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Tenascin-C Promotes Microvascular Cell Migration and Phosphorylation of Focal Adhesion Kinase¹

Microvascular and Molecular Neuro-oncology Laboratory [D. Z., B. S., G. I. J., C. B., D. R. F.], the Department of Pathology, Divisions of Neuropathology [D. Z.] and Pediatric Pathology [M. A. G.], the Department of Neurosurgery [D. Z.], and the Kaplan Comprehensive Cancer Center [D. Z., M. A. G.], New York University Medical Center, New York, New York 10016; The Fred Hutchinson Cancer Center, Seattle, Washington 98104 [H. C.]; Division of Pediatric Neurology, Children’s and Women’s Hospital, Vancouver, British Columbia, V6H 3V4 Canada [J. H.]; and the Institute of Neurology and Neurosurgery, Beth Israel Medical Center, New York, New York 10128 [J. C. A.]

Enhanced expression of tenascin-C (TN-C) at the invasive edges of glioblastomamultiforme in close association with vascular sprouts, suggests a role for TN-C in microvascular cell migration. To test this hypothesis, we studied the migration of endothelial cells in vitro. In an aggregate migration assay, bovine retinal endothelial cells (BRECs) and human umbilical vein endothelial cells spread and migrated similarly on TN-C or fibronectin (FN). In contrast, U251 MG glioma cells migrated less on TN-C than on FN. Morphological features of U251 MG glioma cells on TN-C included poor cell spreading and short processes. In contrast, on FN, U251 MG glioma cells spread and exhibited long radial processes. Using a transmembrane migration assay, we observed that BREC adhesion was similar on TN-C or FN, whereas U251 MG glioma cells adhered better to FN than to TN-C. In addition, BRECs migrated more across the membrane toward regions coated with TN-C than FN, and conversely, U251 MG glioma cells migrated more toward FN than TN-C. Migration of endothelial and glioma cells toward TN-C or FN occurred in a dose-dependent manner and was strongly dependent on cell adhesion. In this assay, ultrastructural study revealed the migrating phenotype of the endothelial cells through the micropores of the membrane and their spread morphology on TN-C. Moreover, in situ hybridization revealed specific expression of TN-C in migrating microvascular cells in a cerebral microvascular ring assay. Finally in a phosphorylation assay, TN-C enhanced focal adhesion kinase phosphorylation of BRECs, but not of U251 MG glioma cells, and FN enhanced focal adhesion kinase phosphorylation of both BRECs and U251 MG cells. The expression of TN-C by migrating endothelial cells and the promotion of endothelial cell adhesion and migration by TN-C suggest a potential role for TN-C in pathological angiogenesis.

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