Davidson Ben, Reich Reuven, Kopolovic Juri, Berner Aasmund, Nesland Jahn M, Kristensen Gunnar B, Tropé Claes G, Bryne Magne, Risberg Bjørn, van de Putte Gregg, Goldberg Iris
Department of Pathology, The Norwegian Radium Hospital, University of Oslo.
Clin Exp Metastasis. 2002;19(2):135-44. doi: 10.1023/a:1014582911680.
Angiogenic factors are involved in tumor growth and spread. The aim of this study was to evaluate the expression of angiogenesis-related genes in malignant serous effusions of patients with advanced-stage (FIGO stage III and IV) ovarian carcinoma. In addition, to compare the results for carcinoma cells in effusions with corresponding primary tumors and metastatic lesions, and analyze their prognostic role. Sections from 66 effusions and 90 primary and metastatic lesions from 62 ovarian and primary peritoneal carcinoma patients, were evaluated for expression of basic fibroblast factor (bFGF), interleukin-8 (IL-8), and vascular endothelial growth factor (VEGF) using mRNA in situ hybridization (ISH). Protein expression was evaluated in a subset of specimens using immunohistochemistry (IHC). ISH results were correlated with clinical parameters. In both effusions and solid tumors, bFGF mRNA was the most commonly expressed factor (93% of effusions and 95% of solid tumors) followed by IL-8, while VEGF was expressed in a minority of the specimens (P < 0.001 for bFGF vs. IL-8 and VEGF). In solid tumors, angiogenic mRNA expression was seen in both tumor and stromal cells in the majority of positive cases. ISH results did not differ in primary and metastatic tumors. However, carcinoma cells in effusions showed down-regulated expression of VEGF, when compared with both primary tumors (P = 0.029) and metastases (P = 0.015). IL-8 showed a similar down-regulation in effusions, when compared with metastases (P = 0.005). IHC showed excellent agreement with mRNA findings on protein level. In the study of clinico-pathologic parameters, IL-8 mRNA expression in effusions was associated with higher tumor grade (P = 0.044). Angiogenic gene expression in effusions showed no correlation with patient age, previous treatment, residual tumor size, FIGO stage or disease outcome in survival analysis (P > 0.05). Peritoneal and pleural effusions showed similar expression patterns. In conclusion, bFGF is the major angiogenic factor expressed in ovarian carcinoma at the mRNA level. It is highly expressed in both solid tumors and serous effusions, while IL-8 and VEGF are down regulated in carcinoma cells in effusions, possibly due to the lack of interaction with stromal cells. mRNA expression of VEGF, bFGF, and IL-8 does not appear to be a predictor of disease outcome in advanced-stage ovarian carcinoma. Carcinoma cells in pleural and peritoneal effusions show a similar metastatic expression profile, in agreement with our previous findings, supporting the true metastatic nature of ovarian carcinoma cells in ascites.
血管生成因子参与肿瘤的生长和扩散。本研究旨在评估晚期（国际妇产科联盟 [FIGO] 分期III期和IV期）卵巢癌患者恶性浆液性积液中血管生成相关基因的表达。此外，比较积液中癌细胞与相应原发性肿瘤和转移灶的结果，并分析它们的预后作用。对62例卵巢癌和原发性腹膜癌患者的66份积液以及90份原发性和转移灶切片，采用mRNA原位杂交（ISH）评估碱性成纤维细胞生长因子（bFGF）、白细胞介素-8（IL-8）和血管内皮生长因子（VEGF）的表达。使用免疫组织化学（IHC）在一部分标本中评估蛋白表达。ISH结果与临床参数相关。在积液和实体瘤中，bFGF mRNA是最常表达的因子（93%的积液和95%的实体瘤），其次是IL-8，而VEGF仅在少数标本中表达（bFGF与IL-8和VEGF相比，P < 0.001）。在实体瘤中，大多数阳性病例的肿瘤细胞和基质细胞中均可见血管生成mRNA表达。原发性肿瘤和转移瘤的ISH结果无差异。然而，与原发性肿瘤（P = 0.029）和转移灶（P = 0.015）相比，积液中的癌细胞VEGF表达下调。与转移灶相比，积液中的IL-8也有类似的下调（P = 0.005）。IHC在蛋白水平上与mRNA结果显示出极好的一致性。在临床病理参数研究中，积液中IL-8 mRNA表达与较高的肿瘤分级相关（P = 0.044）。在生存分析中，积液中血管生成基因表达与患者年龄、既往治疗、残留肿瘤大小、FIGO分期或疾病转归均无相关性（P > 0.05）。腹膜和胸腔积液显示出相似的表达模式。总之，bFGF是卵巢癌在mRNA水平上表达的主要血管生成因子。它在实体瘤和浆液性积液中均高表达，而IL-8和VEGF在积液中的癌细胞中表达下调，可能是由于缺乏与基质细胞的相互作用。VEGF、bFGF和IL-8的mRNA表达似乎不是晚期卵巢癌疾病转归的预测指标。胸腔和腹膜积液中的癌细胞显示出相似的转移表达谱，与我们之前的研究结果一致，支持卵巢癌细胞在腹水中的真正转移性质。
