当前对小细胞肺癌（SCLC）的管理仍具有挑战性。需要有效的生物标志物来划分表现出不同治疗反应和临床结果的患者。对异质性的非整倍体CD31-循环肿瘤细胞（CTCs）和CD31+循环肿瘤内皮细胞（CTECs）的表型了解可能为SCLC的临床管理提供新的见解。在本次转化和前瞻性研究中，观察到在过表达干细胞特性标记物CD44v6的途径中，经过lentivirus感染的SCLC和非小细胞肺癌（NSCLC）细胞增加了与癌症转移相关的细胞增殖和运动性，同时伴随着上调的间质标记物vimentin和下调的上皮标记物E-cadherin。通过SE-iFISH在120例SCLC患者中纵向检测到CD44v6表达的非整倍体CTCs和CTECs。基线CD44v6+ CTCs和CD44v6+ CTECs的阳性检测与增强的肝转移显著相关。核型分析表明，在治疗后的患者中，CD44v6+ CTCs中的染色体8（Chr8）从三倍体8变为多倍性，与治疗前的患者相比。此外，在有限疾病（LD-SCLC）患者中，基线CD44v6+ CTCs的负担量（t0）或治疗期间（t1-2），基线CD31+ CTEC/CD31- CTC的比例（t0）以及CTC-WBC团簇（t0）与治疗反应和远处转移，特别是脑转移有关，但与广泛疾病（ED-SCLC）患者无关。多变量生存分析验证了纵向检测到的CD44v6+/CD31- CTCs是SCLC患者不良生存的独立预后因子。我们的研究首次提供了全面分析CTCs、CTECs及其相应的CD44v6+亚型的证据，能够对SCLC进行临床分层和预后预测，尤其是对于潜在可治愈的LD-SCLC。版权所有 © 2023 Elsevier B.V. 发布

Current management of small cell lung cancer (SCLC) remains challenging. Effective biomarkers are needed to subdivide patients presenting distinct treatment response and clinical outcomes. An understanding of heterogeneous phenotypes of aneuploid CD31- circulating tumor cells (CTCs) and CD31+ circulating tumor endothelial cells (CTECs) may provide novel insights in the clinical management of SCLC. In the present translational and prospective study, increased cancer metastasis-related cell proliferation and motility, accompanied with up-regulated mesenchymal marker vimentin but down-regulated epithelial marker E-cadherin, were observed in both lentivirus infected SCLC and NSCLC cells overexpressing the stemness marker CD44v6. Aneuploid CTCs and CTECs expressing CD44v6 were longitudinally detected by SE-iFISH in 120 SCLC patients. Positive detection of baseline CD44v6+ CTCs and CD44v6+ CTECs was significantly associated with enhanced hepatic metastasis. Karyotype analysis revealed that chromosome 8 (Chr8) in CD44v6+ CTCs shifted from trisomy 8 towards multiploidy in post-therapeutic patients compared to pre-treatment subjects. Furthermore, the burden of baseline CD44v6+ CTCs (t0) or amid the therapy (t1-2), the ratio of baseline CD31+ CTEC/CD31- CTC (t0), and CTC-WBC clusters (t0) were correlated with treatment response and distant metastases, particularly brain metastasis, in subjects with limited disease (LD-SCLC) but not in those with extensive disease (ED-SCLC). Multivariate survival analysis validated that longitudinally detected CD44v6+/CD31- CTCs was an independent prognostic factor for inferior survival in SCLC patients. Our study provides evidence for the first time that comprehensive analyses of CTCs, CTECs, and their respective CD44v6+ subtypes enable clinical stratification and improve prognostic prediction of SCLC, particularly for potentially curable LD-SCLC.Copyright © 2023. Published by Elsevier B.V.