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American Journal of Physiology. Cell... Jul 2016The process of entering the bloodstream, intravasation, is a necessary step in the development of distant metastases. The focus of this review is on the pathways and... (Review)
Review
The process of entering the bloodstream, intravasation, is a necessary step in the development of distant metastases. The focus of this review is on the pathways and molecules that have been identified as being important based on current in vitro and in vivo assays for intravasation. Properties of the vasculature which are important for intravasation include microvessel density and also diameter of the vasculature, with increased intravasation correlating with increased vessel diameter in some tumors. TGFB signaling can enhance intravasation at least in part through induction of EMT, and we discuss other TGFB target genes that are important for intravasation. In addition to TGFB signaling, a number of studies have demonstrated that activation of EGF receptor family members stimulates intravasation, with downstream signaling through PI3K, N-WASP, RhoA, and WASP to induce invadopodia. With respect to proteases, there is strong evidence for contributions by uPA/uPAR, while the roles of MMPs in intravasation may be more tumor specific. Other cells including macrophages, fibroblasts, neutrophils, and platelets can also play a role in enhancing tumor cell intravasation. The technology is now available to interrogate the expression patterns of circulating tumor cells, which will provide an important reality check for the model systems being used. With a better understanding of the mechanisms underlying intravasation, the goal is to provide new opportunities for improving prognosis as well as potentially developing new treatments.
Topics: Angiogenic Proteins; Animals; Biomarkers, Tumor; Cell Movement; Humans; Microvessels; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms; Neoplastic Cells, Circulating; Neovascularization, Pathologic; Signal Transduction
PubMed: 27076614
DOI: 10.1152/ajpcell.00238.2015 -
Biochimica Et Biophysica Acta. Reviews... Apr 2018Traditional 2D cell cultures do not accurately recapitulate tumor heterogeneity, and insufficient human cell lines are available. Patient-derived xenograft (PDX) models... (Review)
Review
Traditional 2D cell cultures do not accurately recapitulate tumor heterogeneity, and insufficient human cell lines are available. Patient-derived xenograft (PDX) models more closely mimic clinical tumor heterogeneity, but are not useful for high-throughput drug screening. Recently, patient-derived organoid cultures have emerged as a novel technique to fill this critical need. Organoids maintain tumor tissue heterogeneity and drug-resistance responses, and thus are useful for high-throughput drug screening. Among various biological tissues used to produce organoid cultures, circulating tumor cells (CTCs) are promising, due to relative ease of ascertainment. CTC-derived organoids could help to acquire relevant genetic and epigenetic information about tumors in real time, and screen and test promising drugs. This could reduce the need for tissue biopsies, which are painful and may be difficult depending on the tumor location. In this review, we have focused on advances in CTC isolation and organoid culture methods, and their potential applications in disease modeling and precision medicine.
Topics: Animals; Antineoplastic Agents; Biomarkers, Tumor; Biomedical Research; Cell Culture Techniques; Cell Separation; Clinical Decision-Making; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; High-Throughput Screening Assays; Humans; Neoplasms; Neoplastic Cells, Circulating; Organoids; Precision Medicine; Predictive Value of Tests
PubMed: 29360544
DOI: 10.1016/j.bbcan.2017.12.005 -
Clinical & Experimental Metastasis Apr 2018Tumors often overcome the cytotoxic effects of chemotherapy through either acquired or environment-mediated drug resistance. In addition, signals from the... (Review)
Review
Tumors often overcome the cytotoxic effects of chemotherapy through either acquired or environment-mediated drug resistance. In addition, signals from the microenvironment obfuscate the beneficial effects of chemotherapy and may facilitate progression and metastatic dissemination. Seminal mediators in chemotherapy-induced metastasis appear to be a wide range of hematopoietic, mesenchymal and immune progenitor cells, originating from the bone marrow. The actual purpose of these cells is to orchestrate the repair response to the cytotoxic damage of chemotherapy. However, these repair responses are exploited by tumor cells at every step of the metastatic cascade, ranging from tumor cell invasion, intravasation and hematogenous dissemination to extravasation and effective colonization at the metastatic site. A better understanding of the mechanistic underpinnings of chemotherapy-induced metastasis will allow us to better predict which patients are more likely to exhibit pro-metastatic responses to chemotherapy and will help develop new therapeutic strategies to neutralize chemotherapy-driven prometastatic changes.
Topics: Animals; Antineoplastic Agents; Humans; Neoplasm Metastasis; Neoplasms; Neoplastic Cells, Circulating
PubMed: 29307118
DOI: 10.1007/s10585-017-9870-x -
Clinical & Experimental Metastasis Oct 2023Cancer cell invasion, intravasation and survival in the bloodstream are early steps of the metastatic process, pivotal to enabling the spread of cancer to distant... (Review)
Review
Cancer cell invasion, intravasation and survival in the bloodstream are early steps of the metastatic process, pivotal to enabling the spread of cancer to distant tissues. Circulating tumor cells (CTCs) represent a highly selected subpopulation of cancer cells that tamed these critical steps, and a better understanding of their biology and driving molecular principles may facilitate the development of novel tools to prevent metastasis. Here, we describe key research advances in this field, aiming at describing early metastasis-related processes such as collective invasion, shedding, and survival of CTCs in the bloodstream, paying particular attention to microenvironmental factors like hypoxia and mechanical stress, considered as important influencers of the metastatic journey.
Topics: Humans; Stress, Mechanical; Neoplastic Cells, Circulating; Neoplasm Metastasis
PubMed: 37490147
DOI: 10.1007/s10585-023-10224-8 -
Trends in Cancer Nov 2021Circulating tumor cells (CTCs) are vital components of liquid biopsies for diagnosis of residual cancer, monitoring of therapy response, and prognosis of recurrence.... (Review)
Review
Circulating tumor cells (CTCs) are vital components of liquid biopsies for diagnosis of residual cancer, monitoring of therapy response, and prognosis of recurrence. Scientific dogma focuses on metastasis mediated by single CTCs, but advancement of CTC detection technologies has elucidated multicellular CTC clusters, which are associated with unfavorable clinical outcomes and a 20- to 100-fold greater metastatic potential than single CTCs. While the mechanistic understanding of CTC cluster formation is still in its infancy, multiple cell adhesion molecules and tight junction proteins have been identified that underlie the outperforming attributes of homotypic and heterotypic CTC clusters, such as cell survival, cancer stemness, and immune evasion. Future directions include high-resolution characterization of CTCs at multiomic levels for diagnostic/prognostic evaluations and targeted therapies.
Topics: Cluster Analysis; Humans; Liquid Biopsy; Neoplastic Cells, Circulating; Prognosis
PubMed: 34481763
DOI: 10.1016/j.trecan.2021.07.001 -
Molecular Oncology Jan 2017The epithelial-mesenchymal transition (EMT) is a developmental program that enables stationary epithelial cells to gain the ability to migrate and invade as single... (Review)
Review
The epithelial-mesenchymal transition (EMT) is a developmental program that enables stationary epithelial cells to gain the ability to migrate and invade as single cells. Tumor cells reactivate EMT to acquire molecular alterations that enable the partial loss of epithelial features and partial gain of a mesenchymal phenotype. Our understanding of the contribution of EMT to tumor invasion, migration, and metastatic outgrowth has evolved over the past decade. In this review, we provide a summary of both historic and recent studies on the role of EMT in the metastatic cascade from various experimental systems, including cancer cell lines, genetic mouse tumor models, and clinical human breast cancer tissues.
Topics: Animals; Breast Neoplasms; Cell Movement; Disease Models, Animal; Epithelial-Mesenchymal Transition; Female; Humans; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms; Neoplastic Cells, Circulating
PubMed: 28085222
DOI: 10.1002/1878-0261.12017 -
Biomolecules Feb 2020Epithelial cell adhesion molecule (EpCAM) is a cell surface protein that was discovered as a tumour marker of epithelial origins nearly four decades ago. EpCAM is... (Review)
Review
Epithelial cell adhesion molecule (EpCAM) is a cell surface protein that was discovered as a tumour marker of epithelial origins nearly four decades ago. EpCAM is expressed at basal levels in the basolateral membrane of normal epithelial cells. However, EpCAM expression is upregulated in solid epithelial cancers and stem cells. EpCAM can also be found in disseminated tumour cells and circulating tumour cells. Various OMICs studies have demonstrated that EpCAM plays roles in several key biological processes such as cell adhesion, migration, proliferation and differentiation. Additionally, EpCAM can be detected in the bodily fluid of cancer patients suggesting that EpCAM is a pathophysiologically relevant anti-tumour target as well as being utilized as a diagnostic/prognostic agent for a variety of cancers. This review will focus on the structure-features of EpCAM protein and discuss recent evidence on the pathological and physiological roles of EpCAM in modulating cell adhesion and signalling pathways in cancers as well as deliberating the clinical implication of EpCAM as a therapeutic target.
Topics: Antigens, Neoplasm; Biomarkers, Tumor; Cell Adhesion; Cell Adhesion Molecules; Cell Line, Tumor; Epithelial Cell Adhesion Molecule; Epithelial-Mesenchymal Transition; Humans; Neoplasm Metastasis; Neoplasms; Neoplastic Cells, Circulating; Prognosis
PubMed: 32046162
DOI: 10.3390/biom10020255 -
Cellular Physiology and Biochemistry :... 2017Precision medicine and personalized medicine are based on the development of biomarkers, and liquid biopsy has been reported to be able to detect biomarkers that carry... (Review)
Review
Precision medicine and personalized medicine are based on the development of biomarkers, and liquid biopsy has been reported to be able to detect biomarkers that carry information on tumor development and progression. Compared with traditional 'solid biopsy', which cannot always be performed to determine tumor dynamics, liquid biopsy has notable advantages in that it is a noninvasive modality that can provide diagnostic and prognostic information prior to treatment, during treatment and during progression. In this review, we describe the source, characteristics, technology for detection and current situation of circulating tumor cells, circulating free DNA and exosomes used for diagnosis, recurrence monitoring, prognosis assessment and medication planning.
Topics: Biopsy; DNA; Exosomes; Humans; MicroRNAs; Neoplasms; Neoplastic Cells, Circulating; Prognosis
PubMed: 28214887
DOI: 10.1159/000458736 -
Trends in Cell Biology Apr 2019Circulating tumor cell (CTC) clusters have an enhanced capacity to initiate metastases, compared with single cells, but it is unclear how they gain such advantage. A... (Review)
Review
Circulating tumor cell (CTC) clusters have an enhanced capacity to initiate metastases, compared with single cells, but it is unclear how they gain such advantage. A recent study by Gkountela etal. (Cell 2019;176:98-112) links the physical state of clusters with increased accessibility of stem cell-related transcription factors, providing novel insights into the epigenetic regulation of 'stemness' in CTC clusters.
Topics: Epigenesis, Genetic; Humans; Neoplasm Metastasis; Neoplastic Cells, Circulating; Transcription Factors
PubMed: 30799250
DOI: 10.1016/j.tcb.2019.02.001 -
Genome Research Jan 2023The identification and characterization of circulating tumor cells (CTCs) are important for gaining insights into the biology of metastatic cancers, monitoring disease...
The identification and characterization of circulating tumor cells (CTCs) are important for gaining insights into the biology of metastatic cancers, monitoring disease progression, and medical management of the disease. The limiting factor in the enrichment of purified CTC populations is their sparse availability, heterogeneity, and altered phenotypes relative to the primary tumor. Intensive research both at the technical and molecular fronts led to the development of assays that ease CTC detection and identification from peripheral blood. Most CTC detection methods based on single-cell RNA sequencing (scRNA-seq) use a mix of size selection, marker-based white blood cell (WBC) depletion, and antibodies targeting tumor-associated antigens. However, the majority of these methods either miss out on atypical CTCs or suffer from WBC contamination. We present unCTC, an R package for unbiased identification and characterization of CTCs from single-cell transcriptomic data. unCTC features many standard and novel computational and statistical modules for various analyses. These include a novel method of scRNA-seq clustering, named deep dictionary learning using -means clustering cost (DDLK), expression-based copy number variation (CNV) inference, and combinatorial, marker-based verification of the malignant phenotypes. DDLK enables robust segregation of CTCs and WBCs in the pathway space, as opposed to the gene expression space. We validated the utility of unCTC on scRNA-seq profiles of breast CTCs from six patients, captured and profiled using an integrated ClearCell FX and Polaris workflow that works by the principles of size-based separation of CTCs and marker-based WBC depletion.
Topics: Humans; Neoplastic Cells, Circulating; Transcriptome; DNA Copy Number Variations; Gene Expression Profiling; Biomarkers, Tumor
PubMed: 36414416
DOI: 10.1101/gr.276600.122