Accumulation of mutation in ocogenes and tumor suppressor genes in normal cells results in malignant tumors. Malignant tumors invade into tissues and finally metastasize to distant organs. The goal of our project is to elucidate the molecular mechanism of tumor metastasis and develop diagnostic and therapeutic application.
Tumor invasion into tissue requires degradation of tissue basement membrane. We discovered a protease which is the key enzyme for tumor metastasis, and named it as MT1-MMP (Nature, 1994). Accumulating evidences indicate that MT1-MMP plays important roles in not only tumor invasion but also regulation of tumor growth and migration.
Induction of MT1-MMP and Invasive Growth by Ocnogenic Transformation of Normal Epithelial Cells
Normal epithelial MDCK cells were transformed with oncogne (erbB2), and showed tumor phenotype including MT1-MMP expression. Normal cells grow to form cysts in collagen gel, but transformed cells which express MT1-MMP show invasive growth. Tumor invasive growth is suppressed by the addition of MMP inhibitor BB94. Normal MDCK cells form branching tubules upon addition of HGF, which is also suppressed by BB94.
Cell Migration and MT1-MMP
HT1080 cells were cultured on collagen, which express MT1-MMP, and were stained for paxillin to visualize focal adhesion and actin. Addition of MT1-MMP inhibitor BB94 altered the localization of focal adhesion, reduced cell polarity and suppressed cell migration. MT1-MMP enhances motility signal by stimulating turnover of focal adhesion.