Esophageal Carcinogenesis

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Author(s) 

Naoki Watanabe¹, Masahito Shimizu², Takahiro Kochi², Yohei Shirakami², Takuji Tanaka^1,3*

Affiliation(s)

¹Department of Diagnostic Pathology (DDP) & Research Center of Diagnostic Pathology (RC-DiP), Gifu Municipal Hospital, Gifu, Japan.
²Department of Internal Medicine/Gastroenterology, Gifu University Graduate School of Medicine, Gifu, Japan.
³Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu, Japan.

ABSTRACT

Esophageal cancer is the sixth leading cause of cancer death and remains one of the least survivable cancers. Esophageal cancers show wide variations in incidence in different population, suggesting that environmental or lifestyle risk factors could be controlled to reduce risk of these diseases. There are two major histopathologic types (squamous cell carcinoma and adenocarcinoma) of esophageal epithelial malignancy. Recently, the rate of adenocarcinoma is increasing in developed countries: in the United States, 50% or more is adenocarcinoma and, in about 70%, the increase especially in a white male serves as adenocarcinoma. Esophageal adenocarcinoma develops in the lower esophagus. In contrast, in Japan, the increase in adenocarcinoma is not clear and most (90%) of esophageal cancers are squamous cell carcinoma. Such squamous cell carcinoma occurs onto the middle part esophagus mostly, and 60% or more of the whole esophagus cancer also develops in the middle and upper parts. These differences also influence the treatment results. The scope of this article is to discuss carcinogenesis in the esophagus by giving an overview about its histopathological characteristics and molecular mechanisms.

KEYWORDS

Esophageal Neoplasms, Preneoplastic Lesions, Squamous Cell Carcinoma, Adenocarcinoma, Risk Factor

Cite this paper

Watanabe, N. , Shimizu, M. , Kochi, T. , Shirakami, Y. and Tanaka, T. (2014) Esophageal Carcinogenesis. Open Journal of Pathology, 4, 151-170. doi: 10.4236/ojpathology.2014.44021. 

 

References

[1]	Jemal, A., Bray, F., Center, M.M., Ferlay, J., Ward, E. and Forman, D. (2011) Global Cancer Statistics. CA: A Cancer Journal for Clinicians, 61, 69-90. http://dx.doi.org/10.3322/caac.20107
[2]	Pisani, P., Parkin, D.M., Bray, F. and Ferlay, J. (1999) Estimates of the Worldwide Mortality from 25 Cancers in 1990. International Journal of Cancer, 83, 18-29. http://dx.doi.org/10.1002/(SICI)1097-0215(19990924)83:1<18::AID-IJC5>3.0.CO;2-M
[3]	Farrow, D.C. and Vaughan, T.L. (1996) Determinants of Survival Following the Diagnosis of Esophageal Adenocarcinoma (United States). Cancer Causes Control, 7, 322-327. http://dx.doi.org/10.1007/BF00052937
[4]	Matsuda, A., Matsuda, T., Shibata, A., Katanoda, K., Sobue, T. and Nishimoto, H. (2013) Cancer Incidence and Incidence Rates in Japan in 2007: A Study of 21 Population-Based Cancer Registries for the Monitoring of Cancer Incidence in Japan (MCIJ) Project. Japanese Journal of Clinical Oncology, 43, 328-336. http://dx.doi.org/10.1093/jjco/hys233
[5]	Enzinger, P.C. and Mayer, R.J. (2003) Esophageal Cancer. The New England Journal of Medicine, 349, 2241-2252. http://dx.doi.org/10.1056/NEJMra035010
[6]	Munoz, N. and Day, N.E. (1996) Esophageal Cancer. In: Schottenfeld, D. and Fraumeni, J.E.J., Eds., Cancer Epidemiology and Prevention, Oxford University Press, New York, 681-706.
[7]	Blot, W.J. (1994) Esophageal Cancer Trends and Risk Factors. Seminars in Oncology, 21, 403-410.
[8]	Craddock, V.M. (1992) Aetiology of Oesophageal Cancer: Some Operative Factors. European Journal of Cancer Prevention, 1, 89-103. http://dx.doi.org/10.1097/00008469-199202000-00002
[9]	Gao, Y.T., McLaughlin, J.K., Blot, W.J., Ji, B.T., Dai, Q. and Fraumeni Jr., J.F. (1994) Reduced Risk of Esophageal Cancer Associated with Green Tea Consumption. Journal of the National Cancer Institute, 86, 855-858. http://dx.doi.org/10.1093/jnci/86.11.855
[10]	Tanaka, T. (1997) Chemoprevention of Human Cancer: Biology and Therapy. Critical Reviews in Oncology/Hematology, 25, 139-174. http://dx.doi.org/10.1016/S1040-8428(97)00232-1
[11]	Tanaka, T., Makita, H., Kawabata, K., Mori, H., Kakumoto, M., Satoh, K., Hara, A., Sumida, T., Fukutani, K. and Ogawa, H. (1997) Modulation of N-Methyl-N-Amylnitrosamine-Induced Rat Oesophageal Tumourigenesis by Dietary Feeding of Diosmin and Hesperidin, Both Alone and in Combination. Carcinogenesis, 18, 761-769. http://dx.doi.org/10.1093/carcin/18.4.761
[12]	Chu, F.S. and Li, G.Y. (1994) Simultaneous Occurrence of Fumonisin B1 and Other Mycotoxins in Moldy Corn Collected from the People’s Republic of China in Regions with High Incidences of Esophageal Cancer. Applied and Environmental Microbiology, 60, 847-852.
[13]	Devesa, S.S., Blot, W.J. and Fraumeni Jr., J.F. (1998) Changing Patterns in the Incidence of Esophageal and Gastric Carcinoma in the United States. Cancer, 83, 2049-2053. http://dx.doi.org/10.1002/(SICI)1097-0142(19981115)83:10<2049::AID-CNCR1>3.0.CO;2-2
[14]	Parkin, D.M., Whelan, S.L., Ferlay, J., Raymond, L. and Young, J. (1997) Cancer Incidence in Five Continents. IARC Scientific Publications, Lyon, 1-1240.
[15]	Blot, W.J., Devesa, S.S., Kneller, R.W. and Fraumeni Jr., J.F. (1991) Rising Incidence of Adenocarcinoma of the Esophagus and Gastric Cardia. JAMA, 265, 1287-1289. http://dx.doi.org/10.1001/jama.1991.03460100089030
[16]	Brown, L.M., Silverman, D.T., Pottern, L.M., Schoenberg, J.B., Greenberg, R.S., Swanson, G.M., Liff, J.M., Schwartz, A.G., Hayes, R.B., Blot, W.J. and Hoover, R.N. (1994) Adenocarcinoma of the Esophagus and Esophagogastric Junction in White Men in the United States: Alcohol, Tobacco, and Socioeconomic Factors. Cancer Causes & Control, 5, 333-340. http://dx.doi.org/10.1007/BF01804984
[17]	Lippman, S.M. and Hong, W.K. (1989) Second Malignant Tumors in Head and Neck Squamous Cell Carcinoma: The Overshadowing Threat for Patients with Early-Stage Disease. International Journal of Radiation Oncology*Biology* Physics, 17, 691-694. http://dx.doi.org/10.1016/0360-3016(89)90126-0
[18]	Slaughter, D.P., Southwick, H.W. and Smejkal, W. (1953) Field Cancerization in Oral Stratified Squamous Epithelium; Clinical Implications of Multicentric Origin. Cancer, 6, 963-968. http://dx.doi.org/10.1002/1097-0142(195309)6:5<963::AID-CNCR2820060515>3.0.CO;2-Q
[19]	Thomson, P.J. (2002) Field Change and Oral Cancer: New Evidence for Widespread Carcinogenesis? International Journal of Oral and Maxillofacial Surgery, 31, 262-266. http://dx.doi.org/10.1054/ijom.2002.0220
[20]	Lightdale, C.J. (1999) Esophageal Cancer. American College of Gastroenterology. The American Journal of Gastroenterology, 94, 20-29. http://dx.doi.org/10.1111/j.1572-0241.1999.00767.x
[21]	Sugimachi, K., Sumiyoshi, K., Nozoe, T., Yasuda, M., Watanabe, M., Kitamura, K., Tsutsui, S., Mori, M. and Kuwano, H. (1995) Carcinogenesis and Histogenesis of Esophageal Carcinoma. Cancer, 75, 1440-1445. http://dx.doi.org/10.1002/1097-0142(19950315)75:6+<1440::AID-CNCR2820751508>3.0.CO;2-9
[22]	Hameeteman, W., Tytgat, G.N., Houthoff, H.J. and van den Tweel, J.G. (1989) Barrett’s Esophagus: Development of Dysplasia and Adenocarcinoma. Gastroenterology, 96, 1249-1256.
[23]	Miros, M., Kerlin, P. and Walker, N. (1991) Only Patients with Dysplasia Progress to Adenocarcinoma in Barrett’s Oesophagus. Gut, 32, 1441-1446. http://dx.doi.org/10.1136/gut.32.12.1441
[24]	Haggitt, R.C. (1994) Barrett’s Esophagus, Dysplasia, and Adenocarcinoma. Human Pathology, 25, 982-993. http://dx.doi.org/10.1016/0046-8177(94)90057-4
[25]	Mosca, S., Manes, G., Monaco, R., Bellomo, P.F., Bottino, V. and Balzano, A. (2001) Squamous Papilloma of the Esophagus: Long-Term Follow Up. Journal of Gastroenterology and Hepatology, 16, 857-861. http://dx.doi.org/10.1046/j.1440-1746.2001.02531.x
[26]	Ide, H., Nakamura, T., Hayashi, K., Endo, T., Kobayashi, A., Eguchi, R. and Hanyu, F. (1994) Esophageal Squamous Cell Carcinoma: Pathology and Prognosis. World Journal of Surgery, 18, 321-330. http://dx.doi.org/10.1007/BF00316810
[27]	Kuwano, H., Ohno, S., Matsuda, H., Mori, M. and Sugimachi, K. (1988) Serial Histologic Evaluation of Multiple Primary Squamous Cell Carcinomas of the Esophagus. Cancer, 61, 1635-1638. http://dx.doi.org/10.1002/1097-0142(19880415)61:8<1635::AID-CNCR2820610822>3.0.CO;2-U
[28]	Schmidt, L.W., Dean, P.J. and Wilson, R.T. (1986) Superficially Invasive Squamous Cell Carcinoma of the Esophagus. A Study of Seven Cases in Memphis, Tennessee. Gastroenterology, 91, 1456-1461.
[29]	Lee, R.G. (1986) Adenomas Arising in Barrett’s Esophagus. American Journal of Clinical Pathology, 85, 629-632.
[30]	McDonald, G.B., Brand, D.L. and Thorning, D.R. (1977) Multiple Adenomatous Neoplasms Arising in Columnarlined (Barrett’s) Esophagus. Gastroenterology, 72, 1317-1321.
[31]	Paraf, F., Flejou, J.F., Pignon, J.P., Fekete, F. and Potet, F. (1995) Surgical Pathology of Adenocarcinoma Arising in Barrett’s Esophagus. Analysis of 67 Cases. The American Journal of Surgical Pathology, 19, 183-191. http://dx.doi.org/10.1097/00000478-199502000-00007
[32]	Falk, G.W. (2009) Risk Factors for Esophageal Cancer Development. Surgical Oncology Clinics of North America, 18, 469-485. http://dx.doi.org/10.1016/j.soc.2009.03.005
[33]	Tanaka, H. (2014) Advances in Cancer Epidemiology in Japan. International Journal of Cancer, 134, 747-754. http://dx.doi.org/10.1002/ijc.28519
[34]	Bartsch, H., Ohshima, H., Pignatelli, B. and Calmels, S. (1992) Endogenously Formed N-Nitroso Compounds and Nitrosating Agents in Human Cancer Etiology. Pharmacogenetics, 2, 272-277. http://dx.doi.org/10.1097/00008571-199212000-00005
[35]	Roshandel, G., Semnani, S., Malekzadeh, R. and Dawsey, S.M. (2012) Polycyclic Aromatic Hydrocarbons and Esophageal Squamous Cell Carcinoma. Archives of Iranian Medicine, 15, 713-722.
[36]	Oze, I., Matsuo, K., Ito, H., Wakai, K., Nagata, C., Mizoue, T., Tanaka, K., Tsuji, I., Tamakoshi, A., Sasazuki, S., Inoue, M. and Tsugane, S. (2012) Cigarette Smoking and Esophageal Cancer Risk: An Evaluation Based on a Systematic Review of Epidemiologic Evidence among the Japanese Population. Japanese Journal of Clinical Oncology, 42, 63-73. http://dx.doi.org/10.1093/jjco/hyr170
[37]	Abdel-Latif, M.M., Duggan, S., Reynolds, J.V. and Kelleher, D. (2009) Inflammation and Esophageal Carcinogenesis. Current Opinion in Pharmacology, 9, 396-404. http://dx.doi.org/10.1016/j.coph.2009.06.010
[38]	Kavanagh, M.E., O’Sullivan, K.E., O’Hanlon, C., O’Sullivan, J.N., Lysaght, J. and Reynolds, J.V. (2014) The Esophagitis to Adenocarcinoma Sequence; the Role of Inflammation. Cancer Letters, 345, 182-189. http://dx.doi.org/10.1016/j.canlet.2013.08.017
[39]	Oze, I., Matsuo, K., Wakai, K., Nagata, C., Mizoue, T., Tanaka, K., Tsuji, I., Sasazuki, S., Inoue, M. and Tsugane, S. (2011) Alcohol Drinking and Esophageal Cancer Risk: An Evaluation Based on a Systematic Review of Epidemiologic Evidence among the Japanese Population. Japanese Journal of Clinical Oncology, 41, 677-692. http://dx.doi.org/10.1093/jjco/hyr026
[40]	Chung, C.S., Lee, Y.C., Wang, C.P., Ko, J.Y., Wang, W.L., Wu, M.S. and Wang, H.P. (2010) Secondary Prevention of Esophageal Squamous Cell Carcinoma in Areas Where Smoking, Alcohol, and Betel Quid Chewing Are Prevalent. Journal of the Formosan Medical Association, 109, 408-421. http://dx.doi.org/10.1016/S0929-6646(10)60072-1
[41]	Erkal, H.S., Mendenhall, W.M., Amdur, R.J., Villaret, D.B. and Stringer, S.P. (2001) Synchronous and Metachronous Squamous Cell Carcinomas of the Head and Neck Mucosal Sites. Journal of Clinical Oncology, 19, 1358-1362.
[42]	Toh, Y., Oki, E., Ohgaki, K., Sakamoto, Y., Ito, S., Egashira, A., Saeki, H., Kakeji, Y., Morita, M., Sakaguchi, Y., Okamura, T. and Maehara, Y. (2010) Alcohol Drinking, Cigarette Smoking, and the Development of Squamous Cell Carcinoma of the Esophagus: Molecular Mechanisms of Carcinogenesis. International Journal of Clinical Oncology, 15, 135-144. http://dx.doi.org/10.1007/s10147-010-0057-6
[43]	Sandler, R.S., Nyren, O., Ekbom, A., Eisen, G.M., Yuen, J. and Josefsson, S. (1995) The Risk of Esophageal Cancer in Patients with Achalasia. A Population-Based Study. JAMA, 274, 1359-1362. http://dx.doi.org/10.1001/jama.1995.03530170039029
[44]	Avisar, E. and Luketich, J.D. (2000) Adenocarcinoma in a Mid-Esophageal Diverticulum. The Annals of Thoracic Surgery, 69, 288-289. http://dx.doi.org/10.1016/S0003-4975(99)01201-1
[45]	Islami, F., Boffetta, P., Ren, J.S., Pedoeim, L., Khatib, D. and Kamangar, F. (2009) High-Temperature Beverages and Foods and Esophageal Cancer Risk—A Systematic Review. International Journal of Cancer, 125, 491-524. http://dx.doi.org/10.1002/ijc.24445
[46]	Spechler, S.J. (2013) Barrett Esophagus and Risk of Esophageal Cancer: A Clinical Review. JAMA, 310, 627-636. http://dx.doi.org/10.1001/jama.2013.226450
[47]	Farrow, D.C., Vaughan, T.L., Sweeney, C., Gammon, M.D., Chow, W.H., Risch, H.A., Stanford, J.L., Hansten, P.D., Mayne, S.T., Schoenberg, J.B., Rotterdam, H., Ahsan, H., West, A.B., Dubrow, R., Fraumeni Jr., J.F. and Blot, W.J. (2000) Gastroesophageal Reflux Disease, Use of H2 Receptor Antagonists, and Risk of Esophageal and Gastric Cancer. Cancer Causes & Control, 11, 231-238. http://dx.doi.org/10.1023/A:1008913828105
[48]	Shaheen, N. and Ransohoff, D.F. (2002) Gastroesophageal Reflux, Barrett Esophagus, and Esophageal Cancer: Scientific Review. JAMA, 287, 1972-1981. http://dx.doi.org/10.1001/jama.287.15.1972
[49]	Lagergren, J., Bergstrom, R., Adami, H.O. and Nyren, O. (2000) Association between Medications That Relax the Lower Esophageal Sphincter and Risk for Esophageal Adenocarcinoma. Annals of Internal Medicine, 133, 165-175. http://dx.doi.org/10.7326/0003-4819-133-3-200008010-00007
[50]	O’Connor, A. and O’Morain, C. (2013) Helicobacter Pylori Infection in Europe: Current Perspectives. Expert Review of Gastroenterology Hepatology, 7, 541-548. http://dx.doi.org/10.1586/17474124.2013.824707
[51]	Rokkas, T., Pistiolas, D., Sechopoulos, P., Robotis, I. and Margantinis, G. (2007) Relationship between Helicobacter Pylori Infection and Esophageal Neoplasia: A Meta-Analysis. Clin Gastroenterol Hepatol, 5, 1413-1417, 1417 e1411-1412.
[52]	Thrift, A.P., Pandeya, N. and Whiteman, D.C. (2012) Current Status and Future Perspectives on the Etiology of Esophageal Adenocarcinoma. Frontiers in Oncology, 2, 11.
[53]	Melhado, R.E., Alderson, D. and Tucker, O. (2010) The Changing Face of Esophageal Cancer. Cancers (Basel), 2, 1379-1404. http://dx.doi.org/10.3390/cancers2031379
[54]	Wolin, K.Y., Carson, K. and Colditz, G.A. (2010) Obesity and Cancer. Oncologist, 15, 556-565. http://dx.doi.org/10.1634/theoncologist.2009-0285
[55]	Romero, Y., Cameron, A.J., Schaid, D.J., McDonnell, S.K., Burgart, L.J., Hardtke, C.L., Murray, J.A., Locke 3rd, G.R. (2002) Barrett’s Esophagus: Prevalence in Symptomatic Relatives. The American Journal of Gastroenterology, 97, 1127-1132. http://dx.doi.org/10.1111/j.1572-0241.2002.05665.x
[56]	Gerson, L.B., Shetler, K. and Triadafilopoulos, G. (2002) Prevalence of Barrett’s Esophagus in Asymptomatic Individuals. Gastroenterology, 123, 461-467. http://dx.doi.org/10.1053/gast.2002.34748
[57]	Wu, A.H., Wan, P. and Bernstein, L. (2001) A Multiethnic Population-Based Study of Smoking, Alcohol and Body Size and Risk of Adenocarcinomas of the Stomach and Esophagus (United States). Cancer Causes & Control, 12, 721-732. http://dx.doi.org/10.1023/A:1011290704728
[58]	Chak, A., Ochs-Balcom, H., Falk, G., Grady, W.M., Kinnard, M., Willis, J.E., Elston, R. and Eng, C. (2006) Familiality in Barrett’s Esophagus, Adenocarcinoma of the Esophagus, and Adenocarcinoma of the Gastroesophageal Junction. Cancer Epidemiology, Biomarkers Prevention, 15, 1668-1673. http://dx.doi.org/10.1158/1055-9965.EPI-06-0293
[59]	Varis, A., Puolakkainen, P., Savolainen, H., Kokkola, A., Salo, J., Nieminen, O., Nordling, S. and Knuutila, S. (2001) DNA Copy Number Profiling in Esophageal Barrett Adenocarcinoma: Comparison with Gastric Adenocarcinoma and Esophageal Squamous Cell Carcinoma. Cancer Genetics and Cytogenetics, 127, 53-58. http://dx.doi.org/10.1016/S0165-4608(00)00423-4
[60]	Walch, A.K., Zitzelsberger, H.F., Bruch, J., Keller, G., Angermeier, D., Aubele, M.M., Mueller, J., Stein, H., Braselmann, H., Siewert, J.R., Hofler, H. and Werner, M. (2000) Chromosomal Imbalances in Barrett’s Adenocarcinoma and the Metaplasia-Dysplasia-Carcinoma Sequence. The American Journal of Pathology, 156, 555-566. http://dx.doi.org/10.1016/S0002-9440(10)64760-8
[61]	Wijnhoven, B.P., Tilanus, H.W. and Dinjens, W.N. (2001) Molecular Biology of Barrett’s Adenocarcinoma. Annals of Surgery, 233, 322-337. http://dx.doi.org/10.1097/00000658-200103000-00005
[62]	D’Amico, T.A. (2006) Molecular Biologic Staging of Esophageal Cancer. Thoracic Surgery Clinics, 16, 317-327. http://dx.doi.org/10.1016/j.thorsurg.2006.09.001
[63]	Kwong, K.F. (2005) Molecular Biology of Esophageal Cancer in the Genomics Era. Surgical Clinics of North America, 85, 539-553. http://dx.doi.org/10.1016/j.suc.2005.01.004
[64]	Buxbaum, J.L. and Eloubeidi, M.A. (2009) Endoscopic Evaluation and Treatment of Esophageal Cancer. Minerva Gastroenterologica e Dietologica, 55, 455-469.
[65]	Koike, T., Nakagawa, K., Iijima, K. and Shimosegawa, T. (2013) Endoscopic Resection (Endoscopic Submucosal Dissection/ Endoscopic Mucosal Resection) for Superficial Barrett’s Esophageal Cancer. Digestive Endoscopy, 25, 20-28.
[66]	Pennathur, A., Farkas, A., Krasinskas, A.M., Ferson, P.F., Gooding, W.E., Gibson, M.K., Schuchert, M.J., Landreneau, R.J. and Luketich, J.D. (2009) Esophagectomy for T1 Esophageal Cancer: Outcomes in 100 Patients and Implications for Endoscopic Therapy. The Annals of Thoracic Surgery, 87, 1048-1054 (Discussion 1054-1045).
[67]	Sgourakis, G., Gockel, I. and Lang, H. (2013) Endoscopic and Surgical Resection of T1a/T1b Esophageal Neoplasms: a Systematic Review. World Journal of Gastroenterology, 19, 1424-1437. http://dx.doi.org/10.3748/wjg.v19.i9.1424
[68]	DiGiovanni, J. (1991) Modification of Multistage Skin Carcinogenesis in Mice. In: Ito, N. and Sugano, H., Eds., Modification of Tumor Development in Rodents, Karger, Basel, 192-229.
[69]	Druckrey, H. (1972) Organospecific Carcinogenesis in the Digestive Tract. In: Nakahara, W., Takayama, S., Sugimura, T. and Odashima, S., Eds., Topics in Chemical Carcinogenesis, University Park Press, Baltimore, 73-84.
[70]	Hodgson, R.M., Schweinsberg, F., Wiessler, M. and Kleihues, P. (1982) Mechanism of Esophageal Tumor Induction in Rats by N-Nitrosomethylbenzylamine and Its Ring-Methylated Analog N-Nitrosomethyl(4-Methylbenzyl)Amine. Cancer Research, 42, 2836-2840.
[71]	Lijinsky, W., Saavedra, J.E., Reuber, M.D. and Singer, S.S. (1982) Esophageal Carcinogenesis in F344 Rats by Nitrosomethylethylamines Substituted in the ethyl Group. Journal of the National Cancer Institute, 68, 681-684.
[72]	Siglin, J.C., Khare, L. and Stoner, G.D. (1995) Evaluation of Dose and Treatment Duration on the Esophageal Tumorigenicity of N-Nitrosomethylbenzylamine in Rats. Carcinogenesis, 16, 259-265. http://dx.doi.org/10.1093/carcin/16.2.259
[73]	Wargovich, M.J., Woods, C., Eng, V.W., Stephens, L.C. and Gray, K. (1988) Chemoprevention of N-Nitrosomethyl-benzylamine-Induced Esophageal Cancer in Rats by the Naturally Occurring Thioether, Diallyl Sulfide. Cancer Research, 48, 6872-6875.
[74]	Kleihues, P., Veit, C., Wiessler, M. and Hodgson, R.M. (1981) DNA Methylation by N-Nitrosomethylbenzylamine in Target and non-target tissues of NMRI Mice. Carcinogenesis, 2, 897-899. http://dx.doi.org/10.1093/carcin/2.9.897
[75]	Yamada, Y., Weller, R.O., Kleihues, P. and Ludeke, B.I. (1992) Effects of Ethanol and Various Alcoholic Beverages on the Formation of O6-Methyldeoxyguanosine from Concurrently Administered N-Nitrosomethylbenzylamine in Rats: A Dose-Response Study. Carcinogenesis, 13, 1171-1175. http://dx.doi.org/10.1093/carcin/13.7.1171
[76]	Barch, D.H., Kuemmerle, S.C., Hollenberg, P.F. and Iannaccone, P.M. (1984) Esophageal Microsomal Metabolism of N-Nitrosomethylbenzylamine in the Zinc-Deficient Rat. Cancer Research, 44, 5629-5633.
[77]	Mehta, R., Labuc, G.E., Urbanski, S.J. and Archer, M.C. (1984) Organ Specificity in the Microsomal Activation and Toxicity of N-Nitrosomethylbenzylamine in Various Species. Cancer Research, 44, 4017-4022.
[78]	Dirsch, O.R., Koenigsmann, M., Ludeke, B.I., Scherer, E. and Kleihues, P. (1990) Bioactivation of N-Ni- trosomethyl-benzylamine and N-Nitrosomethyl-Amylamine in Oesophageal Papillomas. Carcinogene- sis, 11, 1583-1586. http://dx.doi.org/10.1093/carcin/11.9.1583
[79]	Castonguay, A., Stoner, G.D., Schut, H.A. and Hecht, S.S. (1983) Metabolism of Tobacco-Specific N-Nitrosamines by Cultured Human Tissues. Proceedings of the National Academy of Sciences of the United States of America, 80, 6694-6697. http://dx.doi.org/10.1073/pnas.80.21.6694
[80]	Huang, Q., Stoner, G., Resau, J., Nickols, J. and Mirvish, S.S. (1992) Metabolism of N-Nitrosomethyl-n-Amylamine by Microsomes from Human and Rat Esophagus. Cancer Research, 52, 3547-3551.
[81]	Stoner, G.D. and Gupta, A. (2001) Etiology and Chemoprevention of Esophageal Squamous Cell Carcinoma. Carcinogenesis, 22, 1737-1746. http://dx.doi.org/10.1093/carcin/22.11.1737
[82]	Wang, Y., You, M., Reynolds, S.H., Stoner, G.D. and Anderson, M.W. (1990) Mutational Activation of the Cellular Harvey Ras Oncogene in Rat Esophageal Papillomas Induced by Methylbenzy- lnitrosamine. Cancer Research, 50, 1591-1595.
[83]	Lozano, J.C., Nakazawa, H., Cros, M.P., Cabral, R. and Yamasaki, H. (1994) G--> A mutations in p53 and Ha-Ras Genes in Esophageal Papillomas Induced by N-Nitrosomethylbenzylamine in Two Strains of Rats. Molecular Carcinogenesis, 9, 33-39.
[84]	Asamoto, M., Toriyama-Baba, H., Ohnishi, T., Naito, A., Ota, T., Ando, A., Ochiya, T. and Tsuda, H. (2002) Transgenic rats Carrying Human c-Ha-ras Proto-Oncogene Are Highly Susceptible to N-Nitrosomethylbenzylamine Induction of Esophageal Tumorigenesis. Japanese Journal of Cancer Research, 93, 744-751. http://dx.doi.org/10.1111/j.1349-7006.2002.tb01315.x
[85]	Takahashi, M. and Imaida, K. (1991) Modification of Tumor Development in the Gastrointestinal Tract. In: Ito, N. and Sugano, H., Eds., Modification of Tumor Development in Rodents, Karger, Basel, 58-75.
[86]	Mirvish, S.S. (1997) Studies on Experimental Animals Involving Surgical Procedures and/or Nitrosamine Treatment Related to the Etiology of Esophageal Adenocarcinoma. Cancer Letters, 117, 161-174. http://dx.doi.org/10.1016/S0304-3835(97)00228-0
[87]	Miwa, K., Segawa, M., Takano, Y., Matsumoto, H., Sahara, H., Yagi, M., Miyazaki, I. and Hattori, T. (1994) Induction of Oesophageal and Forestomach Carcinomas in Rats by Reflux of Duodenal Contents. British Journal of Cancer, 70, 185-189. http://dx.doi.org/10.1038/bjc.1994.277
[88]	Mirvish, S.S., Huang, Q., Chen, S.C., Birt, D.F., Clark, G.W., Hinder, R.A., Smyrk, T.C. and DeMeester, T.R. (1993) Metabolism of Carcinogenic Nitrosamines in the Rat and Human Esophagus and Induction of Esophageal Adenocarcinoma in Rats. Endoscopy, 25, 627-631. http://dx.doi.org/10.1055/s-2007-1010418
[89]	Fein, M., Peters, J.H., Chandrasoma, P., Ireland, A.P., Oberg, S., Ritter, M.P., Bremner, C.G., Hagen, J.A. and DeMeester, T.R. (1998) Duodenoesophageal Reflux Induces Esophageal Adenocarcinoma without Exogenous Carcinogen. Journal of Gastrointestinal Surgery, 2, 260-268. http://dx.doi.org/10.1016/S1091-255X(98)80021-8
[90]	Fein, M., Peters, J.H., Baril, N., McGarvey, M., Chandrasoma, P., Shibata, D., Laird, P.W. and Skinner, K.A. (1999) Loss of Function of Trp53, but Not Apc, Leads to the Development of Esophageal Adenocarcinoma in Mice with Jejunoesophageal Reflux. Journal of Surgical Research, 83, 48-55. http://dx.doi.org/10.1006/jsre.1998.5559
[91]	Chen, X. and Yang, C.S. (2001) Esophageal Adenocarcinoma: A Review and Perspectives on the Mechanism of Carcinogenesis and Chemoprevention. Carcinogenesis, 22, 1119-1129. http://dx.doi.org/10.1093/carcin/22.8.1119
[92]	Chen, X., Yang, G., Ding, W.Y., Bondoc, F., Curtis, S.K. and Yang, C.S. (1999) An Esophagogastroduodenal Anastomosis Model for Esophageal Adenocarcinogenesis in Rats and Enhancement by Iron Overload. Carcinogenesis, 20, 1801-1808. http://dx.doi.org/10.1093/carcin/20.9.1801
[93]	Melo, L.L., Kruel, C.D., Kliemann, L.M., Cavazzola, L.T., Boeno Rda, L., Silber, P.C. and Grossi, R.S. (1999) Influence of Surgically Induced Gastric and Gastroduodenal Content Reflux on Esophageal Carcinogenesis—Experimental Model in Wistar Female Rats. Diseases of the Esophagus, 12, 106-115. http://dx.doi.org/10.1046/j.1442-2050.1999.00011.x
[94]	Goldstein, S.R., Yang, G.Y., Curtis, S.K., Reuhl, K.R., Liu, B.C., Mirvish, S.S., Newmark, H.L. and Yang, C.S. (1997) Development of Esophageal Metaplasia and Adenocarcinoma in a Rat Surgical Model without the Use of a Carcinogen. Carcinogenesis, 18, 2265-2270. http://dx.doi.org/10.1093/carcin/18.11.2265
[95]	Pera, M., Grande, L., Gelabert, M., Figueras, X., Palacin, A., Elena, M., Cardesa, A., Tiburcio, A.F. and Trastek, V.F. (1998) Epithelial Cell Hyperproliferation after Biliopancreatic Reflux into the Esophagus of Rats. The Annals of Thoracic Surgery, 65, 779-786. http://dx.doi.org/10.1016/S0003-4975(97)01382-9
[96]	Pera, M., Trastek, V.F., Carpenter, H.A., Fernandez, P.L., Cardesa, A., Mohr, U. and Pairolero, P.C. (1993) Influence of Pancreatic and Biliary Reflux on the Development of Esophageal Carcinoma. The Annals of Thoracic Surgery, 55, 1386-1392 (Discussion 1392-1383).
[97]	Xu, X., LoCicero 3rd, J., Macri, E., Loda, M., Ellis Jr., F.H. (2000) Barrett’s Esophagus and Associated Adenocarcinoma in a Mouse Surgical Model. Journal of Surgical Research, 88, 120-124. http://dx.doi.org/10.1006/jsre.1999.5774
[98]	Montesano, R., Hollstein, M. and Hainaut, P. (1996) Genetic Alterations in Esophageal Cancer and Their Relevance to Etiology and Pathogenesis: A Review. International Journal of Cancer, 69, 225-235. http://dx.doi.org/10.1002/(SICI)1097-0215(19960621)69:3<225::AID-IJC13>3.0.CO;2-6
[99]	Schneider, P.M., Casson, A.G., Levin, B., Garewal, H.S., Hoelscher, A.H., Becker, K., Dittler, H.J., Cleary, K.R., Troster, M., Siewert, J.R. and Roth, J.A. (1996) Mutations of p53 in Barrett’s Esophagus and Barrett’s Cancer: A Prospective Study of Ninety-Eight Cases. The Journal of Thoracic and Cardiovascular Surgery, 111, 323-331 (Discussion 331-323).
[100]	Godoy, W., Albano, R.M., Moraes, E.G., Pinho, P.R., Nunes, R.A., Saito, E.H., Higa, C., Filho, I.M., Kruel, C.D., Schirmer, C.C., Gurski, R., Lang, M.A. and Pinto, L.F. (2002) CYP2A6/2A7 and CYP2E1 Expression in Human Oesophageal Mucosa: Regional and Inter-Individual Variation in Expression and Relevance to Nitrosamine Metabolism. Carcinogenesis, 23, 611-616. http://dx.doi.org/10.1093/carcin/23.4.611
[101]	O’Connor, H.J. (1999) Review Article: Helicobacter Pylori and Gastro-Oesophageal Reflux Disease-Clinical Implications and Management. Alimentary Pharmacology Therapeutics, 13, 117-127. http://dx.doi.org/10.1046/j.1365-2036.1999.00460.x        eww141014lx