Beninato Teresa, Lo Russo Giuseppe, Leporati Rita, Roz Luca, Bertolini Giulia
Thoracic Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Unit of Epigenomics and Biomarkers of Solid Tumors, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Int Rev Cell Mol Biol. 2025;392:1-66. doi: 10.1016/bs.ircmb.2024.03.001. Epub 2024 Mar 19.
Circulating tumor cells (CTC), released by primary tumors into the bloodstream, represent a valuable source to inform on cancer heterogeneity, cancer progression, metastatic disease and therapy efficacy without the need of invasive tumor biopsies. However, the extreme rarity and heterogeneity of CTCs, occurring at genotypic, phenotypic and functional levels, poses a major challenge for the study of this population and explains the lack of standardized strategies of CTC isolation. Lung cancer, the leading causes of cancer-related death worldwide, is a paradigmatic example of how CTC heterogeneity can undermine the clinical utility of this biomarker, since contrasting data have been reported using different isolation technologies. Some evidences suggest that only a fraction of CTC, characterized by stem-like feature and partial epithelial-mesenchymal transition (EMT) phenotype, can sustain metastasis initiation. Cancer stem cells (CSCs) have the potential to maintain primary tumors, initiate metastasis and escape both chemotherapy and immunotherapy treatments. Moreover, a close connection has been reported in several tumor types among hybrid phenotype, characterized by retention of epithelial and mesenchymal traits, acquisition of CSC feature and increased metastatic potential. This review focuses on the phenotypic and functional heterogeneity of CTCs and the resulting implications for their isolation and clinical validation, especially in the setting of non-small cell lung cancer (NSCLC). In particular, we discuss the most relevant studies providing evidence for the presence and prognostic/predictive value of CTC subsets characterized by stem-like and hybrid EMT phenotype. Despite technical and conceptual issues, tracking circulating CSCs has the potential to improve the prognostic/predictive value of CTCs in NSCLC setting and could provide novel insights into the comprehension of the metastatic process and identification of novel therapeutic targets.
循环肿瘤细胞（CTC）由原发性肿瘤释放进入血液循环，是一个宝贵的信息来源，可用于了解癌症异质性、癌症进展、转移性疾病和治疗效果，而无需进行侵入性肿瘤活检。然而，CTC在基因型、表型和功能水平上极其罕见且具有异质性，这给该群体的研究带来了重大挑战，并解释了缺乏标准化CTC分离策略的原因。肺癌是全球癌症相关死亡的主要原因，是一个典型例子，说明CTC异质性如何破坏这种生物标志物的临床效用，因为使用不同分离技术报告的数据相互矛盾。一些证据表明，只有一小部分具有干细胞样特征和部分上皮-间质转化（EMT）表型的CTC能够维持转移起始。癌症干细胞（CSC）有潜力维持原发性肿瘤、启动转移并逃避化疗和免疫治疗。此外，在几种肿瘤类型中，已报道具有保留上皮和间质特征、获得CSC特征和增加转移潜力的混合表型之间存在密切联系。本综述重点关注CTC的表型和功能异质性及其对分离和临床验证的影响，特别是在非小细胞肺癌（NSCLC）的背景下。特别是，我们讨论了最相关的研究，这些研究为具有干细胞样和混合EMT表型的CTC亚群的存在及其预后/预测价值提供了证据。尽管存在技术和概念问题，但追踪循环CSC有可能提高NSCLC背景下CTC的预后/预测价值，并可能为理解转移过程和识别新的治疗靶点提供新的见解。
