1 Department of Physiology, University of Louisville , Louisville, Kentucky.
2 James Graham Brown Cancer Center, University of Louisville , Louisville, Kentucky.
Stem Cells Dev. 2017 Dec 15;26(24):1781-1803. doi: 10.1089/scd.2017.0153. Epub 2017 Nov 28.
Ovarian cancer is most lethal among gynecological cancers with often fatal consequences due to lack of effective biomarkers and relapse, which propels ovarian cancer research into unique directions to establish solid targeted therapeutics. "Ovarian stem cells" expressing germline pluripotent markers serve as novel paradigm with potential to address infertility, menopause, and probably influence tumor initiation. Cancer stem cells (CSCs) pose vital role in tumor recurrence and hence it is extremely important to study them with respect to ovarian stem cells across various cancer stages and normal ovaries. Pluripotent (OCT4, NANOG, SOX2, SSEA1, and SSEA4), germline (IFITM3, VASA/DDX4), and cancer stem (CD44, LGR5) cell specific markers were characterized for protein and mRNA expression in tumor tissues to understand their distribution in the surface epithelium and ovarian cortex in benign, borderline, and high-grade malignant stages. To elucidate whether pluripotent ovarian germline stem cells and CSCs are common subset of stem cells in tumor tissues, VASA was colocalized with known pluripotent stem (OCT4, SSEA1, SSEA4) and CSC (CD44, LGR5) specific markers by confocal microscopy. Single, smaller spherical (≤5 μm), and larger elliptical fibroblast like (≥10 μm) cells (also in clusters or multiples) were detected implying probable functional behavioral significance of cells in tumor initiation and metastasis across various cancer stages. Cells revealed characteristic staining pattern in ovarian surface epithelium (OSE) and cortex regions exclusive for each marker. Co-expression studies revealed specific subpopulations existing simultaneously in OSE and cortex and that a dynamic hierarchy of (cancer) stem cells with germline properties prevails in normal ovaries and cancer stages. Novel insights into CSC biology with respect to ovarian and germline stem cell perspective were obtained. Understanding molecular signatures and distribution within ovarian tissue may enable identification of precise tumor-initiating CSC populations and signaling pathways thus improving their efficient targeting and strategies to prevent their dissemination causing fatal relapse.
卵巢癌是妇科癌症中最致命的一种，由于缺乏有效的生物标志物和复发，其后果往往是致命的，这促使卵巢癌研究朝着建立坚实的靶向治疗的独特方向发展。表达生殖系多能标志物的“卵巢干细胞”为解决不孕、绝经以及可能影响肿瘤发生的问题提供了新的范例。癌症干细胞（CSC）在肿瘤复发中起着至关重要的作用，因此，研究不同癌症阶段和正常卵巢中的卵巢干细胞与 CSC 之间的关系非常重要。多能（OCT4、NANOG、SOX2、SSEA1 和 SSEA4）、生殖系（IFITM3、VASA/DDX4）和癌症干细胞（CD44、LGR5）细胞特异性标志物的蛋白和 mRNA 表达在肿瘤组织中进行了特征描述，以了解它们在良性、交界性和高级别恶性阶段的表面上皮和卵巢皮质中的分布。为了阐明多能卵巢生殖系干细胞和 CSC 是否是肿瘤组织中干细胞的共同亚群，通过共聚焦显微镜将 VASA 与已知的多能干细胞（OCT4、SSEA1、SSEA4）和 CSC（CD44、LGR5）特异性标志物共定位。检测到单个、较小的球形（≤5μm）和较大的椭圆形成纤维细胞样（≥10μm）细胞（也呈簇状或倍数增加），这表明细胞在肿瘤起始和转移过程中具有潜在的功能行为意义，跨越各种癌症阶段。细胞在卵巢表面上皮（OSE）和皮质区域显示出独特的染色模式，每个标志物都有其独特的染色模式。共表达研究揭示了 OSE 和皮质中同时存在的特定亚群，并且在正常卵巢和癌症阶段中存在具有生殖系特性的（癌症）干细胞的动态层次结构。从卵巢和生殖系干细胞的角度获得了对 CSC 生物学的新见解。了解卵巢组织内的分子特征和分布可能有助于识别精确的肿瘤起始 CSC 群体和信号通路，从而提高靶向治疗的效率，并制定策略防止其扩散，从而避免致命的复发。
