Zhang Fei, Wang Yun, Sun Peng, Wang Zhi-Qiang, Wang De-Shen, Zhang Dong-Sheng, Wang Feng-Hua, Fu Jian-Hua, Xu Rui-Hua, Li Yu-Hong
Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, Guangdong, People's Republic of China.
State Key Laboratory of Oncology in South China, Guangzhou, 510060, Guangdong, People's Republic of China.
J Cancer Res Clin Oncol. 2017 Dec;143(12):2413-2424. doi: 10.1007/s00432-017-2493-4. Epub 2017 Aug 11.
Hyperfibrinogenemia is associated with unfavorable prognosis and advanced tumor behavior in various malignancies, including esophageal squamous cell carcinoma (ESCC). However, its biological function in ESCC is unknown. The present study was designed to further validate the prognostic value of preoperative plasma hyperfibrinogenemia and evaluate the biological role of fibrinogen, as well as the underlying mechanism in ESCC.
Data from 452 cases with newly diagnosed ESCC followed by curative surgery between 2006 and 2010 were retrospectively evaluated. The Clauss method was utilized to measure the preoperative plasma fibrinogen level. Correlations between the fibrinogen level and clinicopathologic characteristics and survival analysis were performed. The effects of fibrinogen on malignant behaviors, including tumor cell viability, colony formation, migration, and invasion, were also investigated.
The optimal cut-off value for plasma fibrinogen level was defined as 4.0 g/L according to recommendations. Thus, the proportion of hyperfibrinogenemia was 24.8% (112/452). Preoperative plasma hyperfibrinogenemia was significantly associated with advanced tumor length, deep tumor invasion, advanced tumor-node-metastasis stage, alcohol consumption, a higher white blood cell count, a higher platelet count, and high globulin levels. Univariate survival analysis revealed that compared to those with normal plasma fibrinogen levels, patients with hyperfibrinogenemia tended to have poorer disease-free survival (DFS) [hazard ratio (HR), 1.692; 95% confidence interval (CI), 1.304-2.196; P < 0.001] and overall survival (OS) (HR 1.864; 95% CI 1.424-2.440; P < 0.001). In the multivariate Cox regression models, these factors remained independent predictors for impaired DFS (HR 1.491; 95% CI 1.138-1.955; P = 0.004) and OS (HR 1.648; 95% CI 1.246-2.180; P < 0.001) after adjusting for other confounding variables. In addition, fibrinogen could significantly promote cell migration and invasion but not proliferation. Moreover, it could also induce epithelial-mesenchymal transition (EMT) and increase the levels of p-PTEN, p-AKT, and p-mTOR in ESCC cell lines.
Preoperative plasma hyperfibrinogenemia might serve as an independent predictor of unfavorable survival in ESCC. Furthermore, fibrinogen may promote cell motility by inducing EMT via the p-AKT/p-mTOR pathway.
高纤维蛋白原血症与包括食管鳞状细胞癌（ESCC）在内的多种恶性肿瘤的不良预后和肿瘤进展行为相关。然而，其在ESCC中的生物学功能尚不清楚。本研究旨在进一步验证术前血浆高纤维蛋白原血症的预后价值，评估纤维蛋白原的生物学作用及其在ESCC中的潜在机制。
回顾性评估2006年至2010年间452例新诊断为ESCC并接受根治性手术患者的数据。采用Clauss法测定术前血浆纤维蛋白原水平。分析纤维蛋白原水平与临床病理特征之间的相关性并进行生存分析。同时研究纤维蛋白原对恶性行为的影响，包括肿瘤细胞活力、集落形成、迁移和侵袭。
根据建议，血浆纤维蛋白原水平的最佳临界值定义为4.0 g/L。因此，高纤维蛋白原血症的比例为24.8%（112/452）。术前血浆高纤维蛋白原血症与肿瘤长度增加、肿瘤深度浸润、肿瘤-淋巴结-转移分期进展、饮酒、白细胞计数升高、血小板计数升高和球蛋白水平升高显著相关。单因素生存分析显示，与血浆纤维蛋白原水平正常的患者相比，高纤维蛋白原血症患者的无病生存期（DFS）往往较差[风险比（HR），1.692；95%置信区间（CI），1.304-2.196；P < 0.001]，总生存期（OS）也较差（HR 1.864；95% CI 1.424-2.440；P < 0.001）。在多因素Cox回归模型中，在调整其他混杂变量后，这些因素仍然是DFS受损（HR 1.491；95% CI 1.138-1.955；P = 0.004）和OS受损（HR 1.648；95% CI 1.246-2.180；P < 0.001）的独立预测因素。此外，纤维蛋白原可显著促进细胞迁移和侵袭，但不促进增殖。此外，它还可诱导上皮-间质转化（EMT）并增加ESCC细胞系中p-PTEN、p-AKT和p-mTOR的水平。
术前血浆高纤维蛋白原血症可能是ESCC患者生存不良的独立预测因素。此外，纤维蛋白原可能通过p-AKT/p-mTOR途径诱导EMT来促进细胞运动。
