Abstract
BackgroundBiglycan is a proteoglycan found in the extracellular matrix. We have previously shown that biglycan is secreted from tumor endothelial cells and induces tumor angiogenesis and metastasis. However, the function of stroma biglycan in breast cancer is still unclear.MethodsBiglycan gene analysis and its prognostic values in human breast cancers were based on TCGA data. E0771 breast cancer cells were injected into WT and Bgn KO mice, respectively.ResultsBreast cancer patients with high biglycan expression had worse distant metastasis-free survival. Furthermore, biglycan expression was higher in the tumor stromal compartment compared to the epithelial compartment. Knockout of biglycan in the stroma (Bgn KO) in E0771 tumor-bearing mice inhibited metastasis to the lung. Bgn KO also impaired tumor angiogenesis and normalized tumor vasculature by repressing tumor necrosis factor-ɑ/angiopoietin 2 signaling. Moreover, fibrosis was suppressed and CD8+ T cell infiltration was increased in tumor-bearing Bgn KO mice. Furthermore, chemotherapy drug delivery and efficacy were improved in vivo in Bgn KO mice.ConclusionOur results suggest that targeting stromal biglycan may yield a potent and superior anticancer effect in breast cancer.
Highlights
Biglycan is a proteoglycan found in the extracellular matrix
Biglycan expression was higher in the tumor stroma compartment compared to the tumor epithelial compartment of human breast cancers (Fig. 1b)
These results suggested that biglycan is upregulated in breast cancer, especially in tumor stroma, and its expression is negatively associated with the survival of breast cancer patients
Summary
We have previously shown that biglycan is secreted from tumor endothelial cells and induces tumor angiogenesis and metastasis. Tumor vasculature is structurally abnormal relative to normal vasculature and is characterized by highly permeable and leaky blood vessels [1]. The abnormality of tumor vasculature impairs blood perfusion and oxygenation, resulting in hypoxia and acidosis, and promoting tumor growth and progression. Increased pericyte recruitment and vessel functions using bevacizumab has been shown in breast cancer patients [6, 7]. Other trials found no significant effect on prolonging progression-free survival using Bevacizumab resulting in withdrawal of FDA approval [8, 9]. Alternative strategies to modulate abnormal tumor vasculature in breast cancer are still needed
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