YKL-40, a secreted glycoprotein, promotes tumor angiogenesis.
Tumor angiogenesis is of paramount importance in solid tumor development. Elevated serum levels of YKL-40, which is a secreted heparin-binding glycoprotein, have been associated with a worse prognosis from various advanced human cancers. Yet the role of YKL-40 activity in these cancers is still missing. In this study, we showed that ectopic expression of YKL-40 in MDA-MB-231 breast cancer cells and in HCT-116 colon cancer cells led to larger tumor formation with an extensive angiogenic phenotype than did control cancer cells in mice. Affinity-purified recombinant YKL-40 protein promoted vascular endothelial cell angiogenesis in vitro, the effects of which are similar to the activities observed using MDA-MB-231 and HCT-116 cell-conditioned medium after transfection with YKL-40. Furthermore, YKL-40 was found to induce coordination of membrane-bound receptor syndecan-1 and integrin alpha(v)beta(3) and to activate an intracellular signaling cascade, including focal adhesion kinase and mitogen-activated protein kinase extracellular signal-related kinase1/2 in endothelial cells. Moreover, blockade of YKL-40 using small-interfering RNA gene knockdown suppressed tumor angiogenesis in vitro and in vivo. Immunohistochemical analysis of human breast cancer showed a correlation between YKL-40 expression and blood vessel density. These findings provide novel insights into angiogenic activities and molecular mechanisms of YKL-40 in cancer development.
Shao
R
R
Pioneer Valley Life Sciences Institute, Springfield, MA 01199, USA. rong.shao@bhs.org
Hamel
K
K
Petersen
L
L
Cao
Q J
QJ
Arenas
R B
RB
Bigelow
C
C
Bentley
B
B
Yan
W
W
D054392:Adipokines; D000818:Animals; D058578:Biglycan; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D000071451:Chitinase-3-Like Protein 1; D042783:Endothelial Cells / Q000502:physiology; D016326:Extracellular Matrix Proteins / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000502:physiology; D006023:Glycoproteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000502:physiology; D037102:Lectins / Q000037:antagonists & inhibitors / Q000502:physiology*; D051379:Mice; D016513:Mice, SCID; D009369:Neoplasms / Q000098:blood supply* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000209:etiology*; D011509:Proteoglycans / Q000502:physiology
D054392:Adipokines; C546884:BGN protein, human; C546885:Bgn protein, mouse; D058578:Biglycan; C084533:CHI3L1 protein, human; D000071451:Chitinase-3-Like Protein 1; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; D039302:Integrin alphaVbeta3; D037102:Lectins; D011509:Proteoglycans; D051416:Focal Adhesion Protein-Tyrosine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases