Jo Ala, Green Allen, Medina Jamie E, Iyer Sonia, Ohman Anders W, McCarthy Eric T, Reinhardt Ferenc, Gerton Thomas, Demehin Daniel, Mishra Ranjan, Kolin David L, Zheng Hui, Crum Christopher P, Weinberg Robert A, Rueda Bo R, Castro Cesar M, Dinulescu Daniela M, Lee Hahko
bioRxiv. 2023 Jan 20:2023.01.19.524549. doi: 10.1101/2023.01.19.524549.
Ovarian cancer is a heterogeneous group of tumors in both cell type and natural history. While outcomes are generally favorable when detected early, the most common subtype, high-grade serous carcinoma (HGSOC), typically presents at an advanced stage and portends less favorable prognoses. Its aggressive nature has thwarted early detection efforts through conventional detection methods such as serum CA125 and ultrasound screening and thus inspired the investigation of novel biomarkers. Here, we report the systematic development of an extracellular-vesicle (EV)-based test to detect early-stage HGSOC. Our study is based on emerging insights into HGSOC biology, notably that it arises from precursor lesions within the fallopian tube before traveling to ovarian and/or peritoneal surfaces. To identify HGSOC marker candidates, we established murine fallopian tube (mFT) cells with oncogenic mutations in , and genes, and performed proteomic analyses on mFT EVs. The identified markers were then evaluated with an orthotopic HGSOC animal model. In serially-drawn blood samples of tumor-bearing mice, mFT-EV markers increased with tumor initiation, supporting their potential use in early cancer detection. A pilot human clinical study ( = 51) further narrowed EV markers to five candidates, EpCAM, CD24, VCAN, HE4, and TNC. Combined expression of these markers achieved high OvCa diagnostic accuracy (cancer vs. non-cancer) with a sensitivity of 0.89 and specificity of 0.93. The same five markers were also effective in a three-group classification: non-cancer, early-stage (I & II) HGSOC, and late-stage (III & IV) HGSOC. In particular, they differentiated early-stage HGSOC from the rest with a specificity of 0.91. Minimally invasive and repeatable, this EV-based testing could be a versatile and serial tool for informing patient care and monitoring women at high risk for ovarian cancer.
卵巢癌在细胞类型和自然病史方面都是一组异质性肿瘤。虽然早期发现时预后通常较好，但最常见的亚型，即高级别浆液性癌（HGSOC），通常在晚期出现，预后较差。其侵袭性使得通过血清CA125和超声筛查等传统检测方法进行早期检测的努力受挫，因此激发了对新型生物标志物的研究。在此，我们报告了一种基于细胞外囊泡（EV）检测早期HGSOC的系统开发。我们的研究基于对HGSOC生物学的新见解，特别是它起源于输卵管内的前体病变，然后转移到卵巢和/或腹膜表面。为了确定HGSOC标志物候选物，我们建立了在 、 和 基因中具有致癌突变的小鼠输卵管（mFT）细胞，并对mFT EV进行了蛋白质组学分析。然后用原位HGSOC动物模型评估所鉴定的标志物。在荷瘤小鼠的系列采血样本中，mFT-EV标志物随着肿瘤的发生而增加，支持它们在早期癌症检测中的潜在用途。一项初步的人类临床研究（ = 51）进一步将EV标志物缩小到五个候选物，即上皮细胞黏附分子（EpCAM）、CD24、多功能蛋白聚糖（VCAN）、人附睾蛋白4（HE4）和腱生蛋白C（TNC）。这些标志物的联合表达实现了高的卵巢癌诊断准确性（癌症与非癌症），敏感性为0.89，特异性为0.93。相同的五个标志物在三组分类中也有效：非癌症、早期（I和II期）HGSOC和晚期（III和IV期）HGSOC。特别是，它们以0.91的特异性将早期HGSOC与其他类型区分开来。这种基于EV的检测微创且可重复，可能是一种通用的系列工具，用于指导患者护理和监测卵巢癌高危女性。
