Enhanced metastatic dissemination to multiple organs by melanoma and lymphoma cells in timp-3−/− mice

Abstract

Identifying versatile inhibitors of metastasis that operate in multiple sites against distinct cancer cell types is important for designing novel therapeutics for metastasis. We show that multiple tissues of timp-3 À/À mice are more susceptible to metastatic colonization. Overall, a 5-14-fold increase in liver and kidney colonization occurred by EL-4 lymphoma cells, and a twofold increase upon targeting B16F10 melanoma cells to the bone or lung of timp-3 À/À mice. There was a general lack of macrophage or neutrophil localization to metastases in the liver, kidney and lung, and of osteoclasts to bone in both genotypes. Analysis of lung showed that proliferation or angiogenesis were unaltered within the metastatic colonies. Lung-trap assays revealed that initial tumor cell trapping was similar in the lung vasculature of timp-3 À/À and wild-type mice. However, more tumor cells were found in timp-3 À/À lungs at 48 and 96 h after tumor cell injection indicating more efficient extravasation and initial proliferation. Activation of pro-MMP-2 was greater in timp-3 À/À lungs at these time points. These data demonstrate TIMP-3 functions to inhibit metastatic dissemination of diverse cancer cells to multiple organs. TIMP-3 regulates MMP-2 activation to limit tumor cell extravasation and subsequent colonization of the lung, without augmenting inflammatory cell response.

MicroRNAs and the hallmarks of cancer

“…Separate from its metalloproteinase inhibitory activity, TIMP-3 is also antiangiogenic by blocking VEGF binding to VEGFR2 (Qi et al, 2003). These characteristics are borne out by data from knockout mouse studies in which Timp-3À/À mice show exaggerated responses to inflammatory stimuli such as lipopolysaccharide, and increased metastasis to multiple organs (Mohammed et al, 2004;Cruz-Munoz et al, 2006). Overexpression of TIMP-3 promotes apoptosis of many cell types, in part through stabilization of cell surface death domain-containing receptors (Ahonen et al, 2003).…”

Correlation of Matrix Metalloproteinases and Tissue Inhibitors of Matrix Metalloproteinase Expression in Ileal Carcinoids, Lymph Nodes and Liver Metastasis with Prognosis and Survival

“…timp-3 –/– mice show a strong increase in liver and kidney metastasis induced by EL-4 lymphoma or B16F10 melanoma cells, underlining that TIMP-3 inhibits metastatic dissemination of diverse cancer cells [43]. Besides being an inhibitor for MMP-2, TIMP-3 acts as an inducer of apoptosis [42].…”

TIMP‐3 promotes apoptosis in nonadherent small cell lung carcinoma cells lacking functional death receptor pathway

“…25,26 These studies further extend the role of TIMP-3 as tumor suppressor and emphasize the role of stromal cell-derived TIMP-3 in inhibiting tumor progression and tumor cell dissemination. Furthermore, these studies suggest delivery of TIMP-3 to stromal compartment as an option for therapeutic use of TIMP-3 in cancer.…”