Combined Lysophosphatidic Acid/Platelet-Derived Growth Factor Signaling Triggers Glioma Cell Migration in a Tenascin-C Microenvironment

Abstract

The antiadhesive extracellular matrix molecule tenascin-C abrogates cell spreading on fibronectin through competitive inhibition of syndecan-4, thereby preventing focal adhesion kinase (FAK) activation and triggering enhanced proteolytic degradation of both RhoA and tropomyosin 1 (TM1). Here, we show that simultaneous signaling by lysophosphatidic acid (LPA) and platelet-derived growth factor (PDGF) initiates glioma cell spreading and migration through syndecan-4-independent activation of paxillin and FAK and by stabilizing expression of RhoA, TM1, TM2, and TM3. By using gene silencing methods, we show that paxillin, TM1, TM2, and TM3 are essential for LPA/PDGF-induced cell spreading on a fibronectin/tenascin-C (FN/TN) substratum. LPA/PDGFinduced cell spreading and migration on FN/TN depends on phosphatidylinositol 3-kinase, RhoKinase, and mitogenactivated protein kinase/extracellular signal-regulated kinase kinase 1/2 but is independent of phospholipase C and Jun kinase. RNA microarray data reveal expression of tenascin-C, PDGFs, LPA, and the respective receptors in several types of cancer, suggesting that the TN/LPA/PDGF axis exists in malignant tumors. These findings may in turn be relevant for diagnostic or therapeutic applications targeting cancer. [Cancer Res 2008;68(17):6942-52]

Tenascin-C at a glance

“…Tenascin-C itself can be a poor adhesive substrate for cells, and activation of annexin-II-mediated anti-adhesive signaling through its FNIII repeats A-D renders larger tenascin-C isoforms less adhesive than smaller ones (Giblin and Midwood, 2015). The anti-adhesive properties of tenascin-C can also be enhanced, reduced or even abolished by additional signaling that involves lysophosphatidic acid receptor (LPAR), platelet-derived-growth factor receptor (PDGFR), endothelin type A and B receptors (EDNRA and EDNRB, respectively), or cleavage through proteases (Ambort et al, 2010;Gundersen et al, 1997;Lange et al, 2007Lange et al, , 2008.…”

Tenascin-C-derived Peptide TNIIIA2 Highly Enhances Cell Survival and Platelet-derived Growth Factor (PDGF)-dependent Cell Proliferation through Potentiated and Sustained Activation of Integrin α5β1

“…TN-C interferes with the adhesive interaction between syndecan-4 and the heparinbinding domain II of fibronectin, which blocks collaborative signaling induced by integrin ␣5␤1 and syndecan-4 (11,12). Inhibition of integrin ␣5␤1-syndecan-4-mediated cell adhesion causes enhanced cell proliferation by several mechanisms that include disruption of the actin cytoskeleton through reduced tropomyosin1 expression, depression of Wnt signaling, and activation of MAP kinase signaling (13)(14)(15). The hypothesis that the antiadhesive effect of TN-C is responsible for enhanced tumor cell proliferation is supported by several previous reports which show that integrin ␣5␤1 serves as a tumor suppressor gene product (4, 16 -19).…”

Tenascin-C and mechanotransduction in the development and diseases of cardiovascular system

“…TNC binds fibronectin at the binding site to syndecan-4, a coreceptor for integrin α5β 1, and has a negative impact on focal adhesion formation and activation of RhoA (Midwood et al, 2006; Lange et al, 2008; Van Obberghen-Schilling et al, 2011). Therefore, mechanically induced TNC may lead to negative feedback from the mechanotrasduction signal.…”