Circulating tumor cells: indicators of cancer progression, plasticity and utility for therapies

Cancer is a deadly disease affecting millions of people worldwide. Circulating tumor cells (CTCs) represent a critical link between primary malignancies and metastasis, acting as key players in cancer dissemination, progression, and recurrence. Although rare, CTCs offer a valuable, non-invasive window into tumor biology and the evolution of disease in patients. CTCs can exist as single cells in the circulation, but some are shed and travel in larger groups, referred to as CTC clusters. These clusters possess a greater oncogenic potential compared to individual CTCs. In this review, we aim to provide insight into the dynamic biological processes underlying CTC generation, biology, and survival, with a focus on epithelial-to-mesenchymal transition (EMT) and beyond like cancer stem cells (CSCs), cellular plasticity, and senescence. A crucial aspect of CTC biology is EMT, a process that imparts cancer cells with increased motility, invasiveness, resistance to apoptosis, and the ability to intravasate and evade the immune system. Beyond EMT the cancer cells show further plasticity, allowing epithelial tumor cells to adopt mesenchymal or hybrid phenotypes, which enables adaptation to a changing microenvironment and enhances therapy resistance. Moreover, a subset of cancer cells can acquire stem cell-like properties, including self-renewal and tumor-initiating capacity. EMT, along with processes such as dedifferentiation, contributes to the generation of cancer stem cells. In recent years, studies have also highlighted the complex and paradoxical role of senescence in CTC biology. While senescence typically results in permanent cell cycle arrest, in cancer cells it may be reversible and can promote tumor cell dormancy, immune evasion, and metastatic reactivation. By exploring the connections between CTCs, EMT, CSCs, plasticity, and senescence, we aim to shed light on the unique biology of CTCs, their metastatic potential, and their contributions to tumor heterogeneity. We hope that a better understanding of these processes will help advance the development of novel biomarkers and therapeutic targets for solid tumors beyond EMT.