A268: Host-derived MMP-7 inhibits myeloma development via cleavage of galectin-3; an unexpected role for MMP-7 and galectin-3 in myeloma pathogenesis
1University of Oxford, Oxford, UK,2Mayo Clinic, Rochester, USA,3H. Lee Moffitt Cancer Center, Tampa, USA,4Vanderbilt Center for bone biology, Nashvile, USA
Matrix metalloproteinases (MMPs) are key regulators of tumour:host interactions due to their ability to alter the activity of multiple substrates. MMP-7 promotes both breast and prostate cancer-mediated osteolysis. In contrast, inoculation of MM cells into MMP-7-/- mice significantly increased tumour growth and osteolytic bone disease, suggesting that host-derived MMP-7 plays a protective role in MM. Our current aim was to determine how MMP-7 decreases MM development in both murine models and patients with MM.
MMP-7-/- mice were inoculated with 5TGM1-GFP MM cells to investigate the role of host-derived MMP-7 in MM in vivo. Tumour burden was assessed by ELISA and flow cytometry, bone disease was assessed by bone histomorphometry and microCT. Galectin-3, MMP-7 and TIMP-1 were measured in serum of murine model and patients with MM by caesin zymography, ELISA, and western blot.
In support of our murine studies, clinical analysis revealed that patients with myeloma have decreased serum MMP-7 activity and an increase in the MMP inhibitor TIMP-1 (p<0.001). Furthermore, recombinant MMP-7 had a direct anti-tumour effect on MM cells in vitro. Using a candidate list of MMP-7 substrates, we identified that galectin-3 is cleaved by MMP-7. Galectin-3 was found to increase myeloma growth in vitro, an effect that was abrogated by the addition of MMP-7. In vivo, the loss of MMP-7 activity was found to increase full-length galectin-3 in myeloma-bearing mice (p<0.05). Clinical studies revealed a reduction in the proportion of cleaved galectin-3 in patients with myeloma (p<0.001) and a significant positive correlation between MMP-7 activity and cleaved galectin-3 in the serum of patients with myeloma and controls (p<0.0001, r2 = 0.6326, ? = 0.7954).
Our studies suggest that a loss of MMP-7 activity contributes to MM pathogenesis, whereby host-derived MMP-7 inhibits MM growth in vivo, in part via processing of galectin-3.