A YKL-40–Neutralizing Antibody Blocks Tumor Angiogenesis and Progression: A Potential Therapeutic Agent in Cancers

Abstract

Accumulating evidence has indicated that expression levels of YKL-40, a secreted glycoprotein, were elevated in multiple advanced human cancers. Recently, we have identified an angiogenic role of YKL-40 in cancer development. However, blockade of the function of YKL-40, which implicates therapeutic value, has not been explored yet. Our current study sought to establish a monoclonal anti-YKL-40 antibody as a neutralizing antibody for the purpose of blocking tumor angiogenesis and metastasis. A mouse monoclonal anti-YKL-40 antibody (mAY) exhibited specific binding with recombinant YKL-40 and with YKL-40 secreted from osteoblastoma cells MG-63 and brain tumor cells U87. In the functional analysis, we found that mAY inhibited tube formation of microvascular endothelial cells in Matrigel induced by conditioned medium of MG-63 and U87 cells, as well as recombinant YKL-40. mAY also abolished YKL-40-induced activation of the membrane receptor VEGF receptor 2 (Flk-1/KDR) and intracellular signaling mitogen-activated protein (MAP) kinase extracellular signal-regulated kinase (Erk) 1 and Erk 2. In addition, mAY enhanced cell death response of U87 line to g-irradiation through decreased expression of pAKT and AKT and accordingly, abrogated angiogenesis induced by the conditioned medium of U87 cells in which YKL-40 levels were elevated by treatment with g-irradiation. Furthermore, treatment of xenografted tumor mice with mAY restrained tumor growth, angiogenesis, and progression. Taken together, this study has shown the therapeutic use for the mAY in treatment of tumor angiogenesis and metastasis. Mol Cancer Ther; 10(5); 742-51. Ó2011 AACR.

Observational and genetic plasma YKL‐40 and cancer in 96,099 individuals from the general population

“…Indeed, studies on mice with xenografted glioblastoma treated with monoclonal anti-YKL-40 antibody or chitin showed restrained tumour growth, angiogenesis and progression. [46][47][48][49] Furthermore, a combination treatment with anti-YKL-40 neutralizing antibody and ionizing irradiation led to a much more dramatic inhibition in tumour growth and increased survival than either therapy alone. 50 Randomized studies are warranted to examine a potential therapeutic benefit from YKL-40 neutralizing antibodies in patients with cancer.…”

Circulating tumor cell interactions with macrophages: implications for biology and treatment

“…Thus, CHI3L1 seems to represent an important mediator and regulator of local inflammation in benign and malignant diseases and important promoter of angiogenesis, invasion and metastasis expressed in primary tumors, immune cells and CTCs. The molecular interactions of CHI3L1 are involved in metastasis and offer new therapeutic targets for inhibiting tumor dissemination (114).…”

Serum YKL-40 in Risk Assessment for Colorectal Cancer: A Prospective Study of 4,496 Subjects at Risk of Colorectal Cancer

“…IL6 and hypoxia stimulate YKL-40 synthesis (11,12). YKL-40 regulates VEGF and plays a role in angiogenesis (13)(14)(15), and inflammation (3,16), including inflammationassociated carcinogenic changes of colonic epithelial cells (17,18). Furthermore, YKL-40 participates in activation of Akt signaling pathways in these cells (19), in apoptosis (20), in cell proliferation and differentiation (9,10), and in regulation of extracellular tissue remodeling (3), all processes that are important for cancer growth and dissemination (21).…”