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

¹ Institute of Biochemistry and Genetics, Department of Biomedicine, University of Basel, Basel, Switzerland; ² Institute National de la Santé et de la Recherche Médicale, Strasbourg, France; ³ Laboratory of Tumor Biology and Genetics, Centre Universitaire Romand de Neurochirurgie and University of Lausanne, Lausanne, Switzerland; ⁴ National Center of Competence in Research Molecular Oncology, Swiss Institute for Experimental Cancer Research, Epalinges, Switzerland; and ⁵ Sidney Kimmel Cancer Center, San Diego, California

Requests for reprints: Gertraud Orend, Institut National de la Santé et de la Recherche Médicale U682, Faculté de Medicine, Université Louis Pasteur, 3 Avenue Molière, 67200 Strasbourg, France. Phone: 33-3-88-27-53-55; Fax: 33-3-88-26-35-38; E-mail: gertraud.orend{at}inserm.u-strasbg.fr.

Key Words: Tumor microenvironment • glioma • stem cell niche • wound healing • tenascin-C • fibronectin • LPA • PDGF • syndecan-4 • paxillin • syndesmos • tropomyosin

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/PDGF-induced cell spreading and migration on FN/TN depends on phosphatidylinositol 3-kinase, RhoKinase, and mitogen-activated 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]

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