Degradation of extracellular matrix proteins by proteases such as the cysteine protease cathepsin B is critical to malignant progression. We have established that procathepsin B presents on the surface of tumor cells through its interaction with the annexin II tetramer [Mai et al., J. Biol. Chem. 275 (2000),12806-12812]. Cathepsin B activity can also be detected on the tumor cell surface and in their culture medium. Interestingly, the annexin II tetramer also interacts with extracellular matrix proteins, such as collagen I, fibrin and tenascin-C. Both cathepsin B and tenascin-C are expressed at high levels in malignant tumors, especially at the invasive edges of tumors, and are implicated in tumor angiogenesis. In this study, we report that tenascin-C can be degraded by cathepsin B in vitro. We demonstrate by immunohistochemistry that both cathepsin B and tenascin-C are expressed highly in malignant anaplastic astrocytomas and glioblastomas as compared to normal brain tissues. Interestingly, cathepsin B and tenascin-C were also detected in association with tumor neovessels. We suggest that interactions between cathepsin B and tenascin-C are involved in the progression of gliomas including the angiogenesis that is a hallmark of anaplastic astrocytomas.