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.

中文翻译：

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靶向表达 FAPα 的肝星状细胞克服了结直肠癌肝转移模型中抗血管生成药物的耐药性

血管增选已被证明可介导结直肠癌肝转移 (CRCLM) 对抗血管生成治疗的耐药性。目前血管选择的机制主要集中在“劫持者”肿瘤细胞上，而“劫持者”正弦血管的功能尚未得到探索。在这里，我们发现在贝伐珠单抗耐药的 CRCLM 异种移植物中血管共同选择的发生与共同选择的肝星状细胞 (HSC) 中成纤维细胞活化蛋白 α (FAPα) 的表达增加有关，这在 HSC-具体条件FAP- 携带 CRCLM 同种异体移植物的基因敲除小鼠。从机制上讲，贝伐珠单抗治疗诱导缺氧以上调肿瘤细胞中成纤维细胞生长因子结合蛋白 1 (FGFBP1) 的表达。功能获得或丧失实验表明，贝伐珠单抗耐药肿瘤细胞衍生的 FGFBP1 通过增强 HSC 中的旁分泌 FGF2/FGFR1/ERK1/-2/EGR1 信号通路诱导 FAPα 表达。FAPα 促进 HSC 中 CXCL5 的分泌，从而激活 CXCR2 以促进肿瘤细胞的上皮-间质转化和髓源性抑制细胞的募集。这些发现在来自 CRCLM 患者的肿瘤组织中得到了进一步验证。靶向 FAPα ⁺HSC 有效地破坏了增选的正弦血管并克服了贝伐珠单抗耐药性。^{我们的研究强调了 FAPα +} HSC 在血管共同选择中的作用，并提供了一种有效的策略来克服血管共同选择介导的贝伐珠单抗耐药性。