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Targeting the urokinase plasminogen activator receptor with a monoclonal antibody impairs the growth of human colorectal cancer in the liver.

Author(s): Van Buren G 2nd, Gray MJ, Dallas NA, Xia L, Lim SJ, Fan F, Mazar AP, Ellis LM

Affiliation(s): Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.

Publication date & source: 2009-07-15, Cancer., 115(14):3360-8.

Publication type: Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't

BACKGROUND: Urokinase plasminogen activator receptor (uPAR) expression has been shown to correlate with poor prognosis in colorectal cancer (CRC). The authors hypothesized that targeting uPAR, a receptor involved in cell proliferation, migration, invasion, adhesion, and angiogenesis, would impair the growth of CRC in the liver, the most common site of metastasis. METHODS: Human CRC cell lines were examined for uPAR expression by Western blot analysis. The in vitro effects of the uPAR monoclonal antibody (MoAb) (ATN-658) were tested in proliferation and migration assays. For in vivo studies, human HCT116 CRC cells were injected directly into the livers of mice in 2 separate studies, the first to determine the effect of therapy with ATN-658 on small-volume disease (therapy begun on Day 4), and a second study to determine the effect of therapy on established disease (therapy begun on Day 12). Mice were randomized to receive either nonspecific immunoglobulin G MoAb (control) or ATN-658, and were sacrificed 1 month after tumor implantation. RESULTS: uPAR was expressed by all CRC cell lines studied. In vitro, ATN-658 had minimal effect on CRC proliferation in monolayers, but significantly decreased CRC cell migration. In vivo, ATN-658 lead to significant reductions in tumor growth versus control when initiated either 4 or 12 days after tumor implantation (-65% vs control [P < or = .05] and -85% vs control [P < or = .05]). ATN-658 significantly inhibited in vivo tumor cell proliferation in both studies. CONCLUSIONS: uPAR MoAb therapy impaired CRC tumor growth in the liver in both small-volume and large-volume disease models.

Page last updated: 2009-10-20

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