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Background: Metastasis is the leading cause of cancer-related deaths. Most studies have focused on the primary tumor or on overt metastatic lesions, leaving a significant knowledge gap concerning blood-borne cancer cell dissemination, a major step in the metastatic cascade. Circulating tumor cells (CTCs) in the blood of patients with solid cancer can now be enumerated and investigated at the molecular level, giving unexpected information on the biology of the metastatic cascade., Content: Here, we reviewed recent advances in basic and translational/clinical research on CTCs as key elements in the metastatic cascade., Summary: Findings from translational studies on CTCs have elucidated the complexity of the metastatic process. Fully understanding this process will open new potential avenues for cancer therapeutic and diagnostic strategies to propose precision medicine to all cancer patients., (© Association for Diagnostics & Laboratory Medicine 2024. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Circulating tumour cells (CTCs), circulating tumour DNA (ctDNA), and extracellular vesicles (EVs) are minimally invasive liquid biopsy biomarkers. This study investigated whether they predict prognosis, alone or in combination, in heterogenous unbiased non-small cell lung cancer (NSCLC) patients., Methods: Plasma samples of 54 advanced NSCLC patients from a prospective clinical trial. CtDNA mutations were identified using the UltraSEEK™ Lung Panel (MassARRAY® technology). PD-L1 expression was assessed in small EVs (sEVs) using an enzyme-linked immunosorbent assay., Results: At least one ctDNA mutation was detected in 37% of patients. Mutations were not correlated with overall survival (OS) (HR = 1.1, 95% CI = 0.55; 1.83, P = 0.980) and progression-free survival (PFS) (HR = 1.00, 95% CI = 0.57-1.76, P = 0.991). High PD-L1 + sEV concentration was correlated with OS (HR = 1.14, 95% CI = 1.03-1.26, P = 0.016), but not with PFS (HR = 1.08, 95% CI = 0.99-1.18, P = 0.095). The interaction analysis suggested that PD-L1 + sEV correlation with PFS changed in function of CTC presence/absence (P interaction = 0.036). The combination analysis highlighted worse prognosis for patients with CTCs and high PD-L1 + sEV concentration (HR = 7.65, 95% CI = 3.11-18.83, P < 0.001). The mutational statuses of ctDNA and tumour tissue were significantly correlated (P = 0.0001)., Conclusion: CTCs and high PD-L1 + sEV concentration correlated with PFS and OS, but not ctDNA mutations. Their combined analysis may help to identify patients with worse OS., Trial Registration: NCT02866149, Registered 01 June 2015, https://clinicaltrials.gov/ct2/show/study/NCT02866149 ., (© 2023. The Author(s).)

Background: Platelets are active players in hemostasis, coagulation and also tumorigenesis. The cross-talk between platelets and circulating tumor cells (CTCs) may have various pro-cancer effects, including promoting tumor growth, epithelial-mesenchymal transition (EMT), metastatic cell survival, adhesion, arrest and also pre-metastatic niche and metastasis formation . Interaction with CTCs might alter the platelet transcriptome. However, as CTCs are rare events, the cross-talk between CTCs and platelets is poorly understood. Here, we used our established colon CTC lines to investigate the colon CTC-platelet cross-talk in vitro and its impact on the behavior/phenotype of both cell types. Methods: We exposed platelets isolated from healthy donors to thrombin (positive control) or to conditioned medium from three CTC lines from one patient with colon cancer and then we monitored the morphological and protein expression changes by microscopy and flow cytometry. We then analyzed the transcriptome by RNA-sequencing of platelets indirectly (presence of a Transwell insert) co-cultured with the three CTC lines. We also quantified by reverse transcription-quantitative PCR the expression of genes related to EMT and cancer development in CTCs after direct co-culture (no Transwell insert) with platelets. Results: We observed morphological and transcriptomic changes in platelets upon exposure to CTC conditioned medium and indirect co-culture (secretome). Moreover, the expression levels of genes involved in EMT ( p < 0.05) were decreased in CTCs co-cultured with platelets, but not of genes encoding mesenchymal markers ( FN1 and SNAI2 ). The expression levels of genes involved in cancer invasiveness ( MYC, VEGFB, IL33, PTGS2 , and PTGER2 ) were increased. Conclusion: For the first time, we studied the CTC-platelet cross-talk using our unique colon CTC lines. Incubation with CTC conditioned medium led to platelet aggregation and activation, supporting the hypothesis that their interaction may contribute to preserve CTC integrity during their journey in the bloodstream. Moreover, co-culture with platelets influenced the expression of several genes involved in invasiveness and EMT maintenance in CTCs., Competing Interests: CA-P is one of the patent holders (United States Patent Number 16,093,934) for detecting and/or characterizing circulating tumor cells. She received honoraria from Menarini&#169. MB and TW are inventors on relevant patent applications (PCT/NL 2011/050518 and PCT/NL 2018/050110). TW received financial compensation from Illumina, Inc. and is shareholder of GRAIL, Inc. DK-L is shareholder of ExBiome B. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Eslami-S, Cortés-Hernández, Glogovitis, Antunes-Ferreira, D’Ambrosi, Kurma, Garima, Cayrefourcq, Best, Koppers-Lalic, Wurdinger and Alix-Panabières.)

Metastasis formation is the main cause of cancer-related death in patients with solid tumours. At the beginning of this process, cancer cells escape from the primary tumour to the blood circulation where they become circulating tumour cells (CTCs). Only a small subgroup of CTCs will survive during the harsh journey in the blood and colonise distant sites. The in-depth analysis of these metastasis-competent CTCs is very challenging because of their extremely low concentration in peripheral blood. So far, only few groups managed to expand in vitro and in vivo CTCs to be used as models for large-scale descriptive and functional analyses of CTCs. These models have shown already the high variability and complexity of the metastatic cascade in patients with cancer, and open a new avenue for the development of new diagnostic and therapeutic approaches., (© 2022. The Author(s).)

In cancer, many analytes can be investigated through liquid biopsy. They play fundamental roles in the biological mechanisms underpinning the metastatic cascade and provide clinical information that can be monitored in real time during the natural course of cancer. Some of these analytes (circulating tumor cells and extracellular vesicles) share a key feature: the presence of a phospholipid membrane that includes proteins, lipids and possibly nucleic acids. Most cell-to-cell and cell-to-matrix interactions are modulated by the cell membrane composition. To understand cancer progression, it is essential to describe how proteins, lipids and nucleic acids in the membrane influence these interactions in cancer cells. Therefore, assessing such interactions and the phospholipid membrane composition in different liquid biopsy analytes might be important for future diagnostic and therapeutic strategies. In this review, we briefly describe some of the most important surface components of circulating tumor cells and extracellular vesicles as well as their interactions, putting an emphasis on how they are involved in the different steps of the metastatic cascade and how they can be exploited by the different liquid biopsy technologies., Competing Interests: Catherine Alix-Panabières is one of the patent holders (US Patent Number 16,093,934) for detecting and/or characterizing circulating tumor cells. She received an honorarium from Menarini. The remaining authors declare no conflict of interest.

The recent development of sophisticated techniques capable of detecting extremely low concentrations of circulating tumor biomarkers in accessible body fluids, such as blood or urine, could contribute to a paradigm shift in cancer diagnosis and treatment. By applying such techniques, clinicians can carry out liquid biopsies, providing information on tumor presence, evolution, and response to therapy. The implementation of biosensing platforms for liquid biopsies is particularly complex because this application domain demands high selectivity/specificity and challenging limit-of-detection (LoD) values. The interest in photonics as an enabling technology for liquid biopsies is growing owing to the well-known advantages of photonic biosensors over competing technologies in terms of compactness, immunity to external disturbance, and ultra-high spatial resolution. Some encouraging experimental results in the field of photonic devices and systems for liquid biopsy have already been achieved by using fluorescent labels and label-free techniques and by exploiting super-resolution microscopy, surface plasmon resonance, surface-enhanced Raman scattering, and whispering gallery mode resonators. This paper critically reviews the current state-of-the-art, starting from the requirements imposed by the detection of the most common circulating biomarkers. Open research challenges are considered together with competing technologies, and the most promising paths of improvement are discussed for future applications.

Biological rhythms regulate the biology of most, if not all living creatures, from whole organisms to their constitutive cells, their microbiota, and also parasites. Here, we present the hypothesis that internal and external ecological variations induced by biological cycles also influence or are exploited by cancer cells, especially by circulating tumor cells, the key players in the metastatic cascade. We then discuss the possible clinical implications of the effect of biological cycles on cancer progression, and how they could be exploited to improve and standardize methods used in the liquid biopsy field.

The long-term effects of cancer on patient quality of life and its economic burden are important issues that need to be addressed. Therefore, it is critical to assess patient priorities and investigate the value proposition of clinical tests in this field. The minimally invasive liquid biopsy has attracted much attention because it allows serial sampling during cancer progression, and provides valuable biological information on the tumor biology and treatment response through the analysis of analytes in the blood, such as circulating tumor cells (CTCs). To introduce CTC analysis in daily clinical practice, it is still necessary to firmly establish its clinical benefits and extra value for clinical decision-making. A laboratory medicine value proposition of CTC medical applications can help to address these issues. In this review, we discuss the current evidence for a value proposition of CTC detection, isolation, and characterization using the available technologies, and we summarize the unmet requirements for the full integration of CTCs in the care pathway., (© American Association for Clinical Chemistry 2020. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

In the last few decades, the epithelial cell adhesion molecule (EpCAM) has received increased attention as the main membrane marker used in many enrichment technologies to isolate circulating tumor cells (CTCs). Although there has been a great deal of progress in the implementation of EpCAM-based CTC detection technologies in medical settings, several issues continue to limit their clinical utility. The biology of EpCAM and its role are not completely understood but evidence suggests that the expression of this epithelial cell-surface protein is crucial for metastasis-competent CTCs and may not be lost completely during the epithelial-to-mesenchymal transition. In this review, we summarize the most significant advantages and disadvantages of using EpCAM as a marker for CTC enrichment and its potential biological role in the metastatic cascade.

The metastatic cascade describes the process whereby aggressive cancer cells leave the primary tumor, travel through the bloodstream, and eventually reach distant organs to develop one or several metastases. During the last decade, innovative technologies have exploited the recent biological knowledge to identify new circulating biomarkers for the screening and early detection of cancer, real-time monitoring of treatment response, assessment of tumor relapse risk (prognosis), identification of new therapeutic targets and resistance mechanisms, patient stratification, and therapeutic decision-making. These techniques are broadly described using the term of Liquid Biopsy . This field is in constant progression and is based on the detection of circulating tumor cells, circulating free nucleic acids (e.g., circulating tumor DNA), circulating tumor-derived extracellular vesicles, and tumor-educated platelets. The aim of this review is to describe the biological principles underlying the liquid biopsy concept and to discuss how functional studies can expand the clinical applications of these circulating biomarkers., (Copyright © 2020 Eslami-S, Cortés-Hernández and Alix-Panabières.)

The current limitations of cancer diagnosis and molecular profiling based on invasive tissue biopsies or clinical imaging have led to the development of the liquid biopsy field. Liquid biopsy includes the isolation of circulating tumor cells (CTCs), circulating free or tumor DNA (cfDNA or ctDNA), extracellular vesicles (EVs), and tumor-educated platelets (TEPs) from body fluid samples and their molecular characterization to identify biomarkers for early cancer diagnosis, prognosis, therapeutic prediction, and follow-up. These innovative biosources show similar features as the primary tumor from where they originated or interacted. This review describes the different technologies and methods used for processing these biosources as well as their main clinical applications with their advantages and limitations., (Copyright © 2020 Cold Spring Harbor Laboratory Press; all rights reserved.)

Metastases and cancer recurrence are the main causes of cancer death. Circulating Tumor Cells (CTCs) and disseminated tumor cells are the drivers of cancer cell dissemination. The assessment of CTCs' clinical role in early metastasis prediction, diagnosis, and treatment requires more information about their biology, their roles in cancer dormancy, and immune evasion as well as in therapy resistance. Indeed, CTC functional and biochemical phenotypes have been only partially characterized using murine metastasis models and liquid biopsy in human patients. CTC detection, characterization, and enumeration represent a promising tool for tailoring the management of each patient with cancer. The comprehensive understanding of CTCs will provide more opportunities to determine their clinical utility. This review provides much-needed insights into this dynamic field of translational cancer research.

Metastasis is the main cause of death in patients with cancer. The molecular mechanisms underlying the different metastasis steps are not yet fully known, partly because most studies have been focusing only on cancer cells within the tumor. Currently, with the development of technologies for the enrichment and capture of circulating tumor cells (CTCs), it is possible to characterize cancer cells at the exact moment of metastasis initiation. Therefore, CTCs are a promising bio-source for real-time liquid biopsies in patients with cancer. However, their exploitation has been hampered by the limited number of CTCs in the bloodstream and the changing phenotype of cancer cells during the metastatic process. Different methods have been developed to expand CTCs in vitro and in vivo (in animal models) with the aim of characterizing functional metastasis-initiator CTCs with stemness traits, and to obtain new diagnostics and therapeutic tools. In this review, we describe how the establishment of in vitro CTC cultures and of CTC-derived xenografts has led to the identification of molecular mechanisms related to metastasis initiation by CTCs, such as epithelial-to-mesenchymal transition (EMT), stemness, and clustering. These models enable the functional analysis and in-depth proteomic, transcriptomic and genomic profiling of metastasis-competent CTCs. We then discuss the relationship between EMT and stem cell features, and how these aspects might interact with other factors in the tumor microenvironment to induce CTC dissemination and proliferation in distant organs., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: One of the objectives for the liquid biopsy is to become a surrogate to tissue biopsies in diagnosis of cancer as a minimally invasive method, with clinical utility in real-time follow-ups of patients. To achieve this goal, it is still necessary to achieve a better understanding of the mechanisms of cancer and the biological principles that govern its behavior, particularly with regard to circulating tumor cells (CTCs)., Content: The isolation, enumeration, detection, and characterization of CTCs have already proven to provide relevant clinical information about patient prognosis and treatment prediction. Moreover, CTCs can be analyzed at the genome, proteome, transcriptome, and secretome levels and can also be used for functional studies in in vitro and in vivo models. These features, taken together, have made CTCs a very valuable biosource., Summary: To further advance the field and discover new clinical applications for CTCs, several studies have been performed to learn more about these cells and better understand the biology of metastasis. In this review, we describe the recent literature on the topic of liquid biopsy with particular focus on the biology of CTCs., (© 2019 American Association for Clinical Chemistry.)