Abstract 1732: Elevated expression of YKL-40, a cancer biomarker, is associated with tumor angiogenesis

Abstract

Abstract Growing evidence from clinical investigations has shown that increased serum levels of YKL-40 are correlated with short survival and metastasis in a broad type of human cancers. These data suggest that YKL-40 in the blood may present a powerful tool for cancer diagnosis and prognosis. However, pathological activity of YKL-40 in cancer development is poorly understood. Here, we explored a functional role for YKL-40 in vasculature development of human cancer. In a survey of twenty cases of breast ductal carcinoma in situ (DCIS) and thirty-eight cases of infiltrating ductal carcinoma (IDC), we found that expression levels of YKL-40 in specimens from DCIS were barely detectable, but different levels of YKL-40 were present in IDC. Nine out of thirty-eight IDC cases showed high levels of YKL-40 and nine cases displayed medium levels of YKL-40, whereas the rest twenty cases were low or negative. Interestingly, in an analysis of vasculature formation in these IDC samples, we found that different blood vessel densities significantly correlated with different degrees of YKL-40 expression. To test this possible angiogenic activity of YKL-40 in tumor development, we utilized angiogenic xenograft models by subcutaneous injection of SCID/Beige mice with a brain tumor line U87 cells which express strong endogenous YKL-40 and U87 cells with siRNA knockdown of YKL-40. siRNA knockdown of YKL-40 notably suppressed tumor angiogenesis and tumor development relative to high levels of YKL-40 expressed in control U87 cells. Further, to dissect cellular and molecular mechanisms underlying YKL-40-induced tumor angiogenesis, we treated human microvascular endothelial cells with YKL-40 and found that YKL-40 was capable of binding to heparan sulfate on ectodomain of membrane receptor syndecan-1 (S1). The activated S1 prompted its interaction with adjacent receptor integrin αvβ3, leading to activation of intracellular cascades including phosphorylation of focal adhesion kinase and MAP kinase. A series of individual signaling inhibitors blocked YKL-40-induced angiogenesis in vitro. Collectively, these data strongly suggest that YKL-40 expressed in cancer activates vascular endothelial cell angiogenesis to promote tumor development. These findings may hold promise for developing novel therapeutic agents targeting YKL-40, a cancer biomarker that is overexpressed in a wide range of human cancers. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1732.