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A more recent version of this article appeared on October 1, 2006

Published online before print June 22, 2006
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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.1105644

Received for publication November 10, 2005.
Revised April 16, 2006.
Accepted for publication April 17, 2006.

Article

Moderate antiangiogenic activity by local, transgenic expression of endostatin in Rip1Tag2 transgenic mice

Birgit Schaffhauser *, Tanja Veikkola {dagger}, Karin Strittmatter *, Helena Antoniadis *, Kari Alitalo {dagger}, and Gerhard Christofori *@

*Institute of Biochemistry and Genetics, Department of Clinical-Biological Sciences, University of Basel, Switzerland; and {dagger}Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Biomedicum Helsinki, University of Helsinki, Finland

@ To whom correspondence should be addressed. E-mail: gerhard.christofori{at}unibas.ch.


  Abstract

Many previous reports have demonstrated that systemic administration of endostatin (ES), a proteolytic cleavage product of collagen type XVIII and an endogenous angiogenesis inhibitor, represses tumor angiogenesis in different preclinical tumor models with varying efficacy. For example, systemic delivery of recombinant ES to rat insulin promoter 1 (Rip1)T-antigen 2 (Tag2)-transgenic mice, a mouse model of pancreatic {beta}-cell carcinogenesis, has repressed tumor angiogenesis efficiently and with it, tumor growth. Here, we report that the transgenic expression of ES in Rip1ES-transgenic mice only interferes moderately with tumor growth in Rip1Tag2;Rip1ES double-transgenic mice. Tumor incidence is not reduced by the local expression of ES, and tumor outgrowth and progression to tumor malignancy are only retarded slightly. A significant effect of local ES expression on tumor angiogenesis is only apparent during the early stages of tumor development, where less angiogenic hyperplastic lesions are observed. Although efficiently produced and secreted by transgenic {beta} cells, locally expressed ES appears to be sequestered in the microenvironment, and its systemic levels are not increased. The results indicate that the antiangiogenic functions of ES critically depend on the mode of delivery and the site of expression: Although its systemic application represses tumor angiogenesis and tumor growth efficiently, locally expressed ES appears to be less effective, and hence, additional mechanisms of solubilization or activation of latent ES seem to be required. These results have important implications about the modes of delivery used in antiangiogenic, therapeutic strategies, which are based on the antiangiogenic activities of ES.

Key Words: angiogenesis • cancer • inhibitors • tumorigenesis






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