YKL-40, a secreted glycoprotein, promotes tumor angiogenesis

Abstract

Tumor angiogenesis is of paramount importance in solid tumor development. Elevated serum levels of YKL-40, a secreted heparin-binding glycoprotein have been associated with a worse prognosis from a variety of advanced human cancers. Yet the role of YKL-40 activity in these cancers is still missing. Here, we have shown that ectopic expression of YKL-40 in MDA-MB-231 breast cancer cells and 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 similar to the activities observed using MDA-MB-231 and HCT-116 cell conditioned medium after transfection with YKL-40. Further, YKL-40 was found to induce the coordination of membrane-bound receptor syndecan-1 and integrin αvβ3 and activate an intracellular signaling cascade including focal adhesion kinase and MAP kinase Erk1/2 in endothelial cells. Also, blockade of YKL-40 using siRNA gene knockdown suppressed tumor angiogenesis in vitro and in vivo. Immunohistochemical analysis of human breast cancer revealed 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.

YKL-40/CHI3L1 drives inflammation on the road of tumor progression

“…With the use of 4T1 and DA-3 murine mammary tumor models, Libreros et al [11,29] demonstrated that YKL-40/ CHI3L1 is expressed by splenic and pulmonary macrophages with a concurrent increase in tumor growth. In vivo neutralization of YKL-40/CHI3L1 by use of anti-YKL-40/CHI3L1 antibodies caused decreased blood-vessel density, production of proinflammatory mediators, and tumor growth [26,27,30]. More importantly, we have shown that treatment of mammary tumor-bearing mice with chitin microparticles, the natural ligand for YKL-40/CHI3L1, inhibited angiogenesis, production of proinflammatory mediators, YKL-40/CHI3L1 expression, tumor growth, and metastasis [11,29].…”

“…Implantation of breast cancer cell line MDA-MB-231 or colon cancer cell lines HCT-116 or SW480, engineered to express YKL-40/CHI3L1 in mice, showed increased blood vasculature compared with the control tumors [25,26]. In other tumor models, such as breast and glioblastoma, tumor angiogenesis, and vessel density were suppressed when mice were implanted with YKL-40/CHI3L1-shRNA tumors [27,28]. In vitro studies confirmed the angiogenic activity, as demonstrated by decreased endothelial cell migration and tube formation when human microvascular endothelial cells were exposed to YKL-40/CHI3L1 shRNA tumor cell-conditioned medium [27].…”

“…In other tumor models, such as breast and glioblastoma, tumor angiogenesis, and vessel density were suppressed when mice were implanted with YKL-40/CHI3L1-shRNA tumors [27,28]. In vitro studies confirmed the angiogenic activity, as demonstrated by decreased endothelial cell migration and tube formation when human microvascular endothelial cells were exposed to YKL-40/CHI3L1 shRNA tumor cell-conditioned medium [27]. Angiogenesis is vital for tumor growth, and TAMs play a crucial role in controlling tumor angiogenesis.…”

High YKL-40 is associated with poor survival in patients with renal cell carcinoma: a novel independent prognostic marker

“…Intriguingly, YKL-40 is acknowledged as a marker of alternatively activated M2 macrophages, which have been shown to suppress adaptive tumor-specific immune response and promote tumor growth, angiogenesis, invasion, metastasis and stroma remodeling [26,27]. Further, YKL-40 seems to be a pro-angiogenic factor itself as it has been shown to induce VEGF expression in U87 glioblastoma cells and angiogenesis in vitro and in vivo [27][28][29]. In the study by Faibish et al blocking YKL-40 with monoclonal antibody was demonstrated to suppress tumor growth and angiogenesis [30].…”

Utility of Serum YKL-40 as a Tumor-Specific Marker of Hepatobiliary Malignancies

“…Biologically YKL-40 was shown to activate cancer signaling pathways and promote tumor angiogenesis. 11,12 Although oncogenic effect of YKL-40 has not been well studied in hepatobiliary malignancy, YKL-40 is located on human chromosome 1q31-q32, a region frequently amplified in HCC. 13 Currently, the potential utility of YKL-40 in the screening, diagnosis and staging of hepatobiliary malignancies has not been investigated.…”