factor receptor genes. Proc Natl Acad Sci USA 87:5983–5987Google Scholar
  22. Hattori Y, Odagiri H, Katoh O, Sakamoto H, Morita T, Shimotohno K, Tobinai K, Sugimura T, Terada M (1992) K-sam related gene, N-sam, encodes fibroblast growth factor receptor and is expressed in T-lymphocytic tumors. Cancer Research 52:3367–3371Google Scholar
  23. Hiraizumi S, Takasaki S, Nishihira T, Mori S, Kobata A (1990) Comparative study of the N-linked oligosaccharides released from normal human esophageal epithelium and esophageal squamous carcinoma. Jpn J Cancer Res 81:363–371Google Scholar
  24. Hollstein MC, Smits AM, Galiana C, Yamasaki H, Bos JL, Mandard A, Partensky C, Montesano R (1988) Amplification of epidermal growth factor receptor gene but no evidence ofras mutations in primary human esophageal cancers. Cancer Res 48:5119–5123Google Scholar
  25. Hollstein MC, Metcalf RA, Welsh JA, Montesano R, Harris CC (1990) Frequent mutation of the p53 gene in human esophageal cancer. Proc Natl Acad Sci USA 87:9958–9961Google Scholar
  26. Hollstein MC, Peri L, Mandard AM, Welsh JA, Montesano R, Metcalf RA, Bak M, Harriss CC (1991a) Genetic analysis of human esophageal tumors from two high incidence geographic areas: frequent p53 base substitutions and absence ofras mutations. Cancer Res 51:4102–4106Google Scholar
  27. Hollstein M, Sidransky D, Vogelstein B, Harris CC (1991b) p53 mutations in human cancers. Science 253:49–53Google Scholar
  28. Horsfall MJ, Glickman BW (1988) Mutation site specificity ofN-nitroso-N-methyl-N-α-acetoxybenzylamine: a model derivative of an esophageal carcinogen. Carcinogenesis 9:1529–1532Google Scholar
  29. Hu C, Hsieh H, Chien K, Wang P, Wang C, Chen C, Lo SJ, Wuu K, Chang C (1984) Biologic properties of three newly established human esophageal carcinoma cell lines. JNCI 72:577–583Google Scholar
  30. Jiang W, Kahn SM, Guillem JG, Lu S-H, Weinstein IB (1989) Rapid detection ofras oncogenes in human tumors: applications to colon, esophageal, and gastric cancer. Oncogen 4:923–928Google Scholar
  31. Kamata N, Chida K, Rikimaru K, Horikoshi M, Enomoto S, Kuroki T (1986) Growth-inhibitory effects of epidermal growth factor and overexpression of its receptors on human squamous cell carcinomas in culture. Cancer Res 46:1648–1653Google Scholar
  32. Katayama M, Kan M (1991) Heparin-binding (fibroblast) growth factors are potential autocrine regulators of esophageal epithelial cell proliferation. In Vitro Cell Dev Biol 27:533–541Google Scholar
  33. Katayama M, Akaishi T, Nishihira T, Kasai M, Kan M, Yamane I (1984) Primary culture of human esophageal epithelial cells. Tohoku J Exp Med 143:129–140Google Scholar
  34. Katayama M, Akaishi T, Nishihira T, Kasai M, Kan M, Yamane I (1986) Primary cultures of serial passages of normal human esophageal epithelial cells in a serum-free medium. In: Kasai M (ed) Esophageal cancer. Proceedings of the International Symposium Cancer of the Esophagus. Excerpta Medica, Amsterdam Princeton Tokyo, pp 31–34Google Scholar
  35. Kuriya Y, Kitamura M, Akaishi T, Hirayama K, Sekine Y, Nishihira T, Kasai M (1983) A new cell line (TE-3) derived from human squamous cell carcinoma of the esophagus. Tohoku J Exp Med 139:377–387Google Scholar
  36. Lu J-B, Yang W-X, Liu J-M, Li Y-S, Qin Y-M (1985) Trends in morbidity and mortality for esophageal cancer in Linxian county, 1959–1983. Int J Cancer 36:643–645Google Scholar
  37. Lu S-H, Hsieh L-L, Luo F-C, Weinstein IB (1988) Amplification of the EGF receptor and c-myc genes in human esophageal cancers. Int J Cancer 42:502–505Google Scholar
  38. Matsuoka H, Sugimachi K, Mori M, Kuwano H, Ohno S, Nakano S (1989) Effects of hyperthermochemoradiotherapy on KSE-1 cells, a newly established human squamous cell line derived from esophageal carcinoma. Eur Surg Res 21:49–59Google Scholar
  39. Matsuoka H, Hori M, Ueo H, Sugimachi K, Urabe A (1991) Characterization of human esophageal carcinoma cell line established on confluent monolayer and advantage of confluent monolayer surface structure for attachment and growth. Pathobiology 59:76–84Google Scholar
  40. Meltzer SJ, Mane SM, Wood PK, Resau JH, Newkirk C, Terzakis JA, Korelitz BI, Weinstein WM, Needleman SW (1990) Activation of c-Ki-ras in human gastrointestinal dysplasia determined by direct sequencing of polymerase chain reaction products. Cancer Res 50:3627–3630Google Scholar
  41. Meltzer SJ, Yin J, Huang Y, McDaniel TK, Newkirk C, Iseri O, Vogelstein B, Resau JH (1991) Reduction to homozygosity involving p53 in esophageal cancers demonstrated by the polymerase chain reaction. Proc Natl Acad Sci USA 88:4976–4980Google Scholar
  42. Mok CH, Chew EC, Riches DJ, Lee JCK, Huang DP, Hadgis C, Crofts TJ (1987) Biological characteristics of a newly established human oesophageal carcinoma cell line. Anticancer Res 7:409–416Google Scholar
  43. Montesano R, Hall J, Hollstein M, Mironov N, Wild CP (1990) Alkylation repair in human tissues. In: Sutherland BM, Woodhead AD (eds) DNA damage and repair in human tissues. Plenum Press. New York, pp 437–452Google Scholar
  44. Mothersill C, Cusack A, Seymour CB (1988) Radiation-induced out-growth inhibition in explant cultures from surgical specimens of five human organs. Br J Radiol 61:226–230Google Scholar
  45. Nishihira T, Kasai M, Mori S, Watanabe T, Kuriya Y, Suda M, Kitamura M, Hirayama K, Akaishi T, Sasaki T (1979) Characteristics of two two cell lines (TE-1 and TE-2) derived from human squamous cell carcinoma of the esophagus. Gann 70:575–584Google Scholar
  46. Nishihira T, Watanabe T, Ohmori N, Kitamura M, Toyoda T, Hirayama K, Kawachi S, Kuramoto J, Kanoh T, Akaishi T, Sekine Y, Kasai M (1984) Long-term evaluation of patients treated by radical operation for carcinoma of the thoracic esophagus. World J Surg 8:778–785Google Scholar
  47. Nishihira T, Kasai M, Kitamura M, Hirayama K, Akaishi T, Sekine Y (1985) Biological characteristics of cultured cell lines of human esophageal carcinomas and tumors transplantable to nude mice originating from human esophageal carcinomas and their clinical application. In: Webber MM, Sekely LI (eds) In vitro models for cancer research, vol I. Carcinomas of the esophagus and colon. CRC Press, Boca Raton, Fla, pp 65–79Google Scholar
  48. Nishizuka Y (1992) Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C. Science 258:607–614Google Scholar
  49. Osada S, Mizuno K, Saido TC, Akita Y, Suzuki K, Kuroki T, Ohno S (1990) A phorbol ester receptor/protein kinase, nPKCeta, a new member of the protein kinase C family predominantly expressed in lung and skin. J Biol Chem 265:22434–22440Google Scholar
  50. Osada S, Mizuno K, Saido T, Suzuki K, Kuroki T, Ohno S (1992) A new member of the protein kinase C family, nPKC, predominantly expressed in skeletal muscle. Mol Cell Biol 12:3930–3938Google Scholar
  51. Osada S, Hashimoto Y, Nomura S, Kohno Y, Chida K, Tajima O, Kubo K, Akimoto K, Koizumi H, Kitamura Y, Suzuki K, Ohno S, Kuroki T (1993) Predominant expression of nPKC, a Ca2+-independent isoform of protein kinase C in epithelial tissues, in association with epithelial differentiation. Cell Growth Differ (in press)Google Scholar
  52. Pan Q (1989) Studies on esophageal cancer cells in vitro. Pro Chin Acad Sci Peking Union Med Coll 4:52–57Google Scholar
  53. Park JB, Rhim JS, Park SC, Kimm SW, Kraus MH (1989) Amplification, overexpression, and rearrangement of theerbB-2 protooncogene in primary human stomach carcinoma. Cancer Res 49:6605–6609Google Scholar
  54. Rearick JI, Stoner GD, George MA, Jetten AM (1988) Cholesterol sulfate accumulation in tumorigenic and nontumorigenic rat esophageal epithelial cells: evidence for defective differentiation control in tumorigenic cells. Cancer Res 48:5289–5295Google Scholar
  55. Rheinwald JG, Green H (1975) Serial cultivation of strains of human epidermal keratinocytes: the formation of keratinizing colonies from single cells. Cell 6:331–344Google Scholar
  56. Robinson K (1986) Evaluation of the biological properties of continuous human esophageal carcinoma cell lines in vitro in the nude mouse. In: Kasai M (ed) Esophageal cancer. Excerpta Medica, Tokyo, pp 39–42Google Scholar
  57. Robinson KM, Maistry L (1983) Tumorigenicity and other properties of cells from ten continuous human esophageal carcinoma cell lines in nude mice. JNCI 70:89–93Google Scholar
  58. Robinson KM, Haffejee AA, Angorn IB (1980) Tissue culture and prognosis in carcinoma of the oesophagus. Clinical Oncol 6:125–136Google Scholar
  59. Saito M, Shinbo T, Saito T, Kato H, Otagiri H, Karaki Y, Tazawa K, Fujimaki M (1990) Temperature sensitivity on proliferation and morphologic alteration of human esophageal carcinoma cells in culture. In Vitro Cell Dev Biol 26:181–186Google Scholar
  60. Sasajima K, Willey JC, Banks-Schlegel SP, Harris CC (1987) Effects of tumor promoters and cocarcinogens on growth and differentiation of cultured human esophageal epithelial cells. JNCI 78:419–423Google Scholar
  61. Sato K, Kasono K, Ohba Y, Yashiro T, Fujii Y, Yoshida MA, Tsushima T, Shizume K (1987) Establishment of a parathyroid hormone-like factor-producing esophageal carcinoma cell line (EC-GI). Jpn J Cancer Res (Gann) 78:1044–1048Google Scholar
  62. Sato K, Fujii Y, Kasono K, Tsushima T, Shizume K (1988) Production of interleukin-1 and a parathyroid hormone-like factor by a squamous cell carcinoma of the esophagus (EC-GI) derived from a patient with hypercalcemia. J Clin Endocrinol Metab 67:592–601Google Scholar
  63. Shimada Y, Imamura M, Wagata T, Yamaguchi N, Tobe T (1991) Characterization of twenty-one newly established esophageal cancer cell lines. Cancer 69:277–284Google Scholar
  64. Singer GM, Chuan J, Roman J, Li M-S, Linjinsky W (1986) Nitrosamines and nitrosamine precursors in food from Linxian, China, a high incidence area for esophageal cancer. Carinogenesis 7:733–736Google Scholar
  65. Stoner GD, Babcock MS, Scaramuzzino DA, Gunning III WT (1985) Cultured rat esophageal epithelial cells for studies of differentiation and carcinogenesis. In: Webber MM, Sekely LI (eds) In vitro models for cancer research, vol I. Carcinomas of the esophagus and colon. CRC Press, Boca Raton, Fla, pp 81–955Google Scholar
  66. Stoner GD, Babcock MS, McCorquodale MM, Gunning III WT, Jamasbi R, Budd N, Hukku B (1989) Comparative properties of untreated andN-nitrosobenzylmethylamine-transformed rat esophageal epithelial cell lines. In Vitro Cell Dev Biol 25:899–908Google Scholar
  67. Su YA, Wang X, Hu N, Pei X, Wu M (1988a) G-banded chromosome analyses of mucosal epithelium adjacent to esophageal cancer (EC)-some consistent chromosomal changes. Sci Sin [B] 31:710–718Google Scholar
  68. Su YA, Wang X, Hu N, Pei X, Wang Z, Zhou C, Wang J, Wu M (1988 b) Comparison of chromosomal aberrations in epithelium adjacent to esophageal cancer (EC) and in esophageal cancer cell line EC8501. Pro Chin Acad Sci Peking Union Med Coll 5:84–89Google Scholar
  69. Takano R, Nose M, Nishihira T, Kyogoku M (1990a) Increase of 1-6-branched oligosaccharides in human esophageal carcinomas invasive against surrounding tissue in vivo and in vitro. Am J Pathol 137:1007–1011Google Scholar
  70. Takano R, Nose M, Kanno H, Nishihira T, Hiraizumi S, Kobata A, Kyogoku M (1990b) Recognition ofN-glycosidic carbohydrates on esophageal carcinoma cells by macrophage cell line THP-1. Am J Pathol 137:393–401Google Scholar
  71. Tomatis L, Aitio A, Day NE, Heseltine E, Kaldor J, Miller AM, Parkin DM, Riboli E (eds) (1990) Cancer: causes, occurrence and control. IARC Sci Publ 100:55–56, 296–298Google Scholar
  72. Tsuda T, Tahara E, Kajiyama G, Sakamoto H, Terada M, Sugimura T (1989) High incidence of coamplification ofhst-1 andint-2 genes in human esophageal carcinomas. Cancer Res 49:5505–5508Google Scholar
  73. Umbenhauer D, Wild C, Montesano R, Saffhill R, Boyle J, Huh N, Kirstein U, Thomale J, Rajewsky M, Lu S (1985)O 6-Methyldeoxyguanosine in esophageal DNA among individuals at high risk of oesophageal cancer. Int J Cancer 36:661–665Google Scholar
  74. Victor T, Du Toit R, Jordaan AM, Bester AJ, Helden PD van (1990) No evidence for point mutations in codons 12, 13, and 61 of theras gene in a high-incidence area for esophageal and gastric cancers. Cancer Res 50:4911–4914Google Scholar
  75. Wagata T, Ishizaki K, Imamura M, Shimada Y, Ikenaga M, Tobe T (1991) Deletion of 17p and amplification of theint-2 gene in esophageal carcinomas. Cancer Res 51:2113–2117Google Scholar
  76. Whang-Peng J, Banks-Schlegel SP, Lee EC (1990) Cytogenetic studies of esophageal carcinoma cell lines. Cancer Genet Cytogenet 45:101–120Google Scholar
  77. Wild CP, Montesano R (1991) Detection of alkylated DNA adducts in human tissues. In: Groopman JD, Skipper PL (eds) Molecular dosimetry and human cancer: analytical, epidemiological, and social considerations. Telford Press, Boston, pp 263–280Google Scholar
  78. Yamamoto T, Kamata N, Kawano H, Shimizu S, Kuroki T, Toyoshima K, Rikimaru K, Nomura N, Ishizaki R, Pastan I, Gamou S, Shimizu N (1986) High incidence of amplification of the epidermal growth factor receptor gene in human squamous cell lines. Cancer Res 46:414–416Google Scholar
  79. Yeh FS, Mo CC, Yen RC (1985) Risk factors for hepatocellular carcinoma in Guangxi, People's Republic of China. Natl Cancer Inst Monogr 69:47–48Google Scholar
  80. Yokota J, Yamamoto T, Toyoshima K, Terada M, Sugimura T, Battifora H, Cline MJ (1986) Amplification of c-erbB-2 oncogene in human adenocarcinomas in vivo. Lancet I:765–767Google Scholar
  81. Yoshida K, Kyo E, Tsuda T, Tsujino T, Ito M, Niimoto M, Tahara E (1990) EGF- and TGF-α, the ligands of hyperproduced EGFR in human esophageal carcinoma cells, act as autocrine growth factors. Int J Cancer 45:131–135Google Scholar

Copyright information

© Springer-Verlag 1993

Authors and Affiliations

  • Tetsuro Nishihira
    • 1
  • Yu Hashimoto
    • 1
    • 2
  • Masafumi Katayama
    • 1
  • Shozo Mori
    • 2
  • Toshio Kuroki
    • 2
  1. 1.Second Department of SurgeryTohoku University School of MedicineSendaiJapan
  2. 2.Department of Cancer Cell Research, Institute of Medical ScienceUniversity of TokyoTokyoJapan

Personalised recommendations