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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

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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 3

FAPα induces CXCL5 secretion in HSCs to promote MDSC recruitment and tumor cell EMT via activation of CXCR2.

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FAPα induces CXCL5 secretion in HSCs to promote MDSC recruitment and tum...
(A) Heatmap depicting the differentially expressed genes encoding secreted factors in LX-2 cells (fold change > 1.2, P < 0.05; n = 3). (B) RT-qPCR analysis of CSF2, IL18, CXCL5, IL33, and IL1B in LX-2 cells. (C) ELISA analysis of CXCL5 in LX-2 cells (n = 3). (D) Intracellular Ca2+ mobilization in MDSCs and HCT116 cells in response to the conditioned medium from LX-2 cells in the absence or presence of CXCL5-neutralizing antibody or SB225002. (E) Transwell assay for the migration of MDSCs treated with conditioned medium from LX-2 cells in the absence or presence of CXCL5-neutralizing antibody or SB225002 (n = 3). (F) Transwell assays for the migration and invasion of HCT116 cells treated with conditioned medium from LX-2 cells in the absence or presence of CXCL5-neutralizing antibody or SB225002 (n = 3). Scale bars: 100 μm. (G) RT-qPCR analysis of CDH1, CDH2, VIM, and SNAI1 in HCT116 cells treated with conditioned medium from LX-2 cells in the absence or presence of CXCL5-neutralizing antibody or SB225002 (n = 3). (H) Western blotting analysis of E-cadherin, N-cadherin, vimentin, and snail in HCT116 cells treated with conditioned medium from LX-2 cells in the absence or presence of CXCL5-neutralizing antibody or SB225002. Data are presented as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001 (2-tailed, unpaired t test in B and C; 1-way ANOVA with Tukey’s post hoc comparison in E–G). CM, conditioned medium.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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