Department of Surgery, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, P.R. China.
Department of Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, P.R. China.
Cancer Med. 2021 Sep;10(17):6035-6047. doi: 10.1002/cam4.4150. Epub 2021 Jul 31.
Cancer-associated fibroblasts (CAFs) with different gene profiles from normal fibroblasts (NFs) have been implicated in tumor progression. Angiopoietin-like protein 4 (ANGPTL4) has been shown to regulate tumor angiogenesis and metastasis, and predict poor prognosis. However, the ANGPTL4 expression in CAFs, especially in gallbladder CAFs (GCAFs) and its relationship with patient prognosis is unclear.
Affymetrix gene profile chip analysis in vitro was performed to detect the different gene expression profiles between GCAFs and NFs. RT-qPCR, immunohistochemistry, and western blotting were performed to investigate the different expression levels of ANGPTL4 in GCAFs/NFs in vitro and in an in vivo nude mouse model of xenograft tumors. Finally, the ANGPTL4 expression was investigated in the stroma of different lesion tissues of the human gallbladder by immunohistochemistry, especially the expression in GCAFs in vivo by co-immunofluorescence, and their prognostic significance in patients with gallbladder cancer (GBC) was assessed.
ANGPTL4 was upregulated in both GCAFs in vitro and in the xenograft stroma of nude mice in vivo, and its expression was also significantly upregulated in human GBC stroma co-localized with the interstitial markers fibroblast secreted protein-1 and α-smooth muscle actin. In addition, the elevated ANGPTL4 expression in GCAFs was correlated with tumor differentiation, liver metastasis, venous invasion and Nevin staging, and GBC patients with an elevated ANGPTL4 expression in GACFs were found to have a lower survival rate.
Increased ANGPTL4 expression in GCAFs correlates with poor patient prognosis, which indicates a potential therapeutic target for human GBCs.
与正常成纤维细胞（NFs）相比，具有不同基因谱的癌症相关成纤维细胞（CAFs）已被认为与肿瘤进展有关。血管生成素样蛋白 4（ANGPTL4）已被证明可调节肿瘤血管生成和转移，并预测不良预后。然而，CAFs 中的 ANGPTL4 表达，尤其是胆囊 CAFs（GCAFs）中的表达及其与患者预后的关系尚不清楚。
体外采用 Affymetrix 基因谱芯片分析检测 GCAFs 和 NFs 之间的不同基因表达谱。采用 RT-qPCR、免疫组化和 Western blot 检测 GCAFs/NFs 体外和裸鼠异种移植肿瘤体内 ANGPTL4 的不同表达水平。最后，采用免疫组化检测不同人胆囊病变组织基质中 ANGPTL4 的表达，尤其是体内 GCAFs 中 ANGPTL4 的共免疫荧光表达，并评估其在胆囊癌（GBC）患者中的预后意义。
ANGPTL4 在体外 GCAFs 中和体内裸鼠异种移植肿瘤基质中均上调，其表达在人 GBC 基质中也与间质标志物成纤维细胞分泌蛋白-1 和α-平滑肌肌动蛋白共定位明显上调。此外，GCAFs 中升高的 ANGPTL4 表达与肿瘤分化、肝转移、静脉侵犯和 Nevin 分期相关，并且发现 GACFs 中 ANGPTL4 表达升高的 GBC 患者生存率较低。
GCAFs 中 ANGPTL4 表达增加与患者预后不良相关，这表明其可能成为人类 GBC 的潜在治疗靶点。
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