Brückner Luzie, Reinshagen Annika, Hoang Ngoc Anh, Höhn Anne Kathrin, Lordick Florian, Bechmann Ingo, Aktas Bahriye, Nel Ivonne, Kallendrusch Sonja
Institute of Anatomy, University of Leipzig, Liebigstr. 13, 04103 Leipzig, Germany.
Department of Gynecology, University of Leipzig Medical Center, Liebigstr. 20a, 04103 Leipzig, Germany.
Cancers (Basel). 2021 Feb 25;13(5):956. doi: 10.3390/cancers13050956.
Diagnosis in an advanced state is a major hallmark of ovarian cancer and recurrence after first line treatment is common. With upcoming novel therapies, tumor markers that support patient stratification are urgently needed to prevent ineffective therapy. Therefore, the transcription factor FOXM1 is a promising target in ovarian cancer as it is frequently overexpressed and associated with poor prognosis. In this study, fresh tissue specimens of 10 ovarian cancers were collected to investigate tissue cultures in their ability to predict individual treatment susceptibility and to identify the benefit of FOXM1 inhibition. FOXM1 inhibition was induced by thiostrepton (3 µM). Carboplatin (0.2, 2 and 20 µM) and olaparib (10 µM) were applied and tumor susceptibility was analyzed by tumor cell proliferation and apoptosis in immunofluorescence microscopy. Resistance mechanisms were investigated by determining the gene expression of FOXM1 and its targets BRCA1/2 and RAD51. Ovarian cancer tissue was successfully maintained for up to 14 days ex vivo, preserving morphological characteristics of the native specimen. Thiostrepton downregulated FOXM1 expression in tissue culture. Individual responses were observed after combined treatment with carboplatin or olaparib. Thus, we successfully implemented a complex tissue culture model to ovarian cancer and showed potential benefit of combined FOXM1 inhibition.
晚期诊断是卵巢癌的一个主要特征，一线治疗后复发很常见。随着新型疗法的出现，迫切需要能够支持患者分层的肿瘤标志物以防止无效治疗。因此，转录因子FOXM1是卵巢癌中一个有前景的靶点，因为它经常过度表达且与预后不良相关。在本研究中，收集了10例卵巢癌的新鲜组织标本，以研究组织培养预测个体治疗敏感性的能力，并确定FOXM1抑制的益处。用硫链丝菌素（3 μM）诱导FOXM1抑制。应用卡铂（0.2、2和20 μM）和奥拉帕利（10 μM），并通过免疫荧光显微镜下的肿瘤细胞增殖和凋亡分析肿瘤敏感性。通过测定FOXM1及其靶点BRCA1/2和RAD51的基因表达来研究耐药机制。卵巢癌组织在体外成功维持长达14天，保留了天然标本的形态特征。硫链丝菌素在组织培养中下调了FOXM1表达。联合使用卡铂或奥拉帕利治疗后观察到个体反应。因此，我们成功地为卵巢癌建立了一个复杂的组织培养模型，并显示了联合抑制FOXM1的潜在益处。
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