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

Abstract

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.

• Authors: George Van Buren 2nd, Michael J Gray, Nikolaos A Dallas, Ling Xia, Sherry J Lim, Fan Fan, Andrew P Mazar, Lee M Ellis
• Journal: Cancer (Cancer) Vol. 115 Issue 14 Pg. 3360-8 (Jul 15 2009) ISSN: 0008-543X [Print] United States
• PMID: 19484792 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• ATN-658
• Antibodies, Monoclonal
• Receptors, Urokinase Plasminogen Activator

Topics

• Animals
• Antibodies, Monoclonal (pharmacology)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Colorectal Neoplasms (pathology)
• Humans
• Liver Neoplasms, Experimental (prevention & control, secondary)
• Male
• Mice
• Mice, Nude
• Neoplasm Transplantation
• Random Allocation
• Receptors, Urokinase Plasminogen Activator (immunology)
• Xenograft Model Antitumor Assays