Positron Emission Tomography (PET) with combined [18F]-FDG and [11C]-acetate (dual-tracer) is used for the management of hepatocellular carcinoma (HCC) patients, although its prognostic value and underlying molecular mechanism remain poorly understood. We hypothesized that radiotracer uptake might be associated with tumor hypoxia and validated our findings in public and local human HCC cohorts. Twelve orthotopic HCC xenografts were established using MHCC97L cells in female nude mice, with 5 having undergone hepatic artery ligation (HAL) to create tumor hypoxia in vivo. Tumors in both Control and HAL-treated xenografts were imaged with [11C]-acetate and [18F]-FDG PET-MR and RNA sequencing was performed on the resected tumors. Semiquantitative analysis of PET findings was then performed, and the findings were then validated on the Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) cohort and patients from our institution. HAL-treated mice showed lower [11C]-acetate (HAL-treated vs. Control, tumor-to-liver SUV ratio (SUVTLR): 2.14[2.05–2.21] vs 3.11[2.75–5.43], p = 0.02) but not [18F]-FDG (HAL-treated vs. Control, SUVTLR: 3.73[3.12–4.35] vs 3.86[3.7–5.29], p = 0.83) tumor uptakes. Gene expression analysis showed the PET phenotype is associated with upregulation of hallmark hypoxia signature. The prognostic value of the hypoxia gene signature was tested on the TCGA-LIHC cohort with upregulation of hypoxia gene signature associated with poorer overall survival (OS) in late-stage (stage III and IV) HCC patients (n = 66, OS 2.05 vs 1.67 years, p = 0.046). Using a local cohort of late-stage HCC patients who underwent dual-tracer PET-CT, tumors without [11C]-acetate uptake are associated with poorer prognosis (n = 51, OS 0.25 versus 1.21 years, p < 0.0001) and multivariable analyses showed [11C]-acetate tumor uptake as an independent predictor of OS (HR 0.17 95%C 0.06–0.42, p < 0.0001). [11C]-acetate uptake is associated with alteration of tumor hypoxia gene expression and poorer prognosis in patients with advanced HCC.

中文翻译：

---

预后 PET [11C]-乙酸盐摄取与晚期肝细胞癌患者的缺氧基因表达相关——一项从实验室到床位的研究

正电子发射断层扫描 (PET) 结合 [18F]-FDG 和 [11C]-乙酸盐（双示踪剂）用于治疗肝细胞癌 (HCC) 患者，尽管其预后价值和潜在分子机制仍知之甚少。我们假设放射性示踪剂的摄取可能与肿瘤缺氧有关，并在公共和当地人类 HCC 队列中验证了我们的发现。使用 MHCC97L 细胞在雌性裸鼠体内建立 12 个原位 HCC 异种移植物，其中 5 个经过肝动脉结扎 (HAL) 以在体内产生肿瘤缺氧。使用[11C]-乙酸盐和[18F]-FDG PET-MR对对照和HAL处理的异种移植物中的肿瘤进行成像，并对切除的肿瘤进行RNA测序。然后对 PET 结果进行半定量分析，并在癌症基因组图谱肝癌 (TCGA-LIHC) 队列和我们机构的患者中验证了结果。 HAL 处理的小鼠表现出较低的 [11C]-乙酸盐（HAL 处理与对照相比，肿瘤与肝脏 SUV 比率 (SUVTLR)：2.14[2.05–2.21] 与 3.11[2.75–5.43]，p = 0.02），但并非如此[18F]-FDG（HAL 处理与对照，SUVTLR：3.73[3.12–4.35] 与 3.86[3.7–5.29]，p = 0.83）肿瘤摄取。基因表达分析显示 PET 表型与标志性缺氧特征的上调相关。在 TCGA-LIHC 队列中测试了缺氧基因特征的预后价值，缺氧基因特征的上调与晚期（III 期和 IV 期）HCC 患者较差的总生存期 (OS) 相关（n = 66，OS 2.05 vs 1.67 年，p = 0.046）。使用接受双示踪剂 PET-CT 的晚期 HCC 患者局部队列，不摄取 [11C]-乙酸盐的肿瘤与较差的预后相关（n = 51，OS 0.25 年与 1.21 年，p < 0.0001）和多变量分析显示 [11C]-醋酸盐肿瘤摄取是 OS 的独立预测因子（HR 0.17 95%C 0.06–0.42，p < 0.0001）。 [11C]-乙酸盐摄取与晚期 HCC 患者肿瘤缺氧基因表达的改变和较差的预后相关。