Anti-YKL-40 antibody and ionizing irradiation synergistically inhibit tumor vascularization and malignancy in glioblastoma

Abstract

Chemo/radiotherapies are the most common adjuvant modality treated for patients with glioblastoma (GBM) following surgery. However, the overall therapeutic benefits are still uncertain, as the mortality remains high. Elevated expression of YKL-40 in GBM was correlated with increases in mural cell-associated vessel coverage, stability and density, and decreases in vessel permeability and disease survival. To explore the potential role of YKL-40 in mural cell-mediated tumor vascularization, we employed an anti-YKL-40 neutralizing antibody (mAY) and ionizing irradiation (IR) in xenografted brain tumor models. Although single treatment with mAY or IR partially increased mouse survival, their combination led to dramatic inhibition in tumor growth and increases in mouse survival. mAY blocked mural cell-mediated vascular stability, integrity and angiogenesis; whereas IR merely promoted tumor cell and vascular cell apoptosis. Vascular radioresistance is at least partially attributed to expression of YKL-40 in mural cells. These divergent effects were also recapitulated in cultured systems using endothelial cells and mural cells differentiated from glioblastoma stem-like cells (GSCs). Dysfunction of intercellular contact N-cadherin was found to mediate mAY-inhibited vascularization. Collectively, the data suggest that the conjunction therapy with mAY and IR synergistically inhibit tumor vascularization and progression. The evidence may shed light on a new adjuvant therapy in clinic.

TrkB-containing exosomes promote the transfer of glioblastoma aggressiveness to YKL-40-inactivated glioblastoma cells

“…These data correlated with previous study demonstrating that anti-YKL-40 antibodies inhibited angiogenesis in glioblastoma [58] supporting the functions YKL-40 in glioblastoma vascularization [51]. The inhibition of tumor angiogenesis through exosomes from mesenchymal stem cells, was also associated to a down-regulation of VEGF expression [59].…”

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].…”

Mechanistic roles of epithelial and immune cell signaling during the development of colitis-associated cancer

“…Heparan sulfate chains of Syndecan-1 also interact with CHI3L1 and coordinate Syndecan-1/αVβ3 signaling. This interaction has been shown to induce Erk1/2 in macrophages and promote angiogenesis in the tumor microenvironment by increasing Flk-1 expression and sensitizing the angiogenic responses to VEGF (67, 68). Overall, CHI3L1 regulates multiple cellular responses including apoptosis, pyroptosis, inflammasome activation, wound healing, tumorigenesis, and angiogenesis due to its ability to bind with different receptors.…”