TACE/ADAM-17: A component of the epidermal growth factor receptor axis and a promising therapeutic target in colorectal cancer

Nipun B. Merchant, Igor Voskresensky, Christopher M. Rogers, Bonnie LaFleur, Peter J. Dempsey, Ramona Graves-Deal, Frank Revetta, A. Coe Foutch, Mace L. Rothenberg, Mary K. Washington, Robert J. Coffey

Research output: Contribution to journalArticle

82 Scopus citations

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-α (TGF-α) 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-α converting enzyme/a disintegrin and metalloprotease) has been implicated in ectodomain cleavage of TGF-α 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 that TACE 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-α and amphiregulin. Pharmacologic blockade of HCA-7 cells with an EGFR monoclonal antibody, a selective EGFR tyrosine kinase inhibitor, and a selective TACE inhibitor results in concentration-dependent 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 implicate TACE as a promising target of EGFR axis inhibition in CRC.

Original languageEnglish (US)
Pages (from-to)1182-1191
Number of pages10
JournalClinical Cancer Research
Volume14
Issue number4
DOIs
StatePublished - Feb 15 2008

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Merchant, N. B., Voskresensky, I., Rogers, C. M., LaFleur, B., Dempsey, P. J., Graves-Deal, R., Revetta, F., Foutch, A. C., Rothenberg, M. L., Washington, M. K., & Coffey, R. J. (2008). TACE/ADAM-17: A component of the epidermal growth factor receptor axis and a promising therapeutic target in colorectal cancer. Clinical Cancer Research, 14(4), 1182-1191. https://doi.org/10.1158/1078-0432.CCR-07-1216