Lamarca Angela, Mendiola Marta, Bernal Elsa, Heredia Victoria, Díaz Esther, Miguel María, Pastrian Laura G, Burgos Emilio, Feliu Jaime, Barriuso Jorge
Translational Oncology Group, IdIPAZ, La Paz University Hospital, Faculty of Life Sciences, University of Manchester, Manchester, UK, Dover Street, M13 9PL, Manchester, UK.
Curr Cancer Drug Targets. 2015;15(5):435-44. doi: 10.2174/1568009615666150407124747.
Hepatocellular carcinoma (HCC) tends to develop in the liver when there is a high level of background inflammation (cirrhosis). Treatment options are limited and mainly based on systemic therapies such as anti-angiogenic drugs (e.g. sorafenib). Connective tissue growth factor (CTGF) is a matricellular protein involved in inflammation, tumour growth and angiogenesis. The aim of this study is to determine the expression of CTGF and hypoxia inducible factors (HIF) in HCC and to clarify its impact on relapse and survival.
Eligibility criteria for the study consisted of patients with a diagnosis of HCC, formalin-fixed and paraffin-embedded (FFPE) biopsy tissue, as well as relapse and available survival data. A tissue microarray was constructed from ≥ 70% tumoural sections. The expressions of CTGF, HIF1α and HIF2α were analysed by immunohistochemistry. The relationship between expression of CTGF/HIF1α and CTGF/HIF2α were analysed. Univariate and multivariate analyses were performed.
Fifty-three patients were screened; 39 patients were eligible for this study. Patients were treated with radical intent. At the end of follow up, 59% patients relapsed (28.2% locally, 10.3% multicentric liver relapse and 7.7% distant metastases). Estimated median disease-free survival (DFS) and overall survival (OS) were 23.4 (95%CI 7.18-39.66) and 38.6 months (95%CI 30.7-46.6), respectively. Expression of CTGF was: negative 23.1%, focal 48.7% and diffuse 23.1%. A non-statistically significant relationship between expression of CTGF and HIF was shown supporting an alternative pathway for CTGF expression in HCC. In multivariate analysis CTGF expression was an independent factor related to OS, with shorter survival in those patients with focal/diffuse CTGF expression (HR 2.46; 95%CI 1.18-5.15).
Our results support that expression of CTGF is an independent factor associated with shorter OS in HCC. Further analysis of CTGF expression in a larger series of HCC patients is required to confirm CTGF as a prognostic biomarker in HCC.
当存在高水平的背景炎症（肝硬化）时，肝细胞癌（HCC）易于在肝脏中发生。治疗选择有限，主要基于抗血管生成药物（如索拉非尼）等全身治疗。结缔组织生长因子（CTGF）是一种基质细胞蛋白，参与炎症、肿瘤生长和血管生成。本研究的目的是确定CTGF和缺氧诱导因子（HIF）在HCC中的表达，并阐明其对复发和生存的影响。
该研究的纳入标准包括诊断为HCC的患者、福尔马林固定石蜡包埋（FFPE）活检组织以及复发和可用的生存数据。从≥70%的肿瘤切片构建组织微阵列。通过免疫组织化学分析CTGF、HIF1α和HIF2α的表达。分析CTGF/HIF1α和CTGF/HIF2α表达之间的关系。进行单因素和多因素分析。
筛选了53例患者；39例患者符合本研究条件。患者接受根治性治疗。随访结束时，59%的患者复发（28.2%为局部复发，10.3%为多中心肝复发，7.7%为远处转移）。估计的无病生存期（DFS）和总生存期（OS）分别为23.4（95%CI 7.18 - 39.66）个月和38.6（95%CI 30.7 - 46.6）个月。CTGF的表达为：阴性23.1%，局灶性48.7%，弥漫性23.1%。CTGF与HIF表达之间显示出无统计学意义的关系，支持HCC中CTGF表达的另一种途径。在多因素分析中，CTGF表达是与OS相关的独立因素，局灶性/弥漫性CTGF表达的患者生存期较短（HR 2.46；95%CI 1.18 - 5.15）。
我们的结果支持CTGF表达是HCC中与较短OS相关的独立因素。需要对更多系列的HCC患者进行CTGF表达的进一步分析，以确认CTGF作为HCC的预后生物标志物。
