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

Abstract

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)

Identification of a Survival-independent Metastasis-enhancing Role of Hypoxia-inducible Factor-1α with a Hypoxia-tolerant Tumor Cell Line

“…Lentiviruses were generated using respective plasmids and the ViraPower TM lentiviral expression system (Invitrogen, Karlsruhe, Germany). Transduction was done as described previously (23).…”

“…This phenomenon is of great relevance as the invasive steps of tumor progression are characterized by imbalances in the "protease web," comprising the complex network of proteases, their inhibitors, and effector molecules (20 -22). Specifically, up-regulation of MMP-9 in the tumor microenvironment (23,24) accounts for the degradation of the basal membrane and the remodeling of the extracellular matrix (ECM) to clear the path for tumor cells during the invasive steps of metastasis (25). Another important mediator of tumor cell scattering from already established metastases is the hepatocyte growth factor (HGF) signaling pathway (26), initiated by binding of HGF, originally also described as the "scatter factor" (27), to its receptor MET.…”

Antitumor activities of dFv-LDP-AE: An enediyne-energized fusion protein targeting tumor-associated antigen gelatinases

“…Gelatinases are abundantly overexpressed in HCC and its stromal cells, and play an important role in tumor microenvironment (18,19). In this study, it found that the 'naked' fusion protein dFv-LDP had an inhibition rate of 38.8% at a dosage of 0.8 mg/kg in Bel-7402 xenograft, which indicated that the fusion protein dFv-LDP not only played as a carrier of AE, but also possessed certain antitumor efficacy in vivo.…”

Inhibition of Breast Cancer Angiogenesis and Metastasis ay Targeting Hypoxia-Inducible Factor-1α

“…Matrix Metallo-Proteinases (MMPs) are a family of enzymes involved in degradation of extracellular matrix (gelatinases, collagenases) and are vital in tissue remodeling during tumor invasion, metastasis, and angiogenesis. The MMP-9 (a member of the MMP family) is a known mediator of tumor cell invasion [146] and has recently been shown to be critical for the invasive steps of metastasis [147][148], the fact that its expression correlates with HIF-1α expression suggests that HIF-1α is involved in promoting MMP-9-dependent metastasis. As a result of this, we tested whether compounds could inhibit the expression of MMP-9 in MDA-MB-231 cells by western blot assay.…”