What Are the Real Roles of Different ErbB Proteins in Barrett’s Esophagus

Abstract

Accessible online at: www.karger.com/dig The erbB family of receptor tyrosine kinases includes four homologous proteins: the epidermal growth factor (EGF) receptor and erbB2, -3, and -4. These erbB receptors regulate proliferation, differentiation, migration, cell survival or apoptosis through a complex signaling pathway [1, 2]. In human malignant tissue, overexpression of the erbB receptors and/or amplification of their genes are frequent. Among them, EGF receptor is widely distributed throughout the gastrointestinal epithelium. EGF peptides, including transforming growth factor-· (TGF-·), heparin-binding EGF-like growth factor and amphiregulin, activate the tyrosine kinase of the EGF receptor. These peptides are known to exert a variety of effects through EGF receptor on gastrointestinal tract such as stimulation of epithelial cell proliferation and migration, control of acid and mucus secretion, increase of gastric blood flow, stimulation of intestinal NaCl absorption and Na+/H+ exchange [3]. Binding of EGF peptides to EGF receptor forms noncovalent heterodimeric complexes of the EGF receptor with erbB2, which enhances EGF receptor signaling. However, erbB2 overexpression results in production of its ligandindependent homodimeric complexes, followed by the enhancement of its signal transduction pathways [4]. In approximately 20–30% of breast cancers, overexpression of erbB2 has been identified. High levels of erbB2 expression are associated with accelerated tumor progression and metastatic activity. Thus, erbB2 expression levels are considered to be well-characterized indicators of prognosis in patients with breast cancer [5]. Furthermore, erbB2 is now a target of novel breast cancer treatments with trastuzumab (Herceptin), monoclonal antibodies against erbB2. Expression of erbB2 has also been detected in intestinal and colonic epithelia and gastrointestinal cancers [6–8]. Amplification of the erbB2 gene or overexpression of the erbB2 protein has also been reported in gastric adenocarcinoma, correlating with metastasis and survival [9]. In contrast to other erbBs, erbB3 lacks intrinsic tyrosine kinase activity [10]. Therefore, its heterodimer formation with erbB2 is necessary for erbB3 phosphorylation. ErbB3 is found in epithelial cells throughout the digestive tract [11]. In colon cancer, both erbB2 and erbB3 expression levels were higher than in normal mucosa [12]. Heregulin (HRG)/neuregulin isoforms have been identified as erbB3 ligands. Accumulating evidence suggests that regulation of the HRG/erbB2/erbB3 pathway may play an important role in tumor growth of the colon [13]. ErbB4 is also a receptor for HRG. Some studies suggest that erbB4 may contribute to the growth of gastric cancer [14]. Recently, the incidence of Barrett’s esophagus-associated adenocarcinoma is increasing in Western countries. In previous studies, EGF receptor and TGF-· have been shown to be increased in dysplastic lesions of the esophagus and in esophageal adenocarcinoma. In esophageal adenocarcinoma, EGF receptor and TGF-· expressions are associated with poor patient survival and metastases [15, 16]. On the other hand, quite a wide range of percentages of erbB2 overexpression have been reported in esophageal adenocarcinoma, ranging from 10 to 73% [17]. Nakamura et al. [18] studied 80 cases of Barrett’s esophagus-associated adenocarcinoma and found a significant correlation