The molecular mechanism by which cancer-associated fibroblasts (CAFs) confer chemoresistance in ovarian cancer is poorly understood. The purpose of the present study was to evaluate the roles of CAFs in modulating tumor vasculature, chemoresistance, and disease progression. Here, we found that CAFs upregulated the lipoma-preferred partner (LPP) gene in microvascular endothelial cells (MECs) and that LPP expression levels in intratumoral MECs correlated with survival and chemoresistance in patients with ovarian cancer. Mechanistically, LPP increased focal adhesion and stress fiber formation to promote endothelial cell motility and permeability. siRNA-mediated LPP silencing in ovarian tumor–bearing mice improved paclitaxel delivery to cancer cells by decreasing intratumoral microvessel leakiness. Further studies showed that CAFs regulate endothelial LPP via a calcium-dependent signaling pathway involving microfibrillar-associated protein 5 (MFAP5), focal adhesion kinase (FAK), ERK, and LPP. Thus, our findings suggest that targeting endothelial LPP enhances the efficacy of chemotherapy in ovarian cancer. Our data highlight the importance of CAF–endothelial cell crosstalk signaling in cancer chemoresistance and demonstrate the improved efficacy of using LPP-targeting siRNA in combination with cytotoxic drugs.

中文翻译：

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癌症相关的成纤维细胞调节内皮粘附蛋白LPP促进卵巢癌化学耐药性

癌症相关的成纤维细胞（CAFs）赋予卵巢癌化学抗性的分子机制了解甚少。本研究的目的是评估CAF在调节肿瘤血管，化学耐药性和疾病进展中的作用。在这里，我们发现CAFs上调微血管内皮细胞（MECs）中的脂肪瘤首选伴侣（LPP）基因，并且肿瘤内MECs中LPP的表达水平与卵巢癌患者的生存和化学耐药性相关。从机理上讲，LPP增加了粘着斑和应力纤维的形成，从而促进了内皮细胞的运动性和通透性。siRNA介导的LPP通过降低肿瘤内微血管的渗漏，使荷瘤小鼠沉默可以改善紫杉醇向癌细胞的递送。进一步的研究表明，CAF通过钙依赖性信号传导途径调节内皮LPP，该信号传导途径涉及微纤维相关蛋白5（MFAP5），粘着斑激酶（FAK），ERK和LPP。因此，我们的发现表明靶向内皮LPP可增强卵巢癌化疗的疗效。我们的数据突出了CAF-内皮细胞串扰信号在癌症化学耐药性中的重要性，并证明了将靶向LPP的siRNA与细胞毒性药物联合使用可提高疗效。