C-ERBB-2 and C-ERBB-3, but not egfreceptor are overexpressed in (advanced) colorectal cancer

PURPOSE OF THE STUDY The pathogenesis of colorectal cancer is still poorly understood. The epidermal growth factor receptor (EGFR), c-erbB-2 and c-erbB-3 are transmembrane signalling molecules that share close structural homology. They have been implicated in cell transformation and tumour pathogenesis. In the present study we have analysed the expression of these three growth factor receptors in patients with colorectal carcinomas. PATIENTS AND METHODS Cancerous tissue samples were obtained from seven female and 22 male patients with a mean age of 65.8 years (range 42-84 years) undergoing colonie resection due to carcinoma of the colon or rectum. Tumours were classified according to the TNM-system (UICC): 8 stage I, 12 stage II, 2 stage III and 7 stage IV. Normal colonie tissues from the same patients served as controls. Tissues destined for RNA extraction were frozen in liquid nitrogen immediately upon surgical removal. In addition, freshly removed tissue samples were fixed in Bouin solution and paraffin embedded for histological analysis. Expression of the EGFR, c-erbB-2 and cerbB-3 was analysed by Northern blot analysis using specific cRNA probes in 25 of these patients. In addition, immunohistochemical analysis using specific monoclonal antibodies was performed. RESULTS By Northern blot analysis both, c-erbB-2 and c-erbB-3 mRNA were increased in 16 of 25 (64%) carcinomas, respectively in comparison with the normal tissue samples. Densitometric analysis of the Northern blots revealed a 1.5 fold increase of c-erbB-2 (P< 0.02) and a 2.3-fold increase of c-erbB-3 (P< 0.01) in cancerous tissues compared to controls. In contrast, EGFR mRNA was decreased in 16/25 (64%) carcinomas and overexpressed in 6/25 (24%) of the cancer samples. Five of the six cancer samples with EGFR overexpression were obtained from patients with stage I or II disease. All five stage IV tumors examined for EGFR mRNA expression showed lower levels compared with the control. Immunohistochemical analysis revealed strong immunoreactivity for c-erbB-2 in 17/29 (59%) and for c-erbB-3 in 27/29 (93%) in the cancer cells. In contrast, all normal samples exhibited only faint or no c-erbB-2 and c-erbB-3 immunoreactivity. No difference was evident in EGFR immunostaining between normal and cancerous tissue samples. CONCLUSIONS Overexpression of c-erbB-2 and c-erbB-3 suggests a role of these growth factor receptors in the pathogenesis of colorectal cancer, independent of the tumor stage. Overexpression of EGFR mRNA in early tumour stages and its absence in advanced disease might indicate a significant influence on tumor initiation but not on tumour progression.