Abstract：
Intrabdominal dissemination of malignant mesothelioma (MM) and pseudomyxoma peritonei (PMP) is poorly characterized with respect to the stemness window which malignant cells activate during their reshaping on the epithelial-mesenchymal (E/M) axis. To gain insights into stemness properties and their prognostic significance in these rarer forms of peritoneal metastases (PM), primary tumor cultures from 55 patients selected for cytoreductive surgery with hyperthermic intraperitoneal chemotherapy were analyzed for cancer stem cells (CSC) by aldehyde dehydrogenase 1 (ALDH1) and spheroid formation assays, and for expression of a set of plasticity-related genes to measure E/M transition (EMT) score. Intratumor heterogeneity was also analyzed. Samples from PM of colorectal cancer were included for comparison. Molecular data were confirmed using principal component and cluster analyses. Associations with survival were evaluated using Kaplan-Meier and Cox regression models. The activity of acetylsalicylic acid (ASA), a stemness modifier, was tested in five cultures. Significantly increased amounts of ALDH1bright-cells identified high-grade PMP, and discriminated solid masses from ascitic/mucin-embedded tumor cells in both forms of PM. Epithelial/early hybrid EMT scores and an early hybrid expression pattern correlated with pluripotency factors were significantly associated with early peritoneal progression (p = .0343 and p = .0339, respectively, log-rank test) in multivariable models. ASA impaired spheroid formation and increased cisplatin sensitivity in all five cultures. These data suggest that CSC subpopulations and hybrid E/M states may guide peritoneal spread of MM and PMP. Stemness could be exploited as targetable vulnerability to increase chemosensitivity and improve patient outcomes. Additional research is needed to confirm these preliminary data.
摘要：
恶性间皮瘤（MM）和腹膜假性黏液瘤（PMP）的腹腔内播散，在恶性细胞在上皮-间质（E/M）轴上重塑过程中激活的干性窗口方面特征不佳。为了深入了解这些罕见形式的腹膜转移（PM）的干性特性及其预后意义，通过醛脱氢酶1（ALDH1）和球体形成测定法分析了55例接受细胞减灭术和腹腔热化疗的患者的原发性肿瘤培养物的癌症干细胞（CSC）。和一组可塑性相关基因的表达来测量E/M转换（EMT）评分。还分析了瘤内异质性。包括来自结肠直肠癌PM的样品用于比较。使用主成分和聚类分析确认分子数据。使用Kaplan-Meier和Cox回归模型评估与生存的关联。乙酰水杨酸（ASA）的活性，一个stemness修饰符，在五种文化中进行了测试。ALDH1bright-cells鉴定的高级PMP的数量显著增加，并将两种形式的PM中的实体团块与腹水/粘蛋白包埋的肿瘤细胞区分开。上皮/早期混合EMT评分和与多能性因子相关的早期混合表达模式与早期腹膜进展显着相关（分别为p=.0343和p=.0339，对数秩检验)在多变量模型中。ASA在所有五种培养物中都损害了球状体的形成并增加了顺铂的敏感性。这些数据表明CSC亚群和混合E/M状态可能指导MM和PMP的腹膜扩散。Stemness可以被利用作为增加化学敏感性和改善患者预后的目标脆弱性。需要进一步的研究来证实这些初步数据。
