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Research Articles: Therapeutics, Targets, and Development

Identification of Trop-2 as an oncogene and an attractive therapeutic target in colon cancers

¹ Division of Oncology, Department of Internal Medicine, ² Division of Urology, ³ Department of Cell Biology and Physiology, and ⁴ The Alvin J. Siteman Cancer Center, Washington University School of Medicine, Saint Louis, Missouri

Requests for reprints: Loren Michel, Washington University School of Medicine, Campus Box 8069, Saint Louis, MO 63110. Phone: 314-362-8965; Fax: 314-747-9320. E-mail: lmichel{at}im.wustl.edu

Abstract

The cell surface protein Trop-2 is highly expressed in a wide variety of epithelial cancers. In contrast, there is little or no expression of Trop-2 in adult somatic tissue. Because it is a cell surface protein that is selectively expressed in tumor cells, Trop-2 is a potential therapeutic target. However, whether Trop-2 is actively involved in tumorigenesis and whether its targeting for treatment would be effective have not been examined. Here, we show that Trop-2 expression is necessary for tumorigenesis and invasiveness of colon cancer cells, as both are inhibited when Trop-2 expression is suppressed by RNA interference. Conversely, ectopic expression of Trop-2 in colon cancer cells enhances their capacity for anchorage-independent growth and ectopic expression of Trop-2 in NIH3T3 cells is sufficient to promote both anchorage-independent growth and tumorigenesis. Importantly, we show that an antibody against the extracellular domain of Trop-2 reduces tumor cell invasiveness. Therefore, we have identified Trop-2 as an oncogene that has potential as a therapeutic target. Given the restricted expression of Trop-2 in normal tissue, anti–Trop-2 therapeutics would be predicted to have limited toxicity. [Mol Cancer Ther 2008;7(2):280–5]

Grant support: Kimmel Foundation for Cancer Research, Damon Runyon Cancer Research Foundation, and Flight Attendants Medical Research Foundation (L. Michel) and NIH and Elsa U. Pardee Foundation (S.J. Weintraub).

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 8/27/07; revised 10/16/07; accepted 12/29/07.