scholarly journals Key Characteristics of Circulating Tumor Cell Clusters and Implications for Cancer Metastases

2021 ◽  
Vol 10 (2) ◽  
Author(s):  
Yakov Perlov ◽  
Dean Lee
Keyword(s):  
Tumor Cells ◽  
Epithelial Mesenchymal Transition ◽  
Embryonic Stem ◽  
Metastatic Potential ◽  
Circulating Tumor Cell ◽  
Primary Tumors ◽  
Mesenchymal Transition ◽  
Metastatic Lesions ◽  
Key Characteristics ◽  
Single Ctcs

Primary tumors generate metastases by shedding tumor cells into the circulation; these circulating tumor cells (CTCs) implant at distant sites to develop into metastatic lesions. CTCs can travel either as clusters or as single CTCs. Previous studies revealed that the frequency of CTC clusters in a cancer patient positively correlates with the likelihood of developing metastatic lesions. Three key characteristics of CTC clusters - chemoresistance, reduced apoptosis, and epigenetically programmed stemness - enhance their metastatic potential relative to single CTCs: CTC clusters seem to be more resistant to chemotherapy due to their quiescent and necrotic cores, making drug penetration difficult. Their chemoresistance also correlates with specific molecular components of the extracellular matrix. CTC clusters suffer lower rates of apoptosis. This might be attributed to autocrine factors that protect against immune attack and the epithelial-mesenchymal transition. The DNA methylation landscape of CTC clusters closely resembles that of embryonic stem cells. It features hypomethylation of four critical transcription factors associated with stemness and hypermethylation of a set of pro-differentiation genes. Further research might focus on the interdependence of these three characteristics and whether they precede or follow the clustering of CTCs. The answers to these research questions will help drug developers define specific mechanisms that can curb the metastatic potential of CTC clusters.

scholarly journals The functional activity of E-cadherin controls tumor cell metastasis at multiple steps

2020 ◽  
Vol 117 (11) ◽  
pp. 5931-5937 ◽  
Author(s):  
Tae-Young Na ◽  
Leslayann Schecterson ◽  
Alisha M. Mendonsa ◽  
Barry M. Gumbiner
Keyword(s):  
Tumor Cell ◽  
Tumor Cells ◽  
Functional Activity ◽  
Epithelial Mesenchymal Transition ◽  
Important Determinant ◽  
Three Dimensional ◽  
Metastatic Potential ◽  
Primary Tumors ◽  
Mesenchymal Transition ◽  
E Cadherin

E-cadherin is a tumor suppressor protein, and the loss of its expression in association with the epithelial mesenchymal transition (EMT) occurs frequently during tumor metastasis. However, many metastases continue to express E-cadherin, and a full EMT is not always necessary for metastasis; also, positive roles for E-cadherin expression in metastasis have been reported. We hypothesize instead that changes in the functional activity of E-cadherin expressed on tumor cells in response to environmental factors is an important determinant of the ability of the tumor cells to metastasize. We find that E-cadherin expression persists in metastatic lung nodules and circulating tumor cells (CTCs) in two mouse models of mammary cancer: genetically modified MMTV-PyMT mice and orthotopically grafted 4T1 tumor cells. Importantly, monoclonal antibodies that bind to and activate E-cadherin at the cell surface reduce lung metastasis from endogenous genetically driven tumors and from tumor cell grafts. E-cadherin activation inhibits metastasis at multiple stages, including the accumulation of CTCs from the primary tumor and the extravasation of tumor cells from the vasculature. These activating mAbs increase cell adhesion and reduce cell invasion and migration in both cell culture and three-dimensional spheroids grown from primary tumors. Moreover, activating mAbs increased the frequency of apoptotic cells without affecting proliferation. Although the growth of the primary tumors was unaffected by activating mAbs, CTCs and tumor cells in metastatic nodules exhibited increased apoptosis. Thus, the functional state of E-cadherin is an important determinant of metastatic potential beyond whether the gene is expressed.

scholarly journals Involvement of immune system and Epithelial–Mesenchymal-Transition in increased invasiveness of clustered circulatory tumor cells in breast cancer

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Samane Khoshbakht ◽  
Sadegh Azimzadeh Jamalkandi ◽  
Ali Masudi-Nejad
Keyword(s):  
Breast Cancer ◽  
Immune System ◽  
Tumor Cells ◽  
Distant Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Metastatic Potential ◽  
Rank Test ◽  
Support Vector ◽  
Mesenchymal Transition ◽  
Menstrual Cycles

Abstract Background Circulating tumor cells (CTCs) are the critical initiators of distant metastasis formation. In which, the reciprocal interplay among different metastatic pathways and their metastasis driver genes which promote survival of CTCs is not well introduced using network approaches. Methods Here, to investigate the unknown pathways of single/cluster CTCs, the co-expression network was reconstructed, using WGCNA (Weighted Correlation Network Analysis) method. Having used the hierarchical clustering, we detected the Immune-response and EMT subnetworks. The metastatic potential of genes was assessed and validated through the support vector machine (SVM), neural network, and decision tree methods on two external datasets. To identify the active signaling pathways in CTCs, we reconstructed a casual network. The Log-Rank test and Kaplan–Meier curve were applied to detect prognostic gene signatures for distant metastasis-free survival (DMFS). Finally, a predictive model was developed for metastasis risk of patients using VIF-stepwise feature selection. Results Our results showed the crosstalk among EMT, the immune system, menstrual cycles, and the stemness pathway in CTCs. In which, fluctuation of menstrual cycles is a new detected pathway in breast cancer CTCs. The reciprocal association between immune responses and EMT was identified in CTCs. The SVM model indicated a high metastatic potential of EMT subnetwork (accuracy, sensitivity, and specificity scores were 87%). The DMFS model was identified to predict patients’ metastasis risks. (c-index = 0.7). Finally, novel metastatic biomarkers of KRT18 and KRT19 were detected in breast cancer CTCs. Conclusions In conclusion, the reciprocal interplay among critical unknown pathways in CTCs manifests both their survival in blood and metastatic potentials. Such findings may help to develop more precise predictive metastatic-risk models or detect pivotal metastatic biomarkers.

scholarly journals Breast tumor cells promotes the horizontal propagation of EMT, stemness, and metastasis by transferring the MAP17 protein between subsets of neoplastic cells

Oncogenesis ◽  
2020 ◽  
Vol 9 (10) ◽  
Author(s):  
José Manuel García-Heredia ◽  
Daniel Otero-Albiol ◽  
Marco Pérez ◽  
Elena Pérez-Castejón ◽  
Sandra Muñoz-Galván ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Tumor Cells ◽  
Epithelial Mesenchymal Transition ◽  
Notch Pathway ◽  
Metastatic Potential ◽  
Tumor Evolution ◽  
Neoplastic Cells ◽  
Mesenchymal Transition

Abstract MAP17 (PDZK1IP1) is a small protein regulating inflammation and tumor progression, upregulated in a broad range of carcinomas. MAP17 levels increase during tumor progression in a large percentage of advanced tumors. In the present work, we explored the role of this protein shaping tumor evolution. Here we show that in breast cancer, cells increased MAP17 levels in tumors by demethylation induced multiple changes in gene expression through specific miRNAs downregulation. These miRNA changes are dependent on Notch pathway activation. As a consequence, epithelial mesenchymal transition (EMT) and stemness are induced promoting the metastatic potential of these cells both in vitro and in vivo. Furthermore, MAP17 increased the exosomes in tumor cells, where MAP17 was released as cargo, and this horizontal propagation also increased the EMT in the recipient cells. Importantly, an antibody against MAP17 in the media reduces the EMT and stemness alterations promoted by the conditioned media from MAP17-expressing cells. Therefore, MAP17 expression promotes the horizontal propagation of EMT and metastasis by transferring the MAP17 protein between subsets of neoplastic cells. Thus, MAP17 can be used to describe a new mechanism for cell malignity at distance, without the involvement of genetic or epigenetic modifications. MAP17 can also be taken in consideration as new target for metastatic high-grade breast tumors.

scholarly journals Phenotypic Heterogeneity of Triple-Negative Breast Cancer Mediated by Epithelial–Mesenchymal Plasticity

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2188
Author(s):  
Barbora Kvokačková ◽  
Ján Remšík ◽  
Mohit Kumar Jolly ◽  
Karel Souček
Keyword(s):  
Breast Cancer ◽  
Tumor Cells ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Epithelial Mesenchymal Transition ◽  
Intratumoral Heterogeneity ◽  
Primary Tumors ◽  
Mesenchymal Transition ◽  
Metastatic Colonization ◽  
Evolutionarily Conserved

Triple-negative breast cancer (TNBC) is a subtype of breast carcinoma known for its unusually aggressive behavior and poor clinical outcome. Besides the lack of molecular targets for therapy and profound intratumoral heterogeneity, the relatively quick overt metastatic spread remains a major obstacle in effective clinical management. The metastatic colonization of distant sites by primary tumor cells is affected by the microenvironment, epigenetic state of particular subclones, and numerous other factors. One of the most prominent processes contributing to the intratumoral heterogeneity is an epithelial–mesenchymal transition (EMT), an evolutionarily conserved developmental program frequently hijacked by tumor cells, strengthening their motile and invasive features. In response to various intrinsic and extrinsic stimuli, malignant cells can revert the EMT state through the mesenchymal–epithelial transition (MET), a process that is believed to be critical for the establishment of macrometastasis at secondary sites. Notably, cancer cells rarely undergo complete EMT and rather exist in a continuum of E/M intermediate states, preserving high levels of plasticity, as demonstrated in primary tumors and, ultimately, in circulating tumor cells, representing a simplified element of the metastatic cascade. In this review, we focus on cellular drivers underlying EMT/MET phenotypic plasticity and its detrimental consequences in the context of TNBC cancer.

scholarly journals Transcriptomic profiling of single circulating tumor cells provides insight into human metastatic gastric cancer

2022 ◽  
Vol 5 (1) ◽  
Author(s):  
Ryo Negishi ◽  
Hitomi Yamakawa ◽  
Takeru Kobayashi ◽  
Mayuko Horikawa ◽  
Tatsu Shimoyama ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Single Cell ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Transcriptome Analysis ◽  
Epithelial Mesenchymal Transition ◽  
Metastatic Gastric Cancer ◽  
Isolation Technique ◽  
Mesenchymal Transition ◽  
Single Ctcs

AbstractTranscriptome analysis of circulating tumor cells (CTCs), which migrate into blood vessels from primary tumor tissues, at the single-cell level offers critical insights into the biology of metastasis and contributes to drug discovery. However, transcriptome analysis of single CTCs has only been reported for a limited number of cancer types, such as multiple myeloma, breast, hepatocellular, and prostate cancer. Herein, we report the transcriptome analysis of gastric cancer single-CTCs. We utilized an antigen-independent strategy for CTC isolation from metastatic gastric cancer patients involving a size-dependent recovery of CTCs and a single cell isolation technique. The transcriptomic profile of single-CTCs revealed that a majority of gastric CTCs had undergone epithelial-mesenchymal transition (EMT), and indicated the contribution of platelet adhesion toward EMT progression and acquisition of chemoresistance. Taken together, this study serves to employ CTC characterization to elucidate the mechanisms of chemoresistance and metastasis in gastric cancer.

scholarly journals Exploring the Crosstalk between Inflammation and Epithelial-Mesenchymal Transition in Cancer

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Indranil Chattopadhyay ◽  
Rangarao Ambati ◽  
Rohit Gundamaraju
Keyword(s):  
Tumor Cells ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Cell ◽  
The Body ◽  
Primary Tumors ◽  
Mesenchymal Transition ◽  
Complex Interactions ◽  
Protein Encoding ◽  
Inflammatory Molecules ◽  
Encoding Genes

Tumor cells undergo invasion and metastasis through epithelial-to-mesenchymal cell transition (EMT) by activation of alterations in extracellular matrix (ECM) protein-encoding genes, enzymes responsible for the breakdown of ECM, and activation of genes that drive the transformation of the epithelial cell to the mesenchymal type. Inflammatory cytokines such as TGFβ, TNFα, IL-1, IL-6, and IL-8 activate transcription factors such as Smads, NF-κB, STAT3, Snail, Twist, and Zeb that drive EMT. EMT drives primary tumors to metastasize in different parts of the body. T and B cells, dendritic cells (DCs), and tumor-associated macrophages (TAMs) which are present in the tumor microenvironment induce EMT. The current review elucidates the interaction between EMT tumor cells and immune cells under the microenvironment. Such complex interactions provide a better understanding of tumor angiogenesis and metastasis and in defining the aggressiveness of the primary tumors. Anti-inflammatory molecules in this context may open new therapeutic options for the better treatment of tumor progression. Targeting EMT and the related mechanisms by utilizing natural compounds may be an important and safe therapeutic alternative in the treatment of tumor growth.

scholarly journals Mesenchymal Characteristics and Predictive Biomarkers on Circulating Tumor Cells for Therapeutic Strategy

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3588
Author(s):  
Takahiro Okabe ◽  
Shinsaku Togo ◽  
Yuichi Fujimoto ◽  
Junko Watanabe ◽  
Issei Sumiyoshi ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Therapeutic Strategy ◽  
Epithelial Mesenchymal Transition ◽  
Predictive Biomarkers ◽  
Metastatic Potential ◽  
Tumor Stem Cell ◽  
Mesenchymal Transition ◽  
Metastatic Relapse

Metastasis-related events are the primary cause of cancer-related deaths, and circulating tumor cells (CTCs) have a pivotal role in metastatic relapse. CTCs include a variety of subtypes with different functional characteristics. Interestingly, the epithelial–mesenchymal transition (EMT) markers expressed in CTCs are strongly associated with poor clinical outcome and related to the acquisition of circulating tumor stem cell (CTSC) features. Recent studies have revealed the existence of CTC clusters, also called circulating tumor microemboli (CTM), which have a high metastatic potential. In this review, we present current opinions regarding the clinical significance of CTCs and CTM with a mesenchymal phenotype as clinical surrogate markers, and we summarize the therapeutic strategy according to phenotype characterization of CTCs in various types of cancers for future precision medicine.

Metastasis progression through the interplay between the immune system and Epithelial-Mesenchymal-Transition in circulating breast tumor cells

2020 ◽  
Author(s):  
Samane Khoshbakht ◽  
Sadegh Azimzadeh Jamalkandi ◽  
Ali Masudi-Nejad
Keyword(s):  
Breast Cancer ◽  
Immune System ◽  
Immune Responses ◽  
Tumor Cells ◽  
Distant Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Metastatic Potential ◽  
Mesenchymal Transition ◽  
Menstrual Cycles ◽  
Different Types

Abstract BackgroundCirculating tumor cells (CTCs) are the critical initiator of systemic dissemination of cancer, contributing to distant metastasis formation. The metastatic cascades rely on the fundamental roles of different types of CTCs. In which the dual immune responses and epithelial-mesenchymal-transition (EMT) are of two metastasis-driving phenomena and require more molecular assessments.MethodsIn this study, we investigated the transcriptomic modular pattern of single/cluster circulating tumor cells (CTCs). The co-expression analysis implemented, and we could detect two metastatic subnetworks indicating the immune responses and EMT in CTCs. Furthermore, a directed subnetwork identified in the KEGG database. The metastatic potential of subnetworks assessed and validated by classification methods on primary tumors. And, we could fit risk models to distant-metastasis survival of patients.ResultsOur results show the crosstalk among EMT, immune system, menstrual cycles, and stemness in CTCs. In which, fluctuation of menstrual cycles (hormone-related signals) is a new detected pathway in CTCs in breast cancer. The immune SVM model showed high metastatic potential in classifying patients metastatic/non-metastatic groups (accuracy, sensitivity, and specificity scores are 78%). The distant-metastasis free survival model could be used to stratify patients into low, medium, and high-risk groups. Finally, PTCRA, F13A1, LAT, ICAM2, and SNRPC are novel detected biomarkers in breast cancer.ConclusionIn conclusion, different types of CTCs, including cluster/single cells, are metastasis-leading elements in breast cancer. In which, individual assessment of their intrinsic biological properties may assist elucidating metastasis-related mechanisms. These findings may apply to develop superior treatments in the clinic.

scholarly journals Dissection of major cancer gene variants in subsets of circulating tumor cells in advanced breast cancer

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Stella D’Oronzo ◽  
Domenica Lovero ◽  
Raffaele Palmirotta ◽  
Luigia Stefania Stucci ◽  
Marco Tucci ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Stage Iv ◽  
Metastatic Potential ◽  
Gene Variants ◽  
Primary Tumors ◽  
Mesenchymal Transition ◽  
Genomic Markers

AbstractEnumeration of circulating tumor cells (CTCs) may reflect the metastatic potential of breast cancer (BC). By using the DEPArray, we investigated CTCs with respect to their epithelial-to-mesenchymal transition phenotype and compared their genomic heterogeneity with tissue biopsies. Seventeen stage IV BC patients were enrolled. Pre-enriched CTC suspensions were stained with fluorescent-labeled antibodies to epithelial (E) and mesenchymal (M) markers. CTC samples were processed by DEPArray system and clustered in relation to their markers. DNA from CTCs, as well as from primary tumor samples, was sequenced by next generation sequencing to assess the mutational state of 50 major cancer-related genes. We identified four different CTC subsets that harbored different gene variants. The most heterogenous CTC subsets included the M+/E− phenotype, which, however, expressed only 7 repeatedly mutated genes, while in the M−/E+ subset multiple mutations affected only 2 out of 50 genes. When matching all gene variants among CTC subsets, a small number of mutations was shared by only 4 genes, namely ATM, FGFR3, PIK3CA, and TP53 that, however, were absent in primary tumors. Our results postulate that the detected mutations in all CTC subsets may be considered as genomic markers of metastatic dissemination to be investigated during early stages of BC.

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