# American Institute of Mathematical Sciences

2015, 12(6): 1189-1202. doi: 10.3934/mbe.2015.12.1189

## Synergistic effect of blocking cancer cell invasion revealed by computer simulations

 1 Division of Mathematical Oncology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai Minato-ku, Tokyo, 108-8639, Japan

Received  October 2014 Revised  June 2015 Published  August 2015

Invasion and metastasis are the main cause of death in cancer patients. 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 important 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 effective 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 degradation 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 blocking ECM degradation. Then we tested combined strategy including inhibitor for MT1-MMP, reduction of its turnover and its content in vesicles. A synergistic 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.
Citation: Kazuhisa Ichikawa. Synergistic effect of blocking cancer cell invasion revealed by computer simulations. Mathematical Biosciences & Engineering, 2015, 12 (6) : 1189-1202. doi: 10.3934/mbe.2015.12.1189
##### References:
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##### References:
 [1] V. V. Artym, Y. Zhang, F. Seillier-Moiseiwitsch, K. M. Yamada and S. C. Mueller, Dynamic interactions of cortactin and membrane type 1 matrix metalloproteinase at invadopodia: defining the stages of invadopodia formation and function, Cancer Res, 66 (2006), 3034-3043. doi: 10.1158/0008-5472.CAN-05-2177. [2] H. F. Bigg, C. J. Morrison, G. S. Butler, M. A. Bogoyevitch and Z. Wang, et al., Tissue inhibitor of metalloproteinases-4 inhibits but does not support the activation of gelatinase A via efficient inhibition of membrane type 1-matrix metalloproteinase, Cancer Res, 61 (2001), 3610-3618. [3] M. Egeblad and Z. Werb, New functions for the matrix metalloproteinases in cancer progression, NatRevCancer, 2 (2002), 161-174. doi: 10.1038/nrc745. [4] D. Hoshino, N. Koshikawa, T. Suzuki, V. Quaranta and A. M. Weaver, et al., Establishment and validation of computational model for MT1-MMP dependent ECM degradation and intervention strategies, PLoS Comput Biol, 8 (2012), e1002479. doi: 10.1371/journal.pcbi.1002479. [5] K. Ichikawa, A-Cell: graphical user interface for the construction of biochemical reaction models, Bioinformatics, 17 (2001), 483-484. doi: 10.1093/bioinformatics/17.5.483. [6] K. Ichikawa, A modeling environment with three-dimensional morphology, A-Cell-3D, and Ca2+ dynamics in a spine, Neuroinformatics, 3 (2005), 49-64. [7] E. Maquoi, D. Assent, J. Detilleux, C. Pequeux and J. M. Foidart, et al., MT1-MMP protects breast carcinoma cells against type I collagen-induced apoptosis, Oncogene, 31 (2012), 480-493. doi: 10.1038/onc.2011.249. [8] H. Nagase, R. Visse and G. Murphy, Structure and function of matrix metalloproteinases and TIMPs, Cardiovasc Res, 69 (2006), 562-573. doi: 10.1016/j.cardiores.2005.12.002. [9] T. Nonaka, K. Nishibashi, Y. Itoh, I. Yana and M. Seiki, Competitive disruption of the tumor-promoting function of membrane type 1 matrix metalloproteinase/matrix metalloproteinase-14 in vivo, MolCancer Ther, 4 (2005), 1157-1166. [10] M. Schoumacher, R. D. Goldman, D. Louvard and D. M. Vignjevic, Actin, microtubules, and vimentin intermediate filaments cooperate for elongation of invadopodia, J Cell Biol, 189 (2010), 541-556. doi: 10.1083/jcb.200909113. [11] K. Taniwaki, H. Fukamachi, K. Komori, Y. Ohtake and T. Nonaka, et al., Stroma-derived matrix metalloproteinase (MMP)-2 promotes membrane type 1-MMP-dependent tumor growth in mice, Cancer Res, 67 (2007), 4311-4319. doi: 10.1158/0008-5472.CAN-06-4761. [12] A. Watanabe, D. Hosino, N. Koshikawa, M. Seiki and T. Suzuki, et al., Critical role of transient activity of MT1-MMP for ECM degradation in invadopodia, PLoS Comput Biol, 9 (2013), e1003086. [13] A. M. Weaver, Invadopodia: Specialized cell structures for cancer invasion, ClinExpMetastasis, 23 (2006), 97-105. doi: 10.1007/s10585-006-9014-1.
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