Davidson Ben, Goldberg Iris, Gotlieb Walter H, Kopolovic Juri, Risberg Bjørn, Ben-Baruch Gilad, Reich Reuven
Department of Pathology, The Norwegian Radium Hospital, Montebello N-0310 Oslo, affiliated with the University of Oslo, Norway.
Cancer Metastasis Rev. 2003 Mar;22(1):103-15. doi: 10.1023/a:1022272204045.
The events that mediate tumor progression in ovarian carcinoma are poorly understood to date. This review summarizes our results studying metastasis-associated molecules in advanced-stage ovarian carcinomas, details the co-expression of mRNA of these genes, and discusses their prognostic role. Fifty-five primary and metastatic FIGO stage III-IV ovarian carcinomas were analyzed for the expression of alpha v and beta1 integrin subunits, the matrix metalloproteinases MMP-2, MMP-9, and MT1-MMP, the MMP inhibitor TIMP-2, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), interleukin-8 (IL-8), PEA3 and Ets-1 using mRNA in situ hybridization. Tumor and adjacent stromal cell expression was scored. The association between integrin subunit expression and the expression of MMP, TIMP-2, angiogenic genes, PEA3 and Ets-1 was statistically analyzed. Alpha v integrin subunit mRNA expression in carcinoma cells showed significant association with that of MMP-2 and IL-8 in this cellular compartment, while the presence of beta1 integrin subunit mRNA showed similar association with that of PEA3, Ets-1, IL-8, bFGF and MMP-2. Expression of beta1 integrin subunit mRNA in stromal cells was associated with that of TIMP-2 and Ets-1 in this compartment. In addition, significant intercellular associations were found between alpha v integrin subunit mRNA expression in carcinoma cells and stromal cell expression of Ets-1, as well as between stromal cell expression of alpha v integrin subunit and labeling for IL-8 in carcinoma cells. The presence of beta1 integrin subunit mRNA in carcinoma cells showed a significant association with that of Ets-1, IL-8 and bFGF in stromal cells, while the presence of beta1 integrin subunit mRNA in stromal cells was associated with tumor PEA3 mRNA expression. To the best of our knowledge, this is the first evidence for coordinated autocrine and paracrine expression of members of these four families of metastasis-associated genes in human cancer. The results of this analysis support experimental data regarding cross-talk between carcinoma cells and peritumoral fibroblasts. They also suggest the existence of a putative activation sequence of metastatic genes, involving the beta1 (and possibly alpha v) integrin subunits, IL-8, PEA3, Ets-1 and MMP in ovarian carcinoma.
迄今为止，介导卵巢癌肿瘤进展的相关事件仍知之甚少。本综述总结了我们对晚期卵巢癌转移相关分子的研究结果，详细阐述了这些基因mRNA的共表达情况，并讨论了它们的预后作用。采用mRNA原位杂交技术，分析了55例国际妇产科联盟（FIGO）III-IV期原发性和转移性卵巢癌中αv和β1整合素亚基、基质金属蛋白酶MMP-2、MMP-9和MT1-MMP、MMP抑制剂TIMP-2、血管内皮生长因子（VEGF）、碱性成纤维细胞生长因子（bFGF）、白细胞介素-8（IL-8）、PEA3和Ets-1的表达情况。对肿瘤及相邻基质细胞的表达进行评分。对整合素亚基表达与MMP、TIMP-2、血管生成相关基因、PEA3和Ets-1表达之间的相关性进行统计学分析。癌细胞中αv整合素亚基mRNA表达与该细胞区室中MMP-2和IL-8的表达显著相关，而β1整合素亚基mRNA的存在与PEA3、Ets-1、IL-8、bFGF和MMP-2的表达有类似相关性。基质细胞中β1整合素亚基mRNA表达与该细胞区室中TIMP-2和Ets-1的表达相关。此外，还发现癌细胞中αv整合素亚基mRNA表达与基质细胞Ets-1表达之间，以及基质细胞αv整合素亚基表达与癌细胞中IL-8标记之间存在显著的细胞间相关性。癌细胞中β1整合素亚基mRNA的存在与基质细胞中Ets-1、IL-8和bFGF的表达显著相关，而基质细胞中β1整合素亚基mRNA的存在与肿瘤PEA3 mRNA表达相关。据我们所知，这是人类癌症中这四个转移相关基因家族成员自分泌和旁分泌协同表达的首个证据。该分析结果支持了关于癌细胞与肿瘤周围成纤维细胞之间相互作用的实验数据。它们还提示在卵巢癌中存在一个假定的转移基因激活序列，涉及β1（可能还有αv）整合素亚基、IL-8、PEA3、Ets-1和MMP。
