Angiogenic activities of YKL-40 in cancer development: A potential biomarker and target for cancer diagnosis and therapy

Abstract

Pioneer Valley Life Sciences Institute, University of Massachusetts, USA A evidence has shown that elevated serum levels of a secreted glycoprotein YKL-40 are associated with a worse prognosis from a variety of advanced human cancers, including breast cancer, colorectal cancer, ovarian cancer, and brain tumor. Furthermore, these increased levels correlate with poorer survival of cancer patients, suggesting that serum levels of YKL-40 might be a prognostic biomarker. Yet the role of YKL-40 activity in these cancers is poorly understood. To explore a functional role of YKL-40 in tumor development, we engineered cancer cells with YKL-40 cDNA to express ectopic YKL-40. Over-expression of YKL-40 in these cancer cells led to larger tumor formation with an extensive angiogenic phenotype than did control cancer cells in mice. Affi nity purifi ed recombinant YKL-40 protein promoted vascular endothelial cell angiogenesis in vitro, the eff ects of which are similar to the activities observed using cancer cell conditioned medium aft er transfection with YKL-40. Immunohistochemical analysis of human breast cancer revealed a correlation between YKL-40 expression and blood vessel density. YKL-40 levels were positively correlated with tumor grade and Her2/neu, but negatively correlated with estrogen and progesterone receptor. In complementary approaches, we found that blockade of YKL-40 by YKL40 siRNA gene knockdown and a YKL-40 neutralizing antibody restrained tumor growth, angiogenesis, and progression. Taken together, these fi ndings have shed light on the mechanisms by which YKL-40 promotes tumor angiogenesis and progression; thus pointing to a valuable cancer diagnostic and prognostic biomarker as well as a target for cancer therapy.