This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Gerg, M. Articles by Krüger, A. PubMed PubMed Citation Articles by Gerg, M. Articles by Krüger, A.

---

Angiogenesis, Metastasis, and the Cellular Microenvironment

Distinct Functionality of Tumor Cell–Derived Gelatinases during Formation of Liver Metastases

¹ Institut für Experimentelle Onkologie und Therapieforschung, ² Chirurgische Klinik, and ³ Institut für Allgemeine Pathologie und Pathologische Anatomie, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany; ⁴ Institut für Pathologie, Universitätsklinik Heidelberg, Heidelberg, Germany; and ⁵ School of Biological Sciences, University of East Anglia, Norwich, Norfolk, United Kingdom

Requests for reprints: Achim Krüger, Klinikum rechts der Isar der Technischen Universität München, Institut für Experimentelle Onkologie und Therapieforschung, Ismaninger Str. 22, D-81675 Munich, Germany. Phone: 49-89-4140-4463; Fax: 49-89-4140-6182. E-mail: achim.krueger{at}lrz.tum.de

The specific spatiotemporal role of the matrix metalloproteinase 2 (MMP-2) and MMP-9 (gelatinase) during metastasis is still under debate. Host cells have been described as major contributors to these MMPs during metastasis. Here, we show strong overexpression of MMP-2 and MMP-9 by tumor cells of clinical liver specimen of recurrent metachronous metastases, leading us to address the importance of tumor cell–derived MMP-2 or MMP-9 during liver metastasis. Thus far, distinction of their roles was impossible due to lack of inhibitors which can act exclusively on tumor cells or distinguish MMP-2 from MMP-9. We therefore used short hairpin RNA interference technology in the well-established syngeneic L-CI.5s lymphoma model, in which we could analyze the time course of experimental liver colonization (arrest/invasion of single tumor cells, outgrowth, and invasion within the parenchyma) in immunocompetent mice and correlate these steps with MMP-2 or MMP-9 expression levels. In parental tumor cells, MMP-9 expression closely correlated with the invasive phases of liver colonization, whereas MMP-2 expression remained unaltered. Specific knockdown of MMP-9 revealed a close correlation between invasion-dependent events and tumor cell–derived MMP-9 expression. In contrast, knockdown of MMP-2 did not significantly alter the metastatic potential of the cells but led to a marked inhibition of metastatic foci growth. These findings explain the efficacy of gelatinase-specific synthetic inhibitors on invasion and growth of tumor cells and attribute distinct functions of MMP-2 and MMP-9 to aspects of liver metastasis. (Mol Cancer Res 2008;6(3):341–51)