Differential Gene Expression Analysis Reveals Activation of Growth Promoting Signaling Pathways by Tenascin-C

Abstract

Tenascin-C is an adhesion-modulating extracellular matrix molecule that is highly expressed in tumor stroma and stimulates tumor cell proliferation. Adhesion of T98G glioblastoma cells to a fibronectin substratum is inhibited by tenascin-C. To address the mechanism of action, we performed a RNA expression analysis of T89G cells grown in the presence or absence of tenascin-C and found that tenascin-C down-regulates tropomyosin-1. Upon overexpression of tropomyosin-1, cell spreading on a fibronectin/tenascin-C substratum was restored, indicating that tenascin-C destabilizes actin stress fibers through down-regulation of tropomyosin-1. Tenascin-C also increased the expression of the endothelin receptor type A and stimulated the corresponding mitogen-activated protein kinase signaling pathway, which triggers extracellular signal-regulated kinase 1/2 phosphorylation and c-Fos expression. Tenascin-C additionally caused down-regulation of the Wnt inhibitor Dickkopf 1. In consequence, Wnt signaling was enhanced through stabilization of ␤-catenin and stimulated the expression of the ␤-catenin target Id2. Finally, our in vivo data derived from astrocytoma tissue arrays link increased tenascin-C and Id2 expression with high malignancy. Because increased endothelin and Wnt signaling, as well as reduced tropomyosin-1 expression, are closely linked to transformation and tumorigenesis, we suggest that tenascin-C specifically modulates these signaling pathways to enhance proliferation of glioma cells.

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

“…The identification of tenascin-C as a facilitatory factor for glioma invasiveness in a three-dimensional matrix is relevant because it is increased in brain tumors where its expression increases with tumor grade (15,16,18,20,38). In vitro studies have found that tenascin-C increases the migration of glioma cells in monolayer or spheroid cultures (39)(40)(41).…”

“…In malignant gliomas, many ECM components are overexpressed both in the tumor stroma and at the advancing edge of the tumor within brain parenchyma. These ECM molecules include vitronectin, collagen I, collagen IV, osteopontin, tenascin-C, secreted protein acidic and rich in cysteine, and brain enriched hyaluronan binding (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21). Glioma invasion is thought to occur along ECM protein-containing structures, such as along tracts of myelinated fibers (22)(23)(24).…”

Meet the Tenascins: Multifunctional and Mysterious

“…Almost all known binding sites lie in the fibronectin type III repeats or the fibrinogen globe, but evidence has been reported suggesting that the EGF-like repeats act as low affinity ligands for EGF receptors (15). As a consequence, cell interactions with tenascin-C are quite complex, and several signaling mechanisms have been identified, including recent observations that tenascin-C blocks focal adhesion kinase-and Rho-mediated signaling pathways activated by fibronectin (2,16,17) as well as stimulating Wnt and other growth-promoting pathways (18). For a detailed discussion of these mechanisms, please refer to Gertrude Orend's recent review (4).…”

Tenascins and the Importance of Adhesion Modulation

“…In mixed substrata of fibronectin and tenascin-C the antiadhesive effect is mediated by binding of tenascin-C to the HepII/syndecan-4 binding site in the FN3-13 repeat of fibronectin, thereby inhibiting the coreceptor function of syndecan-4 in fibronectin-mediated cell spreading (Huang et al 2001;Midwood et al 2004). In consequence, the activities of RhoA and focal adhesion kinase are compromised: cells redistribute their actin to the cell cortex and downregulate focal adhesion formation (Wenk et al 2000;Midwood and Schwarzbauer 2002;Ruiz et al 2004;Lange et al 2007). This might be a general mechanism for adhesion modulation, because fibulin-1 was also shown to modulate cell adhesion to fibronectin in this way (Williams and Schwarzbauer 2009).…”

“…Activation of many of the major signaling pathways can lead to induction of tenascin-C and/or tenascin-W expression (Table 2). In turn, plating cells on tenascin-C-containing substrata can affect several signaling pathways, such as induction of signaling through 14-3-3 tau Martin et al 2003) MAPK and Wnt (Ruiz et al 2004) or inhibition of the small GTPase RhoA known to induce actin stress fiber formation (Wenk et al 2000). Thus, some of the same pathways that initially trigger tenascin-C expression potentially lead to negative (in the case of RhoA) or positive (in the case of MAPK and Wnt signaling) feedback loops.…”