Heparanase-enhanced shedding of syndecan-1 by myeloma cells promotes endothelial invasion and angiogenesis.
Heparanase enhances shedding of syndecan-1 (CD138), and high levels of heparanase and shed syndecan-1 in the tumor microenvironment are associated with elevated angiogenesis and poor prognosis in myeloma and other cancers. To explore how the heparanase/syndecan-1 axis regulates angiogenesis, we used myeloma cells expressing either high or low levels of heparanase and examined their impact on endothelial cell invasion and angiogenesis. Medium conditioned by heparanase-high cells significantly stimulated endothelial invasion in vitro compared with medium from heparanase-low cells. The stimulatory activity was traced to elevated levels of vascular endothelial growth factor (VEGF) and syndecan-1 in the medium. We discovered that the heparan sulfate chains of syndecan-1 captured VEGF and also attached the syndecan-1/VEGF complex to the extracellular matrix where it then stimulated endothelial invasion. In addition to its heparan sulfate chains, the core protein of syndecan-1 was also required because endothelial invasion was blocked by addition of synstatin, a peptide mimic of the integrin activating region present on the syndecan-1 core protein. These results reveal a novel mechanistic pathway driven by heparanase expression in myeloma cells whereby elevated levels of VEGF and shed syndecan-1 form matrix-anchored complexes that together activate integrin and VEGF receptors on adjacent endothelial cells thereby stimulating tumor angiogenesis.
Purushothaman
Anurag
A
Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Uyama
Toru
T
Kobayashi
Fumi
F
Yamada
Shuhei
S
Sugahara
Kazuyuki
K
Rapraeger
Alan C
AC
Sanderson
Ralph D
RD
D001011:Aorta / Q000166:cytology; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004727:Endothelium / Q000473:pathology; D005109:Extracellular Matrix / Q000378:metabolism; D005966:Glucuronidase / Q000378:metabolism*; D006497:Heparan Sulfate / Q000378:metabolism; D006801:Humans; D009101:Multiple Myeloma / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000503:physiopathology*; D009924:Organ Culture Techniques; D053668:Syndecan-1 / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000099175:Heparanase
D017077:Culture Media, Conditioned; D005966:Glucuronidase; D006497:Heparan Sulfate; D053668:Syndecan-1; D042461:Vascular Endothelial Growth Factor A; D000099175:Heparanase; C508241:SDC1 protein, human; C467484:VEGFA protein, human