Circulating tumor cells (CTCs) are regarded as harbingers of metastases. Their ability to predict response to therapy, relapse, and resistance to treatment has proposed their value as putative diagnostic and prognostic indicators. CTCs represent one of the zeniths of cancer evolution in terms of cell survival; however, the triggers of CTC generation, the identification of potentially metastatic CTCs, and the mechanisms contributing to their heterogeneity and aggressiveness represent issues not yet fully deciphered. Thus, prior to enabling liquid biopsy applications to reach clinical prime time, understanding how the above mechanistic information can be applied to improve treatment decisions is a key challenge. Here, we provide our perspective on how CTCs can provide mechanistic insights into tumor pathogenesis, as well as on CTC clinical value. In doing so, we aim to (a) describe how CTCs disseminate from the primary tumor, and their link to epithelial-mesenchymal transition (EMT); (b) trace the route of CTCs through the circulation, focusing on tumor self-seeding and the possibility of tertiary metastasis; (c) describe possible mechanisms underlying the enhanced metastatic potential of CTCs; (d) discuss how CTC could provide further information on the tissue of origin, especially in cancer of unknown primary origin. We also provide a comprehensive review of meta-analyses assessing the prognostic significance of CTCs, to highlight the emerging role of CTCs in clinical oncology. We also explore how cell-free circulating tumor DNA (ctDNA) analysis, using a combination of genomic and phylogenetic analysis, can offer insights into CTC biology, including our understanding of CTC heterogeneity and tumor evolution. Last, we discuss emerging technologies, such as high-throughput quantitative imaging, radiogenomics, machine learning approaches, and the emerging breath biopsy. These technologies could compliment CTC and ctDNA analyses, and they collectively represent major future steps in cancer detection, monitoring, and management.

中文翻译：

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循环肿瘤细胞作为理解、预防和治疗癌症的特洛伊木马：批判性评估。


循环肿瘤细胞（CTC）被认为是转移的先兆。它们预测治疗反应、复发和治疗耐药的能力表明它们作为假定的诊断和预后指标的价值。从细胞存活率来看，CTC 代表了癌症进化的顶峰之一；然而，CTC 产生的触发因素、潜在转移性 CTC 的识别以及导致其异质性和侵袭性的机制等问题尚未完全阐明。因此，在使液体活检应用进入临床黄金时期之前，了解如何应用上述机制信息来改进治疗决策是一个关键挑战。在这里，我们就 CTC 如何提供肿瘤发病机制的机制见解以及 CTC 的临床价值提供了我们的观点。在此过程中，我们的目标是 (a) 描述 CTC 如何从原发肿瘤中传播，以及它们与上皮间质转化 (EMT) 的联系； (b) 追踪CTC在循环中的路径，重点关注肿瘤自身播种和三级转移的可能性； (c) 描述 CTC 增强转移潜力的可能机制； (d) 讨论 CTC 如何提供有关起源组织的进一步信息，尤其是原发起源不明的癌症。我们还对评估 CTC 预后意义的荟萃分析进行了全面综述，以强调 CTC 在临床肿瘤学中的新兴作用。我们还探索结合基因组和系统发育分析的无细胞循环肿瘤 DNA (ctDNA) 分析如何提供对 CTC 生物学的见解，包括我们对 CTC 异质性和肿瘤进化的理解。 最后，我们讨论新兴技术，例如高通量定量成像、放射基因组学、机器学习方法和新兴的呼吸活检。这些技术可以补充 CTC 和 ctDNA 分析，它们共同代表了未来癌症检测、监测和管理的主要步骤。