TACE/ADAM-17: A Component of the Epidermal Growth Factor Receptor Axis and a Promising Therapeutic Target in Colorectal Cancer

Abstract

Purpose: Activation of the epidermal growth factor receptor (EGFR) requires cell surface cleavage of EGFR ligands, uptake of soluble ligand by the receptor, and initiation of EGFR tyrosine kinase activity. We define these collective events as the EGFR axis. Transforming growth factor-a (TGF-a) and amphiregulin are two EGFR ligands that are delivered preferentially to the basolateral surface of polarized epithelial cells where the EGFR resides. TACE/ADAM-17 (tumor necrosis factor-a converting enzyme/a disintegrin and metalloprotease) has been implicated in ectodomain cleavage of TGF-a and amphiregulin. Experimental Design: Using a human polarizing colorectal cancer (CRC) cell line, HCA-7, and a tissue array of normal colonic mucosa and primary and metastatic CRC, we determined the intracellular localization of TACE and the effects of EGFR axis inhibition in CRC.Results: Herein, we show thatTACE is localized to the basolateral plasma membrane of polarized HCA-7 cells.TACE is overexpressed in primary and metastatic CRC tumors compared with normal colonic mucosa; the intensity of its immunoreactivity is inversely correlated with that of TGF-a and amphiregulin. Pharmacologic blockade of HCA-7 cells with an EGFR monoclonal antibody, a selective EGFR tyrosine kinase inhibitor, and a selectiveTACE inhibitor results in concentrationdependent decreases in cell proliferation and active, phosphorylated mitogen-activated protein kinase. Combining suboptimal concentrations of these agents results in cooperative growth inhibition, increased apoptosis, and reduced mitogen-activated protein kinase pathway activation. Furthermore, an EGFR tyrosine kinase^resistant clone of HCA-7 cells is growth-inhibited by combined monoclonal antibody and TACE inhibition. Conclusion: These results implicateTACE as a promising target of EGFR axis inhibition in CRC.

Role of ADAMs in Cancer Formation and Progression

“…57). WAY-022, which is a selective inhibitor of ADAM-17, was found to decrease DNA replication and cell growth in colorectal cancer cells (57). Furthermore, the combination of suboptimal concentrations of WAY-022 with an EGFR monoclonal antibody or a selective EGFR kinase inhibitor resulted in cooperative growth inhibition (57).…”

Expression and clinical significance of ADAM17 protein in esophageal squamous cell carcinoma

“…Tanaka et al (2005) found that ADAMl7 can mediate the release of specific EGFR ligands, which can bind to epidermal growth factor and activate the EGFR to cause epithelial hyperplasia disorder and then develop into cancer. A previous study found that ADAMselective protease inhibitors could block the EGFR pathway in tumor cells (Merchant et al, 2008). Currently, the EGFR signaling pathway is a known target of anti-cancer drugs.…”

Impact of EGFR immunoexpression on STAT3 activation and association with proinflammatory/regulatory cytokine pattern in laryngeal squamous cell carcinoma

“…EGFR is a key transmembrane glycoprotein triggering a network of downstream signaling pathways, including not only cell proliferation, cell-cell adhesion and migration, but also the invasion of the tumor front, apoptosis and DNAdamage repair in neoplasm cells (8)(9)(10). Over-expression of EGFR and its ligands, such as EGF, TGF·, amphiregulin and the presence of tyrosine kinase domain mutations have been noted in many human cancer types, such as HNSCC (11)(12)(13)(14)(15).…”

“…A large number of malignancies of epithelial origin have been characterized by the overexpression of EGFR and/or its ligands, such as epidermal growth factor (EGF), transforming growth factor-· (TGF·) and amphiregulin (11,12). The amplification of genes encoding EGFR has also been noted in previous studies (13)(14)(15).…”