Annunziata Christina M, Kleinberg Lilach, Davidson Ben, Berner Aasmund, Gius David, Tchabo Nana, Steinberg Seth M, Kohn Elise C
Medical Oncology Branch,Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892, USA.
Clin Cancer Res. 2007 Nov 15;13(22 Pt 1):6585-92. doi: 10.1158/1078-0432.CCR-07-0327.
We hypothesized that elevated expression in ovarian cancer of the BAG family of prosurvival proteins and associated partners would be associated with clinical features of aggressiveness in ovarian cancer.
Expression patterns of BAG-1, BAG-3, BAG-4, and Bcl-xL were determined by immunohistochemical analysis of tissue samples obtained at diagnosis from 28 women with stage III or stage IV ovarian cancer treated with cisplatin, paclitaxel, and cyclophosphamide after initial cytoreduction. Association of these proteins, BAG-6, heat shock protein 70 (Hsp70), Hsp27, and Bcl-2, with clinical variables was tested in ovarian cancer tissue arrays from Gynecologic Oncology Group tissue bank.
A statistically significant relationship was found between elevated cytoplasmic expression of BAG-4 and improved overall (P = 0.0002) and progression-free survival (P = 0.003) in the prospectively collected samples. Bcl-2 staining was significantly more frequent on the tissue array in lower stage (P = 0.005) and grade (P = 0.0009) tumors, whereas Hsp70 was prominent in higher grade cases (P = 0.002). Furthermore, Bcl-xL was more closely associated with serous compared with endometrioid ovarian cancers (P = 0.004).
Unexpectedly, cytoplasmic expression of BAG-4 and Bcl-2 marked less aggressive ovarian cancer, whereas nuclear Hsp70 suggested more aggressive behavior. Bcl-xL may play a more prominent function in the pathology of serous histology ovarian cancers compared with the endometrioid subtype. The findings presented here support involvement of these proteins in the propagation of ovarian cancer and provide a basis for the development of molecular therapeutics modulating these survival pathways.
我们推测，促生存蛋白BAG家族及其相关伴侣在卵巢癌中的高表达与卵巢癌的侵袭性临床特征相关。
通过免疫组织化学分析对28例III期或IV期卵巢癌患者诊断时获取的组织样本进行检测，这些患者在初次细胞减灭术后接受顺铂、紫杉醇和环磷酰胺治疗，以确定BAG-1、BAG-3、BAG-4和Bcl-xL的表达模式。在妇科肿瘤学组组织库的卵巢癌组织芯片中检测这些蛋白（BAG-6、热休克蛋白70（Hsp70）、Hsp27和Bcl-2）与临床变量的相关性。
在前瞻性收集的样本中，发现BAG-4细胞质表达升高与总体生存率提高（P = 0.0002）和无进展生存率提高（P = 0.003）之间存在统计学显著关系。在组织芯片上，较低分期（P = 0.005）和较低分级（P = 0.0009）的肿瘤中Bcl-2染色明显更频繁，而Hsp70在较高分级的病例中更突出（P = 0.002）。此外，与子宫内膜样卵巢癌相比，Bcl-xL与浆液性卵巢癌的相关性更强（P = 0.004）。
出乎意料的是，BAG-4和Bcl-2的细胞质表达表明卵巢癌侵袭性较低，而细胞核Hsp70表明侵袭性更强。与子宫内膜样亚型相比，Bcl-xL可能在浆液性组织学卵巢癌的病理过程中发挥更突出的作用。此处呈现的研究结果支持这些蛋白参与卵巢癌的增殖，并为开发调节这些生存途径的分子疗法提供了基础。
