Castellvi Josep, Garcia Angel, Rojo Federico, Ruiz-Marcellan Carmen, Gil Antonio, Baselga Jose, Ramon y Cajal Santiago
Department of Pathology, Vall d'Hebron University Hospital, Barcelona, Spain.
Cancer. 2006 Oct 15;107(8):1801-11. doi: 10.1002/cncr.22195.
Growth factor receptors and cell signaling factors play a crucial role in human carcinomas and have been studied in ovarian tumors with varying results. Cell signaling involves multiple pathways and a myriad of factors that can be mutated or amplified. Cell signaling is driven through the mammalian target of rapamycin (mTOR) and extracellular regulated kinase (ERK) pathways and by some downstream molecules, such as 4E binding protein 1 (4EBP1), eukaryotic initiation factor 4E, and p70 ribosomal protein S6 kinase (p70S6K). The objectives of this study were to analyze the real role that these pathways play in ovarian cancer, to correlate them with clinicopathologic characteristics, and to identify the factors that transmit individual proliferation signals and are associated with pathologic grade and prognosis, regardless specific oncogenic alterations upstream.
One hundred twenty-nine ovarian epithelial tumors were studied, including 20 serous cystadenomas, 7 mucinous cystadenomas, 11 serous borderline tumors, 16 mucinous borderline tumors, 29 serous carcinomas, 16 endometrioid carcinomas, 15 clear cell carcinomas, and 15 mucinous carcinomas. Tissue microarrays were constructed, and immunohistochemistry for the receptors epidermal growth factor receptor (EGFR) and c-erb-B2 was performed and with phosphorylated antibodies for protein kinase B (AKT), 4EBP1, p70S6K, S6, and ERK.
Among 129 ovarian neoplasms, 17.8% were positive for c-erb-B2, 9.3% were positive for EGFR, 47.3% were positive for phosphorylated AKT (p-AKT), 58.9% were positive for p-ERK, 41.1% were positive for p-4EBP1, 26.4% were positive for p70S6K, and 15.5% were positive for p-S6. Although EGFR, p-AKT, and p-ERK expression did not differ between benign, borderline, or malignant tumors, c-erb-B2, p-4EBP1, p-p70S6K, and p-S6 were expressed significantly more often in malignant tumors. Only p-4EBP1 expression demonstrated prognostic significance (P = .005), and only surgical stage and p-4EBP1 expression had statistical significance in the multivariate analysis.
In patients with ovarian carcinoma, significant expression of p-4EBP1 was associated with high-grade tumors and a poor prognosis, regardless other oncogenic alterations upstream. This finding supports the study of this factor as a hallmark or pivotal factor in cell signaling in ovarian carcinoma that may crucial in the transmission of the proliferation cell signal and may reflect the real oncogenic role of this pathway in ovarian tumors.
生长因子受体和细胞信号传导因子在人类癌症中起着至关重要的作用，并且已在卵巢肿瘤中进行了研究，但结果各异。细胞信号传导涉及多个途径以及大量可能发生突变或扩增的因子。细胞信号传导是通过雷帕霉素哺乳动物靶点（mTOR）和细胞外调节激酶（ERK）途径以及一些下游分子驱动的，如4E结合蛋白1（4EBP1）、真核起始因子4E和p70核糖体蛋白S6激酶（p70S6K）。本研究的目的是分析这些途径在卵巢癌中所起的实际作用，将它们与临床病理特征相关联，并确定传递个体增殖信号且与病理分级和预后相关的因子，而不考虑上游特定的致癌改变。
对129例卵巢上皮性肿瘤进行了研究，包括20例浆液性囊腺瘤、7例黏液性囊腺瘤、11例浆液性交界性肿瘤、16例黏液性交界性肿瘤、29例浆液性癌、16例子宫内膜样癌、15例透明细胞癌和15例黏液性癌。构建了组织微阵列，并对表皮生长因子受体（EGFR）和c-erb-B2受体进行了免疫组织化学检测，同时使用了针对蛋白激酶B（AKT）、4EBP1、p70S6K、S6和ERK的磷酸化抗体。
在129例卵巢肿瘤中，17.8%的c-erb-B2呈阳性，9.3%的EGFR呈阳性，47.3%的磷酸化AKT（p-AKT）呈阳性，58.9%的p-ERK呈阳性，4
