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

Abstract

Bevacizumab exerts anti-angiogenic effects in cancer patients by inhibiting vascular endothelial growth factor (VEGF). However, its use is still limited due to the development of resistance to the treatment. Such resistance can be regulated by various factors, although the underlying mechanisms remain incompletely understood. Here we show that bone marrow-derived fibrocyte-like cells, defined as alpha-1 type I collagen-positive and CXCR4-positive cells, contribute to the acquired resistance to bevacizumab. In mouse models of malignant pleural mesothelioma and lung cancer, fibrocyte-like cells mediate the resistance to bevacizumab as the main producer of fibroblast growth factor 2. In clinical specimens of lung cancer, the number of fibrocyte-like cells is significantly increased in bevacizumab-treated tumours, and correlates with the number of treatment cycles, as well as CD31-positive vessels. Our results identify fibrocyte-like cells as a promising cell biomarker and a potential therapeutic target to overcome resistance to anti-VEGF therapy.

Comprehensive review of targeted therapy for colorectal cancer

“…Upregulation of the FGF/FGFR pathway has also been observed in anti-VEGFresistant cases. [224][225][226] Dual blockade of FGF/FGFR and VEGF/ VEGFR in preclinical studies displayed positive effects against tumor cells, while in clinical trials, agents such as nintedanib and the FGF-VEGF dual blocker dovitinib failed to benefit anti-VEGFrefractory patients. 215,227 Compensatory activation of the c-MET pathway is the mechanism most related to the loss of anti-VEGF agent effectiveness.…”

Targeting the tumour stroma to improve cancer therapy

“…In a mouse model of lung cancer, treatment with bevacizumab led to acquired resistance, at least partially via upregulation of VEGFA, FGF2, FGFR2, and PDGFRA in stromal cells 248 . In addition, in patients with lung adenocarcinoma, the number of FSP-1-positive fibroblasts in tumours was higher in those who received bevacizumab than in those who did not 248 .…”

“…In a mouse model of lung cancer, treatment with bevacizumab led to acquired resistance, at least partially via upregulation of VEGFA, FGF2, FGFR2, and PDGFRA in stromal cells 248 . In addition, in patients with lung adenocarcinoma, the number of FSP-1-positive fibroblasts in tumours was higher in those who received bevacizumab than in those who did not 248 . Treatment of mice with subcutaneous syngeneic myeloma tumours with anti-VEGF antibody resulted in tumours with therapeutic resistance with CAFs present in the resistant tumours reactivating angiogenesis via PDGFC signalling 133 .…”

“…Many therapeutic strategies target FGF receptors, from RTK inhibitors (such as dovitinib, which targets FGFR3) to monoclonal antibodies (such as GP369, which targets FGFR2-IIIb) 311–315 . Targeting the FGF2/FGF2R axis in xenograft models has been shown to prevent resistance to bevacizumab 248 . Another novel strategy is to prevent stromal cell-secreted FGFs from binding to their receptors on cancer cells; for example, with a ligand trap for FGF using a soluble fusion protein (FGFR1-IIIc fused to the Fc domain of IgG1) 312 .…”

How to conjugate the stemness marker ALDH1A1 with tumor angiogenesis, progression, and drug resistance

“…Therefore, there are many clinical failures due to the development of inherent/acquired resistance to antiangiogenic drugs, but the role of ALDH1A1 in this context is debated. Various studies have found a correlation between the expression of stemness marker and resistance to antiangiogenic drugs [100][101][102] . A critical point is that tumor angiogenesis is not only a VEGF-dependent process since there are several key factors responsible for this phenomenon, but most drugs inhibit the VEGF signaling.…”