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Research Articles: Therapeutics, Targets, and Development

Novel xenograft model expressing human hepatocyte growth factor shows ligand-dependent growth of c-Met–expressing tumors

Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York

Requests for reprints: Martin R. Weiser, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Room C-1075, New York, NY 10021. Phone: 212-639-6698; Fax: 212-794-3198. E-mail: weiser1{at}mskcc.org

Abstract

c-Met, a receptor tyrosine kinase responsible for cellular migration, invasion, and proliferation, is overexpressed in human cancers. Although ligand-independent c-Met activation has been described, the majority of tumors are ligand dependent and rely on binding of hepatocyte growth factor (HGF) for receptor activation. Both receptor and ligand are attractive therapeutic targets; however, preclinical models are limited because murine HGF does not activate human c-Met. The goal of this study was to develop a xenograft model in which human HGF (hHGF) is produced in a controllable fashion in the mouse. Severe combined immunodeficient mice were treated with adenovirus encoding the hHGF transgene (Ad-hHGF) via tail vein injection, and transgene expression was determined by the presence of hHGF mRNA in mouse tissue and hHGF in serum. Ad-hHGF administration to severe combined immunodeficient mice resulted in hHGF production that was (a) dependent on quantity of virus delivered; (b) biologically active, resulting in liver hypertrophy; and (c) sustainable over 40 days. In this model, the ligand-dependent human tumor cell line SW1417 showed enhanced tumor growth, whereas the ligand-independent cell lines SW480 and GTL-16 showed no augmented tumor growth. This novel xenograft model is ideal for investigating c-Met/HGF–dependent human tumor progression and for evaluating c-Met targeted therapy. [Mol Cancer Ther 2007;6(4):1460–6]

Grant support: American Society of Clinical Oncology Foundation Clinical Research Career Development Award (M.R. Weiser).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 8/ 7/06; revised 1/ 1/07; accepted 2/ 8/07.