Fibrocyte-like cells mediate acquired resistance to anti-angiogenic therapy with bevacizumab

Bevacizumab represents anti-angiogenic effect in cancer patients by inhibiting vascular endothelial growth factor (VEGF). However, its use is still limited due to the resistance to the initial response. Such resistance could be regulated by various cell types and soluble factors, although the underlying mechanisms, especially cell-based mechanisms, remain incompletely understood. Here, we identified bone marrow-derived fibrocytes as a novel contributor for the acquired resistance to bevacizumab, defined as alpha-1 type I collagen-positive and CXCR4-positive cells. In mouse models of lung cancer and malignant pleural mesothelioma, fibrocytes mediated the resistance to bevacizumab as a main producer of fibroblast growth factor 2. Using clinical specimens of lung cancer that were surgically resected after bevacizumab treatment, we demonstrated that the number of fibrocytes was significantly increased in bevacizumab-treated tumor, and was correlated with the number of treatment cycles as well as CD31-positive vessels. Our results identify fibrocytes as a promising cell biomarker and a potential therapeutic target to overcome resistance to anti-VEGF therapy. In this study, it was found that long term treatment of bevacizumab induce the recruitment of fibrocytes and acquirement of resistance in tumor tissue. In order to determine the mechanism by which fibrocytes were recruited into the tumor environment, we performed global analysis by using human malignant mesothelioma (Y-MESO-14) tumor tissue in orthotopic implantation mouse model. Y-MESO-14 bearing mice were treated with bevacizumab or vheicle continuously and tumor tissue were retrieved on day28. Gene expression profiles were analyzed and compared with both groups using Agilent4 ×44K ver. 2.0 Micro Arrays .