Auer Katharina, Bachmayr-Heyda Anna, Aust Stefanie, Sukhbaatar Nyamdelger, Reiner Agnes Teresa, Grimm Christoph, Horvat Reinhard, Zeillinger Robert, Pils Dietmar
Department of Obstetrics and Gynecology, Comprehensive Cancer Center (CCC), Medical University of Vienna and Ludwig Boltzmann Cluster Translational Oncology, Vienna, Austria.
Department of Pathology, Medical University of Vienna, Vienna, Austria.
Oncotarget. 2015 Jul 10;6(19):17261-75. doi: 10.18632/oncotarget.3746.
In this study we aimed to analyze the biological mechanisms underlying apparently different modes of peritoneal tumor spread in serous ovarian cancer: miliary (widespread, millet-like lesions) versus non-miliary (bigger, exophytically growing implants). Tumor tissues and ascites from 23 chemotherapy naive patients were analyzed by RNA-sequencing and flow cytometry. On the basis of differential gene expression between miliary and non-miliary, gene signatures were developed. A calculated tumor spread factor revealed a significant independent negative impact of miliary spread on overall survival (HR 3.77; CI95 1.14-12.39; p = 0.029) in an independent cohort of 165 serous ovarian cancer patients. Comparing previously published epithelial-mesenchymal transition (EMT) gene signatures, non-miliary spread correlated significantly with a reduced epithelial status. We conclude that serous ovarian cancer is a heterogeneous disease with distinct modes of peritoneal tumor spread, differing not only in clinical appearance, but also in molecular characteristics and outcome. EMT, peritoneal inflammation status, and therapeutic options are discussed.
More than half of serous epithelial ovarian cancer patients present with a newly described type of intraperitoneal tumor spread, associated with differences in the inflammation status, activated oncogenic pathways, lack of EMT, and thus reduced overall survival. Both, the diminished immune reaction and the enhanced epithelial and malignant characteristics of the tumor cells open new avenues for therapeutic options and strategies, like Catumaxomab, already in clinical use.
在本研究中，我们旨在分析浆液性卵巢癌中腹膜肿瘤扩散的两种明显不同模式背后的生物学机制：粟粒样（广泛的、粟粒样病变）与非粟粒样（更大的、外生性生长的种植灶）。对23例未经化疗的患者的肿瘤组织和腹水进行了RNA测序和流式细胞术分析。基于粟粒样和非粟粒样之间的差异基因表达，开发了基因特征。在一个由165例浆液性卵巢癌患者组成的独立队列中，计算得出的肿瘤扩散因子显示粟粒样扩散对总生存期有显著的独立负面影响（HR 3.77；CI95 1.14 - 12.39；p = 0.029）。比较先前发表的上皮 - 间质转化（EMT）基因特征，非粟粒样扩散与上皮状态降低显著相关。我们得出结论，浆液性卵巢癌是一种异质性疾病，具有不同的腹膜肿瘤扩散模式，不仅在临床表现上不同，而且在分子特征和预后方面也不同。讨论了EMT、腹膜炎症状态和治疗选择。
超过一半的浆液性上皮性卵巢癌患者呈现一种新描述的腹膜内肿瘤扩散类型，与炎症状态、激活的致癌途径、EMT缺失的差异相关，因此总生存期降低。肿瘤细胞免疫反应减弱以及上皮和恶性特征增强，都为治疗选择和策略开辟了新途径，如已在临床使用的卡妥索单抗。
