Synergistic effect of blocking cancer cell invasion revealed by computer simulations

Abstract

Invasion and metastasis are the main cause of death in cancer pa- tients. The initial step of invasion is the degradation of extracellular matrix (ECM) by primary cancer cells in a tissue. Membranous metalloproteinase MT1-MMP and soluble metalloproteinase MMP-2 are thought to play an im- portant role in the degradation of ECM. In the previous report, we found that the repetitive insertion of MT1-MMP to invadopodia was crucial for the ef- fective degradation of ECM (Hoshino, D., et al., PLoS Comp. Biol., 2012, e1002479). However, the role of MMP-2 and the effect of inhibitors for these ECM-degrading proteases were still obscure. Here we investigated these two problems by using the same model as in the previous report. First we tested the effect of MMP-2 and found that while MT1-MMP played a major role in the degradation of ECM, MMP-2 played only a marginal effect on the degra- dation of ECM. Based on these findings, we next tested the effect of a putative inhibitor for MT1-MMP and found that such inhibitor was ineffective in block- ing ECM degradation. Then we tested combined strategy including inhibitor for MT1-MMP, reduction of its turnover and its content in vesicles. A syner- gistic effect of combined strategy was observed in the decrease in the efficacy of ECM degradation. Our simulation study suggests the importance of combined strategy in blocking cancer invasion and metastasis.