A urokinase-type plasminogen activator deficiency diminishes the frequency of intestinal adenomas in ApcMin/+ mice.
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.
Ploplis
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VA
WM Keck Center for Transgene Research, University of Notre Dame, Notre Dame, IN 46556, USA. vploplis@nd.edu
Tipton
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Menchen
H
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Castellino
F J
FJ
D011125:Adenomatous Polyposis Coli / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D000818:Animals; D001777:Blood Coagulation; D049109:Cell Proliferation; D051546:Cyclooxygenase 2 / Q000032:analysis; D015232:Dinoprostone / Q000032:analysis; D005770:Gastrointestinal Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D017491:Genes, APC; D007150:Immunohistochemistry; D007422:Intestines / Q000276:immunology; D007962:Leukocytes / Q000276:immunology; D051379:Mice; D008817:Mice, Mutant Strains; D023421:Models, Animal; D009389:Neovascularization, Pathologic; D051057:Proto-Oncogene Proteins c-akt / Q000032:analysis; D013997:Time Factors; D014568:Urokinase-Type Plasminogen Activator / Q000097:blood / Q000172:deficiency* / Q000235:genetics
D051546:Cyclooxygenase 2; D051057:Proto-Oncogene Proteins c-akt; D014568:Urokinase-Type Plasminogen Activator; D015232:Dinoprostone