Abstract
The presence of neuroendocrine (NE) cells in gastric adenocarcinoma (GCa) is well documented, however, their significance is controversial. There is no evidence in the literature concerning the possible effect of these cells on the expression of TGF-a and EGFR, which are believed to confer growth advantage to tumor cells. 101 partial or total gastrectomy specimens from patients operated for conventional gastric adenocarcinoma were included in the study. In each case immunohistochemistry was performed on sequential tissue sections for chromogranin A (ChrA), TGF-a and EGFR. Samples were graded based on the number of ChrA-positive cells (0–3). TGF-a and EGFR expressions were evaluated according to both the intensity (0–2) and quantification of the positively stained areas (0–3). Follow-up data was available in 54 patients. Twenty-seven patients died of disease, while 27 patients were alive with a follow-up of at least 15 months. ChrA expression was detected in 54.4% of the tumor specimens. TGF-a was stained positively in 42.6% and EGFR in 49.5% of the cases. NE cells in GCa was related to TGF-a (p<0.0001) and EGFR expression (p<0.05), and TGF-a/EGFR coexpression (p<0.001). Among histopathologic variables, the presence of NE cells was significantly related to grade, stage and lymph node status. Although the presence of NE cells had no effect on survival, the expression of EGFR (p<0.0001) and TGF-a (p=0.002) were related to survival. The results of our study suggest that the presence of NE cells may have an effect on the expression of TGF-a and EGFR in GCa, and the autocrine mechanism between TGF-α and EGFR plays an important role in the prognosis of gastric carcinoma.
Similar content being viewed by others
References
Adachi Y, Yasuda K, Inomata M, Sato K, Shiraishi N, Kitano S: Pathology and prognosis of gastric carcinoma: well versus poorly differentiated type. Cancer 89:1418–1424, 2000.
Back W, Rohr G, Bleyl U: Expression of TGF-alpha in neuroendocrine tumours of the distal colon and rectum. APMIS 111:931–939, 2003.
Bonar SF, Sweeney EC: The prevalence, prognostic significance and hormonal content of endocrine cells in gastric cancer. Histopathology 10:53–63, 1986.
Carpenter G: Properties of the receptor for epidermal growth factor. Cell 37:357–358, 1984.
Chen WS, Lazar CS, Lund KA, Welsh JB, Chang CP, Walton GM, Der CJ, Wiley HS, Gill GN, Rosenfeld MG: Functional independence of the epidermal growth factor receptor from a domain required for ligand-induced internalization and calcium regulation. Cell 59:33–43, 1989.
Dawson IMP: Diffuse endocrine and neuroendocrine cell tumors. In: Recent Advances in Histopathology. (Eds: Anthony PP, Macween RNM), Churchill Livingstone, Edinburgh, 1984, pp 111–128.
Derynck R: Transforming growth factor-alpha: Structure and biological activities. J Cell Biochem 32:293–304, 1986.
di Sant’ Agnese PA: Neuroendocrine differentiation in prostatic carcinoma: an update. Prostate Suppl 8:74–79, 1998.
Eren F, Çelikel ÇA, Güllüoglu B: Neuroendocrine differentiation in gastric adenocarcinomas; correlation with tumor stage and expression of VEGF and p53. Pathol Oncol Res 10:47–51, 2004.
Gamboa-Dominguez A, Dominguez-Fonseca C, Quintanilla-Martinez L, Reyes-Gutierrez E, Green D, Angeles-Angeles A, Busch R, Hermannstadter C, Nahriq J, Becker KF: Epidermal growth factor receptor expression correlates with poor survival in gastric adenocarcinoma from Mexican patients: a multivariate analysis using a standardized immunohistochemical detection system. Mod Pathol 17:579–587, 2004.
Garcia I, Vizoso F, Martin A, Sanz L, Abdel-Lah O, Raigoso P, Garcia-Muniz JL: Clinical significance of the epidermal growth factor receptor and HER2 receptor in resectable gastric cancer. Ann Surg Oncol 10:234–241, 2003.
Grabowski P, Schindler I, Anagnostopoulos I, Foss HD, Riecken EO, Mansmann U, Stein H, Berger G, Buhr HJ, Scherulb H: Neuroendocrine differentiation is a relevant prognostic factor in stage III–IV colorectal cancer. Eur J Gastroenterol Hepatol 13:405–411, 2001.
Hirayama D, Fujimori T, Satonaka K, Nakamura T, Kitazawa S, Horio M, Maeda S, Nagasako K: Immunohistochemical study of epidermal growth factor and transforming growth factor-b in penetrating type of early gastric cancer. Hum Pathol 23:681–685, 1992.
Hopfner M, Sutter AP, Gerst B, Zeitz M, Scherubl H: A novel approach in the treatment of neuroendocrine gastrointestinal tumours. Targeting the epidermal growth factor receptor by gefitinib (ZD1839). Br J Cancer 89:1766–1775, 2003.
Issing WJ, Liebich C, Wustrow TPU, Ullrich A: Coexpression of epidermal growth factor receptor and TGF-α and survival in upper aerodigestive tract cancer. Anticancer Res 16:283–288, 1996.
Ito R, Nakayama H, Yoshida K, Matsumura S, Oda N, Yasui W Expression of Cbl linking with the epidermal growth factor receptor system is associated with tumor progression and poor prognosis of human gastric carcinoma. Virchows Arch 444:324–331, 2004.
James R, Bradshaw RA: Polypeptide growth factors. Annu Rev Biochem 53:259–292, 1984.
Jiang SX, Mikami T, Umezawa A, Saegusa M, Kameya T, Okayasu I: Gastric large cell neuroendocrine carcinomas: a distinct clinicopathologic entity. Am J Surg Pathol 30:945–953, 2006.
Karameris A, Kanavaros P, Aninos D, Gorgoulis V, Mikou G, Rokas T, Niotis M, Kalogeropoulos N: Expression of epidermal growth factor (EGF) and epidermal growth factor receptor (EGFR) in gastric and colorectal carcinomas: an immunohistochemical study of 63 cases. Path Res Pract 189:133–137, 1993.
Kim KM, Kim MJ, Cho BK, Choi SW, Rhyu MG: Genetic evidence for the multi-step progression of mixed glandular-neuroendocrine gastric carcinomas. Virchows Arch 440:85–93, 2002.
Krishnamurthy S, Dayal Y: Immunohistochemical expression of transforming growth factor alpha and epidermal growth factor receptor in gastric carcinoids. Am J Surg Pathol 21:327–333, 1997.
Kuba T, Watanabe H: Neoplastic argentaffin cells in gastric and intestinal carcinomas. Cancer 27:447–454, 1971.
Lechago J: Gastrointestinal neuroendocrine cell proliferations. Hum Pathol 25:1114–1122, 1994.
Modlin IM, Tang LH: The gastric enterochromaffin-like cell: an enigmatic cellular link. Gastroenterology 111:783–810, 1996.
Murayama H, Imai T, Kikuchi M: Solid carcinomas of the stomach. Cancer 51:1673–1681, 1983.
Nilsson O, Wangberg B, Kolby L, Schultz GS, Ahlman H: Expression of transforming growth factor alpha and its receptor in human neuroendocrine tumours. Int J Cancer 60:645–651, 1995.
Ooi A, Mai M, Ogino T, Ueda H, Kitamura T, Takahashi Y, Kawahara E, Nakanishi I: Endocrine differentiation of gastric adenocarcinoma: the prevalence as evaluated by immunoreactive chromogranin A and its biologic significance. Cancer 62:1096–1104, 1988.
Papouchado B, Erickson LA, Rohlinger AL, Hobday TJ, Erlichman C, Ames MM, Lloyd RV: Epidermal growth factor receptor and activated epidermal growth factor receptor expression in gastrointestinal carcinoids and pancreatic endocrine carcinomas. Mod Pathol 18:1329–1335, 2005.
Park DI, Yun JW Park JH, Oh SJ, Kim HJ, Cho YK, Sohn CI, Jeon WK, Kim BI, Yoo CH, Son BH, Cho EY, Chae SW Kim EJ, Sohn JH, Ryu SH, Sepulveda AR: HER-2/neu amplification is an independent prognostic factor in gastric cancer. Dig Dis Sci 51:1371–1379, 2006.
Park JG, Choe GY, Helman LJ, Gaidar AF, Yang HK, Kim JP, Park SH, Kim YI: Chromogranin-A expression in gastric and colon cancer tissues. Int J Cancer 51:189–194, 1992.
Pueztal L, Lewis CE, Lorenzen J, McGee OD: Growth factors: regulation of normal and neoplastic growth. J Pathol 169:191–201, 1993.
Qyigstad G, Sandvik AK, Brenna E, Aase S, Waldum HL: Detection of chromogranin A in human gastric adenocarcinomas using a sensitive immunohistochemical technique. Histochem J 32:551–556, 2000.
Qvigstad G, Qyigstad T, Westre B, Sandvik AK, Brenna E, Waldum HL: Neuroendocrine differentiation in gastric adenocarcinomas associated with severe hypergastrinemia and/or pernicious anemia. APMIS 110:132–139, 2002.
Shah T, Hochhauser D, Frow R, Quaglia A, Dhillon AP, Caplin ME: Epidermal growth factor receptor expression and activation in neuroendocrine tumours. J Neuroendocrinol 18:355–360, 2006.
Sobin LH, Wittekind CH (eds): TNM Classification of Malignant Tumors. International Union Against Cancer. 5th edition, John Wiley & Sons, New York, 1997.
Tahara E: Growth factors and oncogenes in human gastrointestinal carcinomas. J Cancer Res Clin Oncol 116:121–131, 1990.
Tang LH, Modlin LM, Lawton GP, Kidd M, Chinery R: The role of transforming growth factor a in the enterochromaffinlike cell tumor autonomy in an African rodent Mastomys. Gastroenterology 111:1212–1223, 1996.
Tielemans Y, Chen D, Sundler F, Hakanson R, Willems G: Reversibility of the cell kinetic changes induced by omeprazole in the rat oxyntic mucosa. An autoradiographic study using tritiated thymidine. Scand J Gastroenterol 27:155–160, 1992.
Waldum HL, Aase S, Kvetnol I, Brenna E, Sandvik AK, Syversen U, Johnsen G, Vatten L, Polak JM: Neuroendocrine differentiation in human gastric carcinoma. Cancer 83:435–444, 1998.
Waldum HL, Brenna E, Sandvik AK: Relationship of ECL cells and gastric neoplasia. Yale J Biol Med 71:325–335, 1998.
Wilson BS, Lloyd RV: Detection of chromogranin in neuroendocrine cells with a monoclonal antibody. Am J Pathol 115:458–468, 1984.
Yao GY, Zhou JL, Lai MD, Chen XQ, Chen PH: Neuroendocrine markers in adenocarcinomas: an investigation of 356 cases. World J Gastroenterol 9:858–861, 2003.
Yonemura Y, Takamura H, Ninomiya I, Fushida S, Tsugawa K, Kaji M, Nakai Y, Ohoyama S, Yamaguchi A, Miyazaki I: Interrelationship between transforming growth factor-a and epidermal growth factor receptor in advanced gastric cancer. Oncology 49:157–161, 1992.
Yoshida K, Kyo E, Tsujino T, Sano T, Niimoto M, Tahara E: Expression of epidermal growth factor, transforming growth factor-a and their receptor genes in human gastric carcinomas; implication for autocrine growth. Jpn J Cancer Res 81:43–51, 1990.
Author information
Authors and Affiliations
Corresponding author
Additional information
This work was supported by the Marmara University Research Committee
Rights and permissions
About this article
Cite this article
Celikel, C., Eren, F., Gulluoglu, B. et al. Relation of neuroendocrine cells to transforming growth factor-alpha and epidermal growth factor receptor expression in gastric adenocarcinomas: Prognostic implications. Pathol. Oncol. Res. 13, 215–226 (2007). https://doi.org/10.1007/BF02893502
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF02893502