Basement membrane derived fibulin-1 and fibulin-5 function as angiogenesis inhibitors and suppress tumor growth.
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.
Xie
Liang
L
Division of Matrix Biology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
Palmsten
Kristin
K
MacDonald
Brian
B
Kieran
Mark W
MW
Potenta
Scott
S
Vong
Sylvia
S
Kalluri
Raghu
R
D000595:Amino Acid Sequence; D020533:Angiogenesis Inhibitors / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001485:Basement Membrane / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D002402:Cathepsin D / Q000378:metabolism; D002417:Cattle; D049109:Cell Proliferation / Q000187:drug effects; D003001:Cloning, Molecular; D017124:Conserved Sequence; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008969:Molecular Sequence Data; D008970:Molecular Weight; D009369:Neoplasms / Q000473:pathology*; D011994:Recombinant Proteins / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology; D016415:Sequence Alignment
D020533:Angiogenesis Inhibitors; D002135:Calcium-Binding Proteins; D016326:Extracellular Matrix Proteins; C492373:FBLN5 protein, human; D011994:Recombinant Proteins; C060820:fibulin; D002402:Cathepsin D