A urokinase‐type plasminogen activator deficiency diminishes the frequency of intestinal adenomas in Apc Min /+ mice

• Published in: The Journal of pathology 2007-11, Vol.213 (3), p.266-274
• Main Authors: Ploplis, VA, Tipton, H, Menchen, H, Castellino, FJ
• Format: Article
• Language: English
• ISSN: 0022-3417; 1096-9896
• DOI: 10.1002/path.2236

The interaction of urokinase‐type plasminogen activator (uPA) and its receptor, uPAR, on cell surfaces facilitates the generation of cell‐bound plasmin, thus allowing cells to establish a proteolytic front that enables their migration through protein barriers. This complex also activates cell signalling pathways that influence cell functions. Clinical studies have identified uPA as an indicator of poor overall survival in patients with colorectal cancer. In the current study, a mouse model of colon cancer, Apc Min /+ , with an additional deficiency of uPA ( Apc Min /+ / Plau −/− ) was used to determine the effects of uPA on tumour initiation and growth. Utilizing this model, it was found that the number of tumours was diminished in these mice relative to Apc Min /+ mice, which correlated with the decreased leukocyte infiltration in the tumours. However, tumour growth was not impeded in Apc Min /+ / Plau −/− mice, and proliferation and tumour vascularization were, in fact, enhanced in Apc Min /+ / Plau −/− mice. These latter effects are consistent with a mechanism involving up‐regulation of COX‐2 expression and Akt pathway activation in Apc Min /+ / Plau −/− mice. The results from this study suggest that uPA plays dual and opposing roles in regulating lesion development: one early, during the transition from normal epithelia to dysplastic lesions, and another later during tumour growth. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.