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ORIGINAL RESEARCH ARTICLE

Basement Membrane Derived Fibulin-1 and Fibulin-5 Function as Angiogenesis Inhibitors and Suppress Tumor Growth

Liang Xie^*, Kristin Palmsten^*, Brian MacDonald^*, Mark W. Kieran, Scott Potenta^*, Sylvia Vong^* and Raghu Kalluri^*,,,1

^* Division of Matrix Biology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215; Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, MA 02115; Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02215; and Harvard-MIT Division of Health Sciences and Technology, Boston, MA 02215

To whom requests for reprints should be addressed at ¹ Harvard Medical School, Division of Matrix Biology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston MA 02215. E-mail: rkalluri{at}bidmc.harvard.edu

The fibulins are a family of secreted glycoproteins that are characterized by repeated epidermal-growth-factor–like domains and a unique C-terminus structure. Fibulins modulate cell morphology, growth, adhesion, and motility. Our initial basement membrane degradome screen using Cathepsin D, a tumor microenvironment–associated protease, contained fragments of fibulin-1 and full length fibulin-5. In this report, we evaluate the antiangiogenic activity of fibulin-1 and fibulin-5. Tumor studies demonstrate that both fibulin-1 and fibulin-5 suppress HT1080 tumor growth. CD31 labeling and TUNEL assay further reveal that fibulin-1 suppression of HT1080 tumor growth is associated with diminished angiogenesis and also enhanced apoptosis of endothelial cells and tumor cells. In contrast, fibulin-5 inhibits tumor angiogenesis with a minimal anti-apoptotic affect. Cathepsin D digestion of fibulin-1 produces a fragment with nearly the same molecular weight as fibulin-5, and this fragment (named Neostatin) inhibits endothelial cell proliferation. Additionally, degradation of basement membrane by cathepsin D liberates both fibulin-1 fragments and fibulin-5, which function to inhibit angiogenesis.

Key Words: fibulin • angiogenesis • tumor • neostatin • basement membrane • cancer