Research Center for Cancer, Infections and Immunity, Institute of Biomedicine, University of Turku, Turku, Finland.
Integrated Cardio Metabolic Centre (ICMC), Department of Medicine, Karolinska Institutet, Huddinge, Sweden.
J Pathol. 2020 Feb;250(2):159-169. doi: 10.1002/path.5356. Epub 2019 Dec 3.
Poor chemotherapy response remains a major treatment challenge for high-grade serous ovarian cancer (HGSC). Cancer stem cells are the major contributors to relapse and treatment failure as they can survive conventional therapy. Our objectives were to characterise stemness features in primary patient-derived cell lines, correlate stemness markers with clinical outcome and test the response of our cells to both conventional and exploratory drugs. Tissue and ascites samples, treatment-naive and/or after neoadjuvant chemotherapy, were prospectively collected. Primary cancer cells, cultured under conditions favouring either adherent or spheroid growth, were tested for stemness markers; the same markers were analysed in tissue and correlated with chemotherapy response and survival. Drug sensitivity and resistance testing was performed with 306 oncology compounds. Spheroid growth condition HGSC cells showed increased stemness marker expression (including aldehyde dehydrogenase isoform I; ALDH1A1) as compared with adherent growth condition cells, and increased resistance to platinum and taxane. A set of eight stemness markers separated treatment-naive tumours into two clusters and identified a distinct subgroup of HGSC with enriched stemness features. Expression of ALDH1A1, but not most other stemness markers, was increased after neoadjuvant chemotherapy and its expression in treatment-naive tumours correlated with chemoresistance and reduced survival. In drug sensitivity and resistance testing, five compounds, including two PI3K-mTOR inhibitors, demonstrated significant activity in both cell culture conditions. Thirteen compounds, including EGFR, PI3K-mTOR and aurora kinase inhibitors, were more toxic to spheroid cells than adherent cells. Our results identify stemness markers in HGSC that are associated with a decreased response to conventional chemotherapy and reduced survival if expressed by treatment-naive tumours. EGFR, mTOR-PI3K and aurora kinase inhibitors are candidates for targeting this cell population. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
化疗反应差仍然是高级别浆液性卵巢癌（HGSC）的主要治疗挑战。癌症干细胞是导致复发和治疗失败的主要原因，因为它们可以耐受常规治疗。我们的目标是在原发性患者来源的细胞系中描述干性特征，将干性标志物与临床结果相关联，并测试我们的细胞对常规和探索性药物的反应。前瞻性地收集了组织和腹水样本，包括治疗前和/或新辅助化疗后的样本。在有利于贴壁或球体生长的条件下培养原发性癌细胞，测试干性标志物；分析组织中的相同标志物，并与化疗反应和生存相关联。使用 306 种肿瘤化合物进行药物敏感性和耐药性检测。与贴壁生长条件下的细胞相比，球体生长条件下的 HGSC 细胞显示出更高的干性标志物表达（包括醛脱氢酶同工酶 I；ALDH1A1），并且对铂类和紫杉烷类药物的耐药性增加。一组 8 个干性标志物将治疗前的肿瘤分为两个簇，并鉴定出具有丰富干性特征的 HGSC 亚群。ALDH1A1 的表达（而非大多数其他干性标志物）在新辅助化疗后增加，其在治疗前肿瘤中的表达与化疗耐药性和降低的生存相关联。在药物敏感性和耐药性检测中，五种化合物，包括两种 PI3K-mTOR 抑制剂，在细胞培养条件下均显示出显著的活性。13 种化合物，包括 EGFR、PI3K-mTOR 和 Aurora 激酶抑制剂，对球体细胞的毒性比对贴壁细胞更大。我们的结果确定了与常规化疗反应降低和治疗前肿瘤表达时生存降低相关的 HGSC 干性标志物。EGFR、mTOR-PI3K 和 Aurora 激酶抑制剂是针对该细胞群体的候选药物。©2019 英国和爱尔兰病理学会。由 John Wiley & Sons，Ltd. 出版。
