Amphiregulin Is a Promising Prognostic Marker for Liver Metastases of Colorectal Cancer

Abstract

Purpose: Aberrant activation of epidermal growth factor receptors (EGFR/HER1) by ligand stimulation or heterodimerization with human epidermal growth factor 2 (HER2) is considered to play an important role in the development of colorectal carcinoma. Amphiregulin (AR) is a ligand of EGFR that might be related to the development and progression of gastrointestinal tumors.The aim of this study was to determine the AR, EGFR, and HER2 protein expression levels and to evaluate their prognostic relevance to the clinical course of colorectal cancer. Experimental Design: The AR, EGFR, and HER2 protein levels in primary tumors of colorectal cancer (n = 106) were examined using immunohistochemistry. Metastatic sites in liver specimens (n = 16) were also analyzed in the same manner. Results: Thirteen (81.6%) metastatic lesions of the liver stained positive for AR. Among the primary lesions of colorectal cancer, 58 (54.7%) stained positive for AR, 13 (12.3%) stained positive for EGFR, and 5 (4.7%) stained positive for HER2. When the relationships between each protein expression level and the clinicopathologic factors were examined, only the AR expression level was significantly related to liver metastasis (P = 0.0296). A multivariate analysis of liver metastasis proved that AR expression was an independent prognostic factor of liver metastasis from colorectal cancer (P = 0.0217). Conclusions: AR expression in primary lesions of colorectal cancer is an important predictive marker of liver metastasis. Epidermal growth factor (EGF) receptors (EGFR) and theirvarious ligands seem to be involved in the progression of gastrointestinal tumors (1). The EGF signal pathway is reportedly activated by several kinds of stimulation. First, ligands like amphiregulin (AR), transforming growth factor-a (TGF-a), and EGF may bind to EGFR. EGFR, a 170-kDa transmembrane glycoprotein (2), is composed of an extracellular ligand-binding domain, a transmembrane region, and an intracellular protein tyrosine kinase domain (3 -5). The above-mentioned ligands bind to the extracellular ligand-binding domain of EGFR and stimulate the pathway. Second, the heterodimerization of EGFR and HER2 can reportedly stimulate signaling in the absence of ligands (2). These steps are followed by the stimulation of intrinsic tyrosine kinase activity and tyrosine autophosphorylation (3, 6 -8). Receptor activity is modulated by intracellular kinases that mediate negative feedback control via receptor phosphorylation at specific regulatory domains, and receptor inactivation is mediated by receptor internalization and ligandreceptor dissociation. AR has been implicated in the growth and regeneration of intestinal mucosa and might be related to the development and progression of gastrointestinal tumors (9 -12). Our microarray analysis in colorectal tumors and liver metastases revealed that AR was down-regulated in adenomatous tumors but was up-regulated in metastatic tumors of the liver (data not shown). These findings suggested that AR might contribute to liver meta...

The EGFR Ligands Amphiregulin and Heparin-Binding EGF-like Growth Factor Promote Peritoneal Carcinomatosis in CXCR4-Expressing Gastric Cancer

“…Amphiregulin is reported crucial in several types of tumors, including breast cancer, colon cancer, and hepatocellular carcinoma (11,12). Although the expression of amphiregulin mRNA and protein has been assessed in gastric cancers (36), its role in gastric cancer pathogenesis, especially in the development of peritoneal carcinomatosis, remains poorly understood.…”

“…To date, 7 ligands for EGFR have been identified: EGF, transforming growth factor a (TGFa); heparin-binding EGF-like growth factor (HB-EGF); amphiregulin; betacellulin; epiregulin; and epigen. Amphiregulin has been shown to play a crucial role in several types of tumors (11,12), and HB-EGF has also been reported critical for tumor formation (13). However, the association between each EGFR ligand and tumor type, in particular the development of peritoneal carcinomatosis, is largely unknown.…”

Lung Tumor-Associated Dendritic Cell-Derived Amphiregulin Increased Cancer Progression

“…Amphiregulin is upregulated in various cancers and associated with cancer progression, such as cancer cell growth, proliferation, migration or invasiveness after the activation of EGFR (9,10,25). In addition, amphiregulin is not only involved in cancer growth but also is responsible for resistance to conventional chemotherapeutic drugs, such as cisplatin, and to hormonal antitumor aromatase inhibitors and EGFR-tyrosine kinase inhibitors (12,26,27).…”

“…Amphiregulin is produced as a transmembrane precursor that is released from the cell membrane by a disintegrin and metalloproteinases (ADAM17) (8). Elevated levels of amphiregulin have been characterized in various types of tumors, and amphiregulin is assumed to play a role in promoting cancer progression (9,10). Amphiregulin also elevates angiogenic activity, promoting tumor growth and metastasis in pancreatic, colorectal, liver, and lung cancers (9)(10)(11)(12).…”

“…Elevated levels of amphiregulin have been characterized in various types of tumors, and amphiregulin is assumed to play a role in promoting cancer progression (9,10). Amphiregulin also elevates angiogenic activity, promoting tumor growth and metastasis in pancreatic, colorectal, liver, and lung cancers (9)(10)(11)(12). A recent study has indicated that cancer-derived ATP increased the expression of amphiregulin in DCs in a mouse lung cancer cell line (13).…”