Zanotti Laura, Romani Chiara, Tassone Laura, Todeschini Paola, Tassi Renata Alessandra, Bandiera Elisabetta, Damia Giovanna, Ricci Francesca, Ardighieri Laura, Calza Stefano, Marchini Sergio, Beltrame Luca, Tognon Germana, D'Incalci Maurizio, Pecorelli Sergio, Sartori Enrico, Odicino Franco, Ravaggi Antonella, Bignotti Eliana
"Angelo Nocivelli" Institute of Molecular Medicine, Division of Obstetrics and Gynecology, University of Brescia, P.le Spedali Civili 1, 25123, Brescia, Italy.
Department of Oncology, IRCCS, "Mario Negri" Institute for Pharmacological Research, Milan, Italy.
BMC Cancer. 2017 May 25;17(1):366. doi: 10.1186/s12885-017-3334-1.
The existence of cancer stem cells (CSCs) within a tumor bulk has been demonstrated for many solid tumors including epithelial ovarian carcinoma (EOC). CSCs have been associated to tumor invasion, metastasis and development of chemoresistant recurrences. In this context, we aim to characterize EOC CSCs from the molecular point of view in order to identify potential biomarkers associated with chemoresistance.
We isolated a population of cells with stem-like characteristics (OVA-BS4 spheroids) from a primary human EOC cell line under selective conditions. OVA-BS4 spheroids were characterized for drug response by cytotoxicity assays and their molecular profile was investigated by microarray and RT-qPCR. Finally, we performed a gene expression study in a cohort of 74 high-grade serous EOC (HGSOC) patients by RT-qPCR.
Spheroids exhibited properties of self-renewal and a pronounced expression of well-known stem cell genes. Moreover, they demonstrated greater resistance towards several anticancer drugs compared to parent cell line, consistent with their higher ABCG2 gene expression. From microarray studies MAL (T-cell differentiation protein) emerged as the most up-regulated gene in spheroids, compared to parent cell line. In HGSOC patients, MAL was significantly overexpressed in platinum-resistant compared to platinum-sensitive patients and resulted as an independent prognostic marker of survival.
This investigation provides an important contribution to the identification of molecular markers of ovarian CSCs and chemoresistance. Successful translation of molecular findings would lead to a better comprehension of the mechanisms triggering chemoresistant recurrences, to the individuation of novel therapeutic targets and to the personalization of treatment regimens.
肿瘤组织中癌症干细胞（CSCs）的存在已在包括上皮性卵巢癌（EOC）在内的多种实体瘤中得到证实。癌症干细胞与肿瘤侵袭、转移及化疗耐药复发的发生有关。在此背景下，我们旨在从分子角度对EOC癌症干细胞进行表征，以识别与化疗耐药相关的潜在生物标志物。
我们在选择性条件下从原发性人EOC细胞系中分离出具有干细胞样特征的细胞群体（OVA-BS4球体）。通过细胞毒性试验对OVA-BS4球体的药物反应进行表征，并通过微阵列和RT-qPCR研究其分子谱。最后，我们通过RT-qPCR对74例高级别浆液性EOC（HGSOC）患者队列进行了基因表达研究。
球体表现出自我更新特性以及众所周知的干细胞基因的显著表达。此外，与亲本细胞系相比，它们对几种抗癌药物表现出更强的耐药性，这与其较高的ABCG2基因表达一致。从微阵列研究中发现，与亲本细胞系相比，MAL（T细胞分化蛋白）是球体中上调最明显的基因。在HGSOC患者中，与铂敏感患者相比，MAL在铂耐药患者中显著过表达，并成为生存的独立预后标志物。
本研究为卵巢癌癌症干细胞和化疗耐药分子标志物的识别做出了重要贡献。分子研究结果的成功转化将有助于更好地理解引发化疗耐药复发的机制，确定新的治疗靶点，并实现治疗方案的个性化。
