The inherent molecular heterogeneity of metastatic tumors and the ability of cancer genomes to dynamically evolve are not properly captured by tissue specimens. Analysis of cell-free DNA and ...circulating tumor cells has the potential to change clinical practice by exploiting blood rather than tissue as a source of information. Liquid biopsies are already used to monitor disease response and track the emergence of drug resistance. The suitability of blood-based molecular profiles for early detection and monitoring minimal residual disease is being evaluated. In this review, we address open questions in this fast-evolving field of research.
The inherent molecular heterogeneity of metastatic tumors and the ability of cancer genomes to dynamically evolve are not properly captured by tissue specimens. Analysis of cell-free DNA and circulating tumor cells has the potential to change clinical practice by exploiting blood rather than tissue as a source of information. Liquid biopsies are already used to monitor disease response and track the emergence of drug resistance. The suitability of blood-based molecular profiles for early detection and monitoring minimal residual disease is being evaluated. In this review, Bardelli and Pantel address open questions in this fast-evolving field of research.
Cancer-related deaths are mainly caused by metastatic spread of tumor cells from the primary lesion to distant sites via the blood circulation. Understanding the mechanisms of blood-borne tumor cell ...dissemination by the detection and molecular characterization of circulating tumor cells (CTCs) in the blood of patients with cancer has opened a new avenue in cancer research. Recent technical advances have enabled a comprehensive analysis of the CTCs at the genome, transcriptome and protein level as well as first functional studies using patient-derived CTC cell lines. In this review, we describe and discuss how research on CTCs has yielded important insights into the biology of cancer metastasis and the response of patients with cancer to therapies directed against metastatic cells. Future investigations will show whether CTCs leaving their primary site are more vulnerable to attacks by immune effector cells and whether cancer cell dissemination might be the ‘Achilles heel’ of metastatic progression. Here, we focus on the lessons learned from CTC research on the biology of cancer metastasis in patients with particular emphasis on the interactions of CTCs with the immune system. Moreover, we describe and discuss briefly the potential and challenges for implementing CTCs into clinical decision-making including detection of minimal residual disease, monitoring efficacies of systemic therapies and identification of therapeutic targets and resistance mechanisms.
Early dissemination, blood circulation, or homing of single tumor cells in bone marrow and other organs is usually undetectable at primary diagnosis, even by high resolution imaging technologies. ...However, ultrasensitive approaches now enable the detection of “occult” tumor cells. Many researchers are currently focusing on circulating tumor cells (CTC) in peripheral blood, and several publications have described associations of CTC in patients with metastatic cancer and worse prognosis. However, evidence has emerged that the currently used detection methods lack sensitivity or specificity to track all CTC, especially those that have lost characteristic epithelial features. Therefore, new developments in this field are of utmost interest and will be reviewed here. Moreover, molecular CTC analysis will provide insights into the selection of tumor cells and resistance mechanisms in patients undergoing systemic therapies. This information might support assessing individual prognosis, stratifying patients at risk to systemic therapies, and monitoring therapeutic efficacy.
Metastatic seeding is driven by cell-intrinsic and environmental cues, yet the contribution of biomechanics is poorly known. We aim to elucidate the impact of blood flow on the arrest and the ...extravasation of circulating tumor cells (CTCs) in vivo. Using the zebrafish embryo, we show that arrest of CTCs occurs in vessels with favorable flow profiles where flow forces control the adhesion efficacy of CTCs to the endothelium. We biophysically identified the threshold values of flow and adhesion forces allowing successful arrest of CTCs. In addition, flow forces fine-tune tumor cell extravasation by impairing the remodeling properties of the endothelium. Importantly, we also observe endothelial remodeling at arrest sites of CTCs in mouse brain capillaries. Finally, we observed that human supratentorial brain metastases preferably develop in areas with low perfusion. These results demonstrate that hemodynamic profiles at metastatic sites regulate key steps of extravasation preceding metastatic outgrowth.
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•Arrest of circulating tumor cells occurs in blood vessels with permissive flow profiles•pN-range adhesion forces favor rapid and stable intravascular adhesion•Flow-mediated endothelial remodeling drives extravasation of tumor cells
Follain et al. demonstrate that blood flow forces tune both the arrest and extravasation of circulating tumor cells in vivo. Permissive flow forces allow stable intravascular arrest of circulating tumor cells. Flow forces drive endothelial remodeling around arrested tumor cells, favoring extravasation preceding metastatic outgrowth.
Transcriptome analysis of circulating tumor cells (CTCs) holds great promise to unravel the biology of cancer cell dissemination and identify expressed genes and signaling pathways relevant to ...therapeutic interventions.
CTCs were enriched based on their EpCAM expression (CellSearch
) or by size and deformability (Parsortix
), identified by EpCAM and/or pan-keratin-specific antibodies, and isolated for single cell multiplex RNA profiling.
Distinct breast and prostate CTC expression signatures could be discriminated from RNA profiles of leukocytes. Some CTCs positive for epithelial transcripts (EpCAM and KRT19) also coexpressed leukocyte/mesenchymal associated markers (PTPRC and VIM). Additional subsets of CTCs within individual patients were characterized by divergent expression of genes involved in epithelial-mesenchymal transition (e.g., CDH2, MMPs, VIM, or ZEB1 and 2), DNA repair (RAD51), resistance to cancer therapy (e.g., AR, AR-V7, ERBB2, EGFR), cancer stemness (e.g., CD24 and CD44), activated signaling pathways involved in tumor progression (e.g., PIK3CA and MTOR) or cross talks between tumors and immune cells (e.g., CCL4, CXCL2, CXCL9, IL15, IL1B, or IL8).
Multimarker RNA profiling of single CTCs reveals distinct CTC subsets and provides important insights into gene regulatory networks relevant for cancer progression and therapy.
Most breast cancer patients die due to metastases, and the early onset of this multistep process is usually missed by current tumor staging modalities. Therefore, ultrasensitive techniques have been ...developed to enable the enrichment, detection, isolation and characterization of disseminated tumor cells in bone marrow and circulating tumor cells in the peripheral blood of cancer patients. There is increasing evidence that the presence of these cells is associated with an unfavorable prognosis related to metastatic progression in the bone and other organs. This review focuses on investigations regarding the biology and clinical relevance of circulating tumor cells in breast cancer.
The focus of this study is to identify particular microRNA (miRNA) signatures in exosomes derived from plasma of 435 human epidermal growth factor receptor 2 (HER2)-positive and triple-negative (TN) ...subtypes of breast cancer (BC).
First, miRNA expression profiles were determined in exosomes derived from the plasma of 15 TNBC patients before neoadjuvant therapy using a quantitative TaqMan real-time PCR-based microRNA array card containing 384 different miRNAs. Forty-five miRNAs associated with different clinical parameters were then selected and mounted on microRNA array cards that served for the quantification of exosomal miRNAs in 435 BC patients before therapy and 20 healthy women. Confocal microscopy, Western blot, and ELISA were used for exosome characterization.
Quantification of 45 exosomal miRNAs showed that compared with healthy women, 10 miRNAs in the entire cohort of BC patients, 13 in the subgroup of 211 HER2-positive BC, and 17 in the subgroup of 224 TNBC were significantly deregulated. Plasma levels of 18 exosomal miRNAs differed between HER2-positive and TNBC subtypes, and 9 miRNAs of them also differed from healthy women. Exosomal miRNAs were significantly associated with the clinicopathological and risk factors. In uni- and multivariate models, miR-155 (p = 0.002, p = 0.003, respectively) and miR-301 (p = 0.002, p = 0.001, respectively) best predicted pathological complete response (pCR).
Our findings show a network of deregulated exosomal miRNAs with specific expression patterns in exosomes of HER2-positive and TNBC patients that are also associated with clinicopathological parameters and pCR within each BC subtype.
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