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Tenascin-C Expression by Angiogenic Vessels in Human Astrocytomas and by Human Brain Endothelial Cells in Vitro¹

Department of Pathology, Divisions of Neuropathology [D. Z.], and Pediatric Pathology [M. A. G.], Department of Pharmacology [D. R. F., J. D., S. C., M. G.], Department of Neurology [D. R. F., J. C. A.], Brain Tumor Research Center [D. Z., D. R. F., J. C. A., M. G.], In Situ Hybridization Laboratory [W. C.], and the Kaplan Comprehensive Cancer Center [D. Z., M. A. G., J. C. A., M. G.] of New York University Medical Center, New York, NY 10016, and Department of Pathology, Division of Neuropathology, University of British Columbia, Vancouver, Canada V5Z 1M9 [K. D-Z.]

The expression of the extracellular matrix glycoprotein tenascin-C (TN) is enhanced in human astrocytomas and correlates with angiogenesis. To determine whether vascular cells are able to synthesize TN, we investigated the expression of TN protein and mRNA in nine astrocytomas. Immunogold electron microscopy in two glioblastomas multiforme detected the presence of TN in an extracellular perivascular location and to a lesser extent among tumor cells, confirming light microscopy immunohistochemical findings. In situ hybridization of astrocytomas using a digoxigenin-labeled antisense riboprobe detected strong staining for TN mRNA in vascular cells, especially in hyperplastic vessels, including those at the invasive edge of the tumors but not in vessels of normal brains. We observed weaker staining in tumor cells indicating a higher level of TN mRNA in vascular than in tumor cells. No staining was detected with the sense probe. Moreover, we investigated the ability of human brain microvessel endothelial cells (HBMECs) in primary culture to synthesize TN in vitro. Western blot analysis of the culture supernatants from HBMECs detected large amounts of TN. Immunogold silver staining demonstrated the presence of TN on the surface of HBMECs and in the subendothelial matrix. The distribution of TN mRNA in vascular cells of astrocytomas and the ability of HBMECs to synthesize TN in vitro demonstrate that vascular cells, including endothelial cells, are a major source of TN associated with angiogenesis. Furthermore, our results suggest that TN expression may be associated with endothelial cell activation and may play an important role in angiogenesis.

¹ Presented in part at the 71st Annual Meeting of the American Association of Neuropathologists, June 7–11, 1995, San Antonio, Texas. This work was supported by NIH Grants NS 31088 and CA 16087-17, the Kaplan Comprehensive Cancer Center, the Children's Brain Tumor Foundation, and the Medical Research Council of Canada (MT-12209; to K. D-Z.).

² To whom requests for reprints should be addressed, at Department of Pathology, Division of Neuropathology, New York University Medical Center, 550 First Avenue, New York, NY 10016. Phone: (212) 263-6449; Fax: (212) 263-8994; E-mail: zagzad01@popmail.med.nyu.edu.

Received 8/ 7/95. Accepted 10/31/95.

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