Tenascin-C Stimulates Glioma Cell Invasion through Matrix Metalloproteinase-12

Abstract

The capacity of glioma cells to invade extensively within the central nervous system is a major cause of the high morbidity rate of primary malignant brain tumors. Glioma cell invasion involves the attachment of tumor cells to extracellular matrix (ECM), degradation of ECM components, and subsequent penetration into adjacent brain structures. These processes are accomplished in part by matrix metalloproteinases (MMP) within a three-dimensional milieu of the brain parenchyma. As the majority of studies have used a two-dimensional monolayer culture system, we have used a three-dimensional matrix of collagen type I gel to address glioma-secreted proteases, ECM, and invasiveness of glioma cells. We show that in a threedimensional collagen type I matrix, the presence of tenascin-C, commonly elevated in high-grade gliomas, increased the invasiveness of glioma cells. The tenascin-C-mediated invasiveness was blocked by metalloproteinase inhibitors, but this did not involve the gelatinases (MMP-2 and MMP-9) commonly implicated in two-dimensional glioma growth. A thorough analysis of 21 MMPs and six members of a disintegrin and metalloproteinase domain showed that MMP-12 was increased in gliomas by tenascin-C in three-dimensional matrix. Furthermore, examinations of resected specimens revealed high MMP-12 levels in the high-grade glioblastoma multiforme tumors. Finally, a function-blocking antibody as well as small interfering RNA to MMP-12 attenuated the tenascin-C-stimulated glioma invasion. These results identify a new factor, MMP-12, in regulating glioma invasiveness through interaction with tenascin-C. (Cancer Res 2006; 66(24): 11771-80)

Tenascins and the Importance of Adhesion Modulation

“…Tenascin-C is strongly implicated in mediating the invasive behavior of glioma cells, and early studies showed that tenascin-C stimulated fibronectinmediated cell migration (Deryugina and Bourdon 1996). Similar observations have been made by several different research groups (Hirata et al 2009;Sivasankaran et al 2009); in one report, this migration was found to be dependent on the induction of metalloproteinase-12 (Sarkar et al 2006). The connection between tenascin-C expression and invasion is, however, not restricted to brain tumors.…”

Fucosyltransferase IV Enhances Expression of MMP-12 Stimulated by EGF via the ERK1/2, p38 and NF-kB Pathways in A431Cells

“…Excessive production of MMPs could increase the invasion and mobility of tumor cells. A recent study has shown that MMP-12 is overexpresssed in various human cancers, e.g., epithelial ovarian carcinoma (Li et al, 2009), prostate cancer (Nabha et al, 2008), endometrial adenocarcinoma (Yang et al, 2007a), glioma cell (Sarkar et al, 2006), non-small cell lung cancer (Hofmann et al, 2005), oral verrucous and squamous cell cancer (Impola et al, 2004) and squamous cell carcinoma (Kerkela et al, 2002). In addition, FUT4 is mainly expressed in leukocytes and some epithelial cells (Allahverdian et al, 2006).…”

Molecular Mechanisms of Glioma Cell Motility

“…MMP-14 activates MMP-2 by cleaving its pro-peptide (54,55). Furthermore, MMP-3, -7, -12, -13, -16, -19, and -26 are also highly expressed and mostly associated with enhanced glioma invasion (56)(57)(58)(59)(60)(61)(62)(63). MMPs are inhibited by the four tissue inhibitors of metalloproteinases (TIMP), TIMP-1-4.…”