Correlation of c-erbB-2, EGF and EGFR expression with postoperative survival of patients with advanced carcinoma of the stomach.

The c-erbB-2 (HER-2/neu), EGF and EGFR (erbB-1) proteins, members of the epidermal growth factor receptor family, play a role in cell growth by binding to cell membrane receptors. The aim of the current study was to evaluate the expression of c-erbB-2, EGF and EGFR in advanced gastric carcinoma and to analyze its relationship with chosen anatomo-clinical parameters and prognosis. Standard avidin-biotin-peroxidase was used for c-erbB-2, EGF and EGFR immuno-histochemical staining (Novostain Super ABC Kit Universal); anti-human c-erbB-2 protein monoclonal antibody NCL-cerbB-2-316, anti-Epidermal Growth Factor monoclonal antibody (clone EGF-10) and EGFR goat polyclonal IgG (p-EGFR). A statistically significant correlation was found between c-erbB-2, EGF, EGRF expressions in the main mass of tumor and lymph node metastasis (p=0.000; p=0.000; p=0.00001, respectively). Also an association was observed between c-erbB-2 expression and Bormann's and Lauren's classifications (p=0.05; p=0.006, respectively). Similarly, the expression of EGFR in main mass of tumor was correlated with the depth of invasion (p=0.007) and histological differentiation (p=0.04). Moreover, the expression of c-erbB-2 in the main mass of tumor and lymph node metastasis was associated with the age of the patients (p=0.03; p=0.0002 respectively). Strong association was found between the expression of EGRF in lymph node metastasis and histological differentiation (p=0.04). Positive expression of c-erbB-2 in lymph node metastasis was correlated with lymph node involvement (p=0.04). Positive expression of c-erbB-2 in the main mass of tumor and in lymph node metastasis was strongly correlated with postoperative survival (p=0.00001; p=0.003 respectively). We also found a relationship between EGF expression in gastric tumor and survival time (p=0.003). No association was noted between the expression of EGFR in the main mass of tumor and in lymph node metastasis and between the expression of EGF in lymph node metastasis and survival time. Our results suggest that the expression of c-erbB-2 and EGF protein can help predict the postoperative survival time.

[1]  H. Hoefler,et al.  The use of molecular biology in diagnosis and prognosis of gastric cancer. , 2000, Surgical oncology.

[2]  M. Manns,et al.  Regulation of gastric epithelial cell growth by Helicobacter pylori: offdence for a major role of apoptosis. , 1997, Gastroenterology.

[3]  W. Coyle,et al.  Eradication of Helicobacter pylori normalizes elevated mucosal levels of epidermal growth factor and its receptor , 1999, American Journal of Gastroenterology.

[4]  Atsushi Ochiai,et al.  Interaction between epidermal growth factor and its receptor in progression of human gastric carcinoma , 1988, International journal of cancer.

[5]  A. Dursun,et al.  Expression of c-erbB-2 Oncoprotein in Gastric Carcinoma: Correlation with Histopathologic Characteristics and Analysis of Ki-67 , 1999, Pathology & Oncology Research.

[6]  H. Höfler,et al.  Gastric adenocarcinoma: pathomorphology and molecular pathology , 2001, Journal of Cancer Research and Clinical Oncology.

[7]  M. Vasei,et al.  The expression of c-erbB-1 and c-erbB-2 in Iranian patients with gastric carcinoma , 2009, Pathology Oncology Research.

[8]  M. Ruge,et al.  Impact of epidermal growth factor (EGF) radioreceptor analysis on long-term survival of gastric cancer patients. , 2002, Anticancer research.

[9]  I. Biunno,et al.  Expression of the epidermal growth factor receptor gene in human intestinal metaplasia: a preliminary report. , 1997, Scandinavian journal of gastroenterology.

[10]  T. Mitsudomi,et al.  Serum level and tissue expression of c-erbB-2 protein in lung adenocarcinoma. , 1995, Chest.

[11]  R. Nicholson,et al.  EGFR and cancer prognosis. , 2001, European journal of cancer.

[12]  H. P. Wang,et al.  Relationship of p53 and c-erbB-2 expression to histopathological features, Helicobacter pylori infection and prognosis in gastric cancer. , 1997, Hepato-gastroenterology.

[13]  G. Carpenter Receptor tyrosine kinase substrates: src homology domains and signal transduction , 1992, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[14]  J. V. van Sandick,et al.  Prognostic Value of Laurén Classification and c-erbB-2 Oncogene Overexpression in Adenocarcinoma of the Esophagus and Gastroesophageal Junction , 1999, Annals of Surgical Oncology.

[15]  Yao-zong Yuan,et al.  Effects of epidermal growth factor on the growth of human gastric cancer cell and the implanted tumor of nude mice. , 2002, World journal of gastroenterology.

[16]  N. Normanno,et al.  Epidermal growth factor-related peptides and their receptors in human malignancies. , 1995, Critical reviews in oncology/hematology.

[17]  J. Furui,et al.  erbB-2 expression in well-differentiated adenocarcinoma of the stomach predicts shorter survival after curative resection. , 1994, Surgery.

[18]  John Mendelsohn,et al.  The EGF receptor family as targets for cancer therapy , 2000, Oncogene.

[19]  H. P. Wang,et al.  Overexpression of mutant p53 and c‐erbB‐2 proteins and mutations of the p15 and p16 genes in human gastric carcinoma: With respect to histological subtypes and stages , 1998, Journal of gastroenterology and hepatology.

[20]  R. Playford,et al.  Why is epidermal growth factor present in the gut lumen? , 1996, Gut.

[21]  Y. Yarden,et al.  Advances in Brief Tumor-inhibitory Antibodies to HER-2 / ErbB2 May Act by Recruiting c-Cbl and Enhancing Ubiquitination of HER-21 , 2000 .

[22]  Hiroshi Yamamoto,et al.  Amplification of the c-met, c-erbB-2 and Epidermal Growth Factor Receptor Gene in Human Gastric Cancers: Correlation to Clinical Features , 1998, Oncology.

[23]  H. Allgayer,et al.  c-erbB-2 is of independent prognostic relevance in gastric cancer and is associated with the expression of tumor-associated protease systems. , 2000, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[24]  C. Messa Epidermal Growth Factor and 17ß-Estradiol Effects on Proliferation of a Human Gastric Cancer Cell Line (AGS) , 2000, Scandinavian journal of gastroenterology.

[25]  C. Cordon-Cardo,et al.  Expression of the HER-2/neu proto-oncogene in normal human adult and fetal tissues. , 1990, Oncogene.

[26]  B. Groner,et al.  Correlation of c-erbB-2 gene amplification and protein expression in human breast carcinoma with nodal status and nuclear grading. , 1988, Cancer research.

[27]  N. Nomura,et al.  Similarity of protein encoded by the human c-erb-B-2 gene to epidermal growth factor receptor , 1986, Nature.

[28]  T. Okuda,et al.  Clinical significance of epidermal growth factor (EGF), EGF receptor, and c‐erbb‐2 in human gastric cancer , 1995, Cancer.

[29]  C. la Vecchia,et al.  Trends of cancer mortality in Europe, 1955-1989: I, Digestive sites. , 1992, European journal of cancer.

[30]  H. Tsuda,et al.  Combined measurement of the c‐erbb‐2 protein in breast carcinoma tissues and sera is useful as a sensitive tumor marker for monitoring tumor relapse , 2000, International journal of cancer.

[31]  S. Gurel,et al.  The Relationship between c-erbB-2 Oncogene Expression and Clinicopathological Factors in Gastric Cancer , 1999, The Journal of international medical research.

[32]  K. Choe,et al.  Prognostic significance of p53, nm23, PCNA and c-erbB-2 in gastric cancer. , 2003, Japanese journal of clinical oncology.

[33]  T. Hirao,et al.  The prognostic significance of amplification and overexpression of c‐met and c‐erb B‐2 in human gastric carcinomas , 1999, Cancer.

[34]  L. David,et al.  c-erb B-2 Expression Is Associated with Tumor Location and Venous Invasion and Influences Survival of Patients with Gastric Carcinoma , 2002, International journal of surgical pathology.

[35]  K. Syrigos,et al.  Clinical significance of soluble c-erbB-2 levels in the serum and urine of patients with gastric cancer. , 2002, Anticancer research.

[36]  Y. Shiratori,et al.  Activation of epidermal growth factor receptor kinase in gastric carcinoma: a preliminary study , 2000, American Journal of Gastroenterology.

[37]  H. Yazici,et al.  Utility of c-crbB-2 Expression in Tissue and Sera of Ovarian Cancer Patients , 2000, Cancer investigation.

[38]  E. Wynder,et al.  The decline in gastric cancer: epidemiology of an unplanned triumph. , 1986, Epidemiologic reviews.

[39]  J. Nährig,et al.  Epidermal growth factor receptor expression correlates with poor survival in gastric adenocarcinoma from Mexican patients: a multivariate analysis using a standardized immunohistochemical detection system , 2004, Modern Pathology.

[40]  Shenhua Xu,et al.  Study on the relationship between P-glycoprotein (P-gp) and C-erbB-2 expression in gastric carcinoma , 2007 .

[41]  Y. Maehara,et al.  c-erbB-2 expression is predictive for lymphatic spread of clinical gastric carcinoma. , 1997, Hepato-gastroenterology.