Targeting FAPα-expressing hepatic stellate cells overcomes resistance to antiangiogenics in colorectal cancer liver metastasis models
Ming Qi, … , Wencai Ye, Dongmei Zhang
Ming Qi, … , Wencai Ye, Dongmei Zhang
Published August 11, 2022
Citation Information: J Clin Invest. 2022;132(19):e157399. https://doi.org/10.1172/JCI157399.
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Research Article Gastroenterology

Targeting FAPα-expressing hepatic stellate cells overcomes resistance to antiangiogenics in colorectal cancer liver metastasis models

Abstract

Vessel co-option has been demonstrated to mediate colorectal cancer liver metastasis (CRCLM) resistance to antiangiogenic therapy. The current mechanisms underlying vessel co-option have mainly focused on “hijacker” tumor cells, whereas the function of the “hijackee” sinusoidal blood vessels has not been explored. Here, we found that the occurrence of vessel co-option in bevacizumab-resistant CRCLM xenografts was associated with increased expression of fibroblast activation protein α (FAPα) in the co-opted hepatic stellate cells (HSCs), which was dramatically attenuated in HSC-specific conditional Fap-knockout mice bearing CRCLM allografts. Mechanistically, bevacizumab treatment induced hypoxia to upregulate the expression of fibroblast growth factor–binding protein 1 (FGFBP1) in tumor cells. Gain- or loss-of-function experiments revealed that the bevacizumab-resistant tumor cell–derived FGFBP1 induced FAPα expression by enhancing the paracrine FGF2/FGFR1/ERK1/-2/EGR1 signaling pathway in HSCs. FAPα promoted CXCL5 secretion in HSCs, which activated CXCR2 to promote the epithelial-mesenchymal transition of tumor cells and the recruitment of myeloid-derived suppressor cells. These findings were further validated in tumor tissues derived from patients with CRCLM. Targeting FAPα+ HSCs effectively disrupted the co-opted sinusoidal blood vessels and overcame bevacizumab resistance. Our study highlights the role of FAPα+ HSCs in vessel co-option and provides an effective strategy to overcome the vessel co-option–mediated bevacizumab resistance.

Authors

Ming Qi, Shuran Fan, Maohua Huang, Jinghua Pan, Yong Li, Qun Miao, Wenyu Lyu, Xiaobo Li, Lijuan Deng, Shenghui Qiu, Tongzheng Liu, Weiqing Deng, Xiaodong Chu, Chang Jiang, Wenzhuo He, Liangping Xia, Yunlong Yang, Jian Hong, Qi Qi, Wenqian Yin, Xiangning Liu, Changzheng Shi, Minfeng Chen, Wencai Ye, Dongmei Zhang

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Figure 6

FGF2/FGFR1/FAPα axis is essential for the secretion of CXCL5 in HSCs, tumor cell EMT, and MDSC recruitment.

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FGF2/FGFR1/FAPα axis is essential for the secretion of CXCL5 in HSCs, tu...
(A) H&E staining of the tumor-liver interface of HCT116 CRCLM xenografts. Scale bar: 100 μm. Quantification of RHGP is shown (n = 6). (B) Immunofluorescence staining of the EpCAM+ tumor cells (green) that infiltrated the liver parenchyma and hijacked the CD31+ sinusoidal blood vessels (red) in the tumor-liver interface of HCT116 CRCLM xenografts. Scale bar: 20 μm. Quantification of the co-opted sinusoidal blood vessels is shown (n = 6). (C) Immunofluorescence staining of FAPα+ (green) or p-FGFR1+ (green) HSCs attached to the CD31+ sinusoidal blood vessels (red) in the tumor-liver interface of HCT116 CRCLM xenografts. Scale bars: 20 μm. (D) Immunofluorescence staining of the EpCAM+ (green) tumor cells and Gr-1+ MDSCs (red) in the tumor-liver interface of HCT116 CRCLM xenografts. Scale bar: 20 μm. Quantification of the Gr-1+ MDSCs is shown (n = 6). (E) ELISA analysis of CXCL5 concentration in the culture medium of LX-2 cells. (F) Transwell assay for the migration of MDSCs treated with the conditioned medium from LX-2 cells (n = 3). (G) Transwell assays for the migration and invasion of HCT116 cells treated with the conditioned medium from LX-2 cells (n = 3). (H) Western blotting analysis of E-cadherin, N-cadherin, vimentin, and snail in HCT116 cells treated with the conditioned medium from LX-2 cells. Dotted lines indicate the tumor-liver interface. Bev AR, bevacizumab acquired resistance; CM, conditioned medium; T, tumor; L, liver. Data are presented as mean ± SEM. **P < 0.01; ***P < 0.001 (1-way ANOVA with Tukey’s post hoc comparison).