Activation of Growth Factor Receptors in Esophageal Cancer—Implications for Therapy

Abstract

Esophageal cancer is a highly aggressive disease and is the seventh most common cause of cancer-related death in the western world. Worldwide, it ranks as the sixth most frequent cause of cancer death. Despite advances in surgical techniques and treatment, the prognosis of esophageal cancer remains poor, with very few longterm survivors. The need for novel strategies to detect esophageal cancer earlier and to improve current therapy is urgent.It is well established that growth factors and growth factor receptor-mediated signaling pathways are important components of the transformation process in many forms of cancer, including esophageal cancer. With the recent advances in drug development, there are emerging possibilities to use growth factor signal transduction pathways in targeted therapy. This review provides a summary of the role of growth factors and their receptors in esophageal cancer and discusses their potential roles as biomarkers and as targets in therapy.

Growth Factors, Signal Transduction Pathways, and Tumor Suppressor Genes in Esophageal Cancer

“…The significant role of growth factors and growth factor-mediated signaling pathways in the tumorigenesis of esophagus has been well established and similar to many other types of cancers as a preferred target for esophageal cancer therapy [4].…”

“…Such phosphorylated cytoplasmic domains serve as docking sites for downstream signal transduction molecules and trigger signaling pathways that induce expression of cyclin D1, promoting cellular proliferation and survival (Fig 1, Fig 2) [10]. Aberrant regulation of growth factors and their corresponding receptors in addition to structural alterations in receptors play important role in tumorigenesis of esophageal cancer [4].…”

“…The EGFR family composes of four members: EGFR (HER-1, erbB-1), HER2 (erbB-2, Neu), HER3 (erbB-3) and HER4 (erbB-4) [4,18], all of which are tyrosine kinase receptors that are activated by ligand-induced homo or hetero dimerization. Overexpression of EGFRs is common in esophageal cancer and has been reported in several cell lines of SCCE, 29-92% of tumor samples of SCCE [19,20] and 80% of patients with adeno and squamous cell carcinoma [21,22].…”

“…EGF overexpression has also been detected in Barrett's-associated adenocarcinomas [13,27,28]. EGF may also serve growth inhibitory effect that shown to be mediated by STAT-1 (signal transducer and activator of transcription1) pathway and its mediation in the upregulation of p21 cyclin dependent kinase inhibitor [4,29,30].…”

“…These events include genetic and epigenetic alterations in oncogenes, tumor suppressor genes, cell adhesion molecules, DNA repair genes, cell cycle regulatory genes, genetic instability as well as telomerase activation, and aberrant regulation of growth factors and their receptors. Recent studies have indicated that activation of cyclin D1, erbB-2, and c-myc oncogenes and inactivation of p53, Rb, APC, and p16 tumor suppressor genes are frequently involved in esophageal cancers [3][4][5][6].…”