Faculty Collaboration Database

Targeting of urokinase plasminogen activator receptor in human pancreatic carcinoma cells inhibits c-Met- and insulin-like growth factor-I receptor-mediated migration and invasion and orthotopic tumor growth in mice. Cancer Res 2005 Sep 01;65(17):7775-81

Date

09/06/2005

Pubmed ID

16140945

DOI

10.1158/0008-5472.CAN-05-0946

Scopus ID

2-s2.0-24744449559 (requires institutional sign-in at Scopus site)   134 Citations

Abstract

Pancreatic carcinomas express high levels of urokinase-type plasminogen activator (uPA) and its receptor (uPAR), both of which mediate cell migration and invasion. We investigated the hypotheses that (a) insulin-like growth factor-I (IGF-I)- and hepatocyte growth factor (HGF)-mediated migration and invasion of human pancreatic carcinoma cells require uPA and uPAR function and (b) inhibition of uPAR inhibits tumor growth, retroperitoneal invasion, and hepatic metastasis of human pancreatic carcinomas in mice. Using transwell assays, we investigated the effect of IGF-I and HGF on L3.6pl migration and invasion. We measured the induction of uPA and uPAR following treatment of cells with IGF-I and HGF using immunoprecipitation and Western blot analysis. The importance of uPA and uPAR on L3.6pl cell migration and invasion was studied by inhibiting their activities with amiloride and antibodies before cytokine treatment. In an orthotopic mouse model of human pancreatic carcinoma, we evaluated the effect of anti-uPAR monoclonal antibodies with and without gemcitabine on primary tumor growth, retroperitoneal invasion, and hepatic metastasis. IGF-I and HGF mediated cell migration and invasion in L3.6pl cells. In addition, IGF-I and HGF induced uPA and uPAR expression in L3.6pl cells. In vitro, blockade of uPA and uPAR activity inhibited IGF-I- and HGF-mediated cell migration and invasion. Treatment of mice with anti-uPAR monoclonal antibody significantly decreased pancreatic tumor growth and hepatic metastasis and completely inhibited retroperitoneal invasion. Our study shows the importance of the uPA/uPAR system in pancreatic carcinoma cell migration and invasion. These findings suggest that uPAR is a potential target for therapy in patients with pancreatic cancer.

Author List

Bauer TW, Liu W, Fan F, Camp ER, Yang A, Somcio RJ, Bucana CD, Callahan J, Parry GC, Evans DB, Boyd DD, Mazar AP, Ellis LM

Author

Douglas B. Evans MD Chair, Professor in the Surgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Amiloride
Animals
Antibodies, Monoclonal
Apoptosis
Cell Growth Processes
Cell Line, Tumor
Cell Movement
Hepatocyte Growth Factor
Humans
Insulin-Like Growth Factor I
Liver Neoplasms, Experimental
Male
Mice
Mice, Inbred BALB C
Mice, Nude
Neoplasm Invasiveness
Neovascularization, Pathologic
Pancreatic Neoplasms
Proto-Oncogene Proteins c-met
Receptor, IGF Type 1
Receptors, Cell Surface
Receptors, Urokinase Plasminogen Activator
Urokinase-Type Plasminogen Activator