scholarly journals Associations between the Epithelial-Mesenchymal Transition Phenotypes of Circulating Tumor Cells and the Clinicopathological Features of Patients with Colorectal Cancer

2017 ◽  
Vol 2017 ◽  
pp. 1-6 ◽  
Author(s):  
Fengjie Wu ◽  
Jun Zhu ◽  
Yongjiang Mao ◽  
Xiaomei Li ◽  
Baoguang Hu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Peripheral Blood ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Cell ◽  
Blood Samples ◽  
Mesenchymal Transition ◽  
Enrichment Technique ◽  
Tumor Node Metastasis Stage ◽  
Mesenchymal Cell Marker ◽  
Circulating Tumor Microemboli

In this study, we identified CTCs using the previously reported CanPatrol CTC enrichment technique from peripheral blood samples of 126 patients with colorectal cancer (CRC) and found that CTCs could be classified into three subpopulations based on expression of epithelial cell adhesion molecule (EpCAM) (E-CTCs), the mesenchymal cell marker vimentin (M-CTCs), or both EpCAM and vimentin (biphenotypic E/M-CTCs). Circulating tumor microemboli (CTMs) were also identified in peripheral blood samples. Meanwhile, E-CTCs, M-CTCs, E/M-CTCs, and CTMs were detected in 76.98%, 42.06%, 56.35%, and 36.51% of the 126 patients, respectively. Interestingly, the presence of CTMs and each CTC subpopulation was significantly associated with blood lymphocyte counts and tumor-node-metastasis stage (P<0.001). Lymphocyte counts and the neutrophil-to-lymphocyte ratio (NLR) in patients lacking CTCs were significantly different from those in patients testing positive for CTMs and each CTC subpopulation (P<0.001). Our results indicate that tumor metastasis is more significantly associated with the presence of CTMs and M-CTCs than with other CTC subpopulations and suggest that EMT may be involved in CTC evasion of lymphocyte-mediated clearance.

Relationship between circulating tumor cells and ZEB1 expression in tumor cells in colorectal cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15509-e15509
Author(s):  
Inna A. Novikova ◽  
Oleg I. Kit ◽  
Elena Yu. Zlatnik ◽  
Elena P. Ulianova ◽  
Aleksandr B. Sagakyants ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Peripheral Blood ◽  
Epithelial Mesenchymal Transition ◽  
Detection System ◽  
Morphological Characteristics ◽  
Cellsearch System ◽  
Mesenchymal Transition ◽  
Zeb1 Expression

e15509 Background: Intravasation and circulation of tumor cells involves active invasion of cells with an enhanced migration potential as a result of the epithelial-mesenchymal transition (EMT). The ZEB1 protein is one of the key regulators of this process. Our purpose was to evaluate the association between the amount of circulating tumor cells (CTCs) in the peripheral blood of patients with different stages of colorectal cancer and the expression of ZEB1 by tumor cells. Methods: The study included 299 patients (aged 42-86 years, mean age 64.2±1.7) with stage II-IV CRC T1-4N0-2M0-1; histologically verified G1-G3 adenocarcinoma in all patients. The numbers of CTCs were measured in the peripheral blood before surgery using the Veridex CellSearch system (Janssen). CTCs were registered taking into account morphological characteristics and expression of epithelial cell adhesion markers EpCAM, CD45, cytokeratins 8,18,19. The blood sample was evaluated according to the following criteria: 0 CTCs, 1-3 CTCs, and more than 3 CTCs. Tissues of surgically removed tumors were studied with IHC analysis using rabbit polyclonal anti-ZEB1 antibodies (Biorbyt Ltd.) diluted 1:200 and the Reveal Polyvalent HRP-DAB Detection System. The percentage and the intensity of staining were assessed: 0, 1+ weak, 2+ moderate, 3+ strong. ZEB1 expression was considered positive when staining was detected in more than 10% (cut-off) tumor cells with intensities of 2+ and 3+. Statistical analysis of results was performed in the Statistica 13.0 program (StatSoftInc., USA). Results: From 1 to 402 CTCs were determined in 62.9% cases (in 188 of 299 patients); CTCs were not registered in 37.1% cases (111 of 299). Positive ZEB1 expression was observed in 80.6% (241 of 299 patients), while the negative one was much more rare – 19.4% (58 of 299 patients). The rates of CTC detection significantly increased with the positive ZEB1+ expression, compared to the negative expression (75.1% vs. 12.1%). CTCs >3 were detected in the blood in 39.0% in ZEB1+ tumors, but not in ZEB1- tumors. 1-3 CTCs were observed 3 times more often in ZEB1+ tumors (36.1% vs. 12.1; p≤0.05). Conclusions: Statistically significant association was revealed between the epithelial-mesenchymal transition marker ZEB1 expression by tumor cells and the amount of CTCs in the peripheral blood (p < 0.001).

scholarly journals Genome-Wide Lymphocytic mRNA Sequencing to Identify Epithelial-Mesenchymal Transition Mechanism in Silicosis

2021 ◽  
Author(s):  
Hai bin Li ◽  
Lin Zhang ◽  
Yi Guan ◽  
Yingzheng Zhao ◽  
Ning Li ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Signaling Pathway ◽  
Peripheral Blood ◽  
Epithelial Mesenchymal Transition ◽  
Janus Kinase ◽  
Gene Set Enrichment Analysis ◽  
Healthy Controls ◽  
Blood Samples ◽  
Mesenchymal Transition ◽  
Transition Mechanism

Abstract Background Lymphocytes are immune cells that play dual roles in the pathogenesis of silicosis. Epithelial-mesenchymal transition (EMT), a vital phenomenon in the pathogenesis of silicosis, is regulated by cytokines, chemokines, and other molecules secreted by lymphocytes; however, the underlying regulatory mechanism is unclear. Here, we investigated the role of lymphocytes in EMT in silicosis. Methods Three patients with silicosis and three healthy controls that underwent pre-job physical examination were recruited; fasting venous blood samples were collected and lymphocytes were separated by Ficoll. High-throughput sequencing technology and bioinformatic analysis were used to identify specific genes and signaling pathways. The results were verified through the detection of related indices of peripheral blood samples. Results The baseline characteristics of subjects from silicosis group were matched with those of healthy controls. In comparison with healthy controls, patients with silicosis showed 1915 dysregulated genes that were thought to participate in various biological processes, including angiogenesis, tissue repair, cell proliferation, invasion, migration, and EMT. Protein-protein interaction analysis grouped these genes into three hub targets, including phosphoinositide 3-kinase (PI3K), integrin beta 1 (ITGB1), and integrin-linked protein kinase (ILK). Gene set enrichment analysis (GSEA) confirmed that PI3K, ITGB1, and ILK were tightly associated with EMT through the Wnt signaling pathway, Janus kinase/signal transducer and activator of transcription (JAK-STAT) signaling pathway, and cell adhesion molecular pathway. ITGB1 is a member of the adhesion molecule family. The identified genes were verified through the detection of soluble adhesion molecules in peripheral blood samples of patients with silicosis and healthy subjects. Conclusion Dysregulation of PI3K, ITGB1, and ILK in lymphocytes may contribute to EMT via JAK-STAT, Wnt, and cell adhesion molecular pathways in patients with silicosis.

scholarly journals Epithelial-Mesenchymal-Transition-Like Circulating Tumor Cell-Associated White Blood Cell Clusters as a Prognostic Biomarker in HR-Positive/HER2-Negative Metastatic Breast Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Xiuwen Guan ◽  
Chunxiao Li ◽  
Yiqun Li ◽  
Jiani Wang ◽  
Zongbi Yi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Blood Cell ◽  
White Blood Cell ◽  
Peripheral Blood ◽  
Epithelial Mesenchymal Transition ◽  
Metastatic Breast ◽  
Blood Samples ◽  
Mesenchymal Transition ◽  
Cell Clusters

BackgroundAlthough positive Circulating tumor cells (CTCs) status has been validated as a prognostic marker in breast cancer, the interaction between immune cells and CTCs during the progress of Epithelial-mesenchymal-transition (EMT), and the clinical implications of CTC-associated white blood cell clusters (CTC-WBC clusters) for metastatic breast cancer are largely uncharacterized.MethodsWe optimized a filter-based method combined with an RNA in situ hybridization technique according to the epithelial- and mesenchymal-markers to analyze EMT in CTC-WBC clusters. Serial peripheral blood samples from 135 patients with Hormone receptor (HR)-positive/HER2-negative metastatic breast cancer receiving first-line chemotherapy with docetaxel plus capecitabine were prospectively collected until disease progression from Nov 2013 to March 2019. Follow-up data collection was conducted until July 2020.ResultsA total of 452 blood samples at all time-points were collected and analyzed. Median age of the cohort was 51.0 years (range, 27 to 73 years), and most of them (76.3%) had visceral metastases. Median progression-free survival (PFS) was 10.6 months (95% CI, 8.8 to 12.3 months). The presence of EMT-like CTC-WBC clusters was more frequently evident among patients with simultaneous bone and lymph node metastases (87.5% vs 36.2%, P=0.006), whereas no associations were observed between CTC-WBC clusters and other clinicopathologic characteristics before chemotherapy. The patients with EMT-like CTC-WBC clusters tended to show a significantly increased number of total CTC count (median,19.0 vs 5.0, P&lt;0.001). The patients with at least one detectable EMT-like CTC-WBC cluster at baseline were characterized by significantly worse PFS, when compared to the patients with no EMT-like CTC-WBC clusters detected (7.0 vs 10.7 months, P=0.023), and those with five or more epithelial-based CTCs detected per 5mL of peripheral blood (7.0 vs 12.7 months, P=0.014). However, the total CTC-WBC clusters were not correlated with patients’ survival in the cohort (8.4 vs 10.6 months, P=0.561).ConclusionsOur data provide evidence that the emergence of CTC-WBC clusters underwent EMT before treatment is associated with significantly poorer PFS in HR-positive/HER2-negative metastatic breast cancer patients receiving docetaxel plus capecitabine, which may be used as a parameter to predict the clinical outcomes and a potential target for individualized therapy.

scholarly journals Epithelial-Mesenchymal Transition and MicroRNAs in Colorectal Cancer Chemoresistance to FOLFOX

Pharmaceutics ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 75
Author(s):  
Paula I. Escalante ◽  
Luis A. Quiñones ◽  
Héctor R. Contreras
Keyword(s):  
Colorectal Cancer ◽  
Tumor Cells ◽  
Methylenetetrahydrofolate Reductase ◽  
Epithelial Mesenchymal Transition ◽  
Late Onset ◽  
Dihydropyrimidine Dehydrogenase ◽  
Acquired Resistance ◽  
Potential Effect ◽  
Mesenchymal Transition ◽  
Folfox Chemotherapy

The FOLFOX scheme, based on the association of 5-fluorouracil and oxaliplatin, is the most frequently indicated chemotherapy scheme for patients diagnosed with metastatic colorectal cancer. Nevertheless, development of chemoresistance is one of the major challenges associated with this disease. It has been reported that epithelial-mesenchymal transition (EMT) is implicated in microRNA-driven modulation of tumor cells response to 5-fluorouracil and oxaliplatin. Moreover, from pharmacogenomic research, it is known that overexpression of genes encoding dihydropyrimidine dehydrogenase (DPYD), thymidylate synthase (TYMS), methylenetetrahydrofolate reductase (MTHFR), the DNA repair enzymes ERCC1, ERCC2, and XRCC1, and the phase 2 enzyme GSTP1 impair the response to FOLFOX. It has been observed that EMT is associated with overexpression of DPYD, TYMS, ERCC1, and GSTP1. In this review, we investigated the role of miRNAs as EMT promotors in tumor cells, and its potential effect on the upregulation of DPYD, TYMS, MTHFR, ERCC1, ERCC2, XRCC1, and GSTP1 expression, which would lead to resistance of CRC tumor cells to 5-fluorouracil and oxaliplatin. This constitutes a potential mechanism of epigenetic regulation involved in late-onset of acquired resistance in mCRC patients under FOLFOX chemotherapy. Expression of these biomarker microRNAs could serve as tools for personalized medicine, and as potential therapeutic targets in the future.

B7-H4 induces epithelial–mesenchymal transition and promotes colorectal cancer stemness

2021 ◽  
pp. 153323
Author(s):  
Ying Feng ◽  
Zhaoting Yang ◽  
Chengye Zhang ◽  
Nan Che ◽  
Xingzhe Liu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Epithelial Mesenchymal Transition ◽  
Cancer Stemness ◽  
Mesenchymal Transition

scholarly journals The microRNA-210-Stathmin1 Axis Decreases Cell Stiffness to Facilitate the Invasiveness of Colorectal Cancer Stem Cells

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1833
Author(s):  
Tsai-Tsen Liao ◽  
Wei-Chung Cheng ◽  
Chih-Yung Yang ◽  
Yin-Quan Chen ◽  
Shu-Han Su ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Cell Motility ◽  
Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Cell Stiffness ◽  
Mesenchymal Transition ◽  
Cytoskeletal Dynamics ◽  
Colorectal Cancer Stem Cells

Cell migration is critical for regional dissemination and distal metastasis of cancer cells, which remain the major causes of poor prognosis and death in patients with colorectal cancer (CRC). Although cytoskeletal dynamics and cellular deformability contribute to the migration of cancer cells and metastasis, the mechanisms governing the migratory ability of cancer stem cells (CSCs), a nongenetic source of tumor heterogeneity, are unclear. Here, we expanded colorectal CSCs (CRCSCs) as colonospheres and showed that CRCSCs exhibited higher cell motility in transwell migration assays and 3D invasion assays and greater deformability in particle tracking microrheology than did their parental CRC cells. Mechanistically, in CRCSCs, microRNA-210-3p (miR-210) targeted stathmin1 (STMN1), which is known for inducing microtubule destabilization, to decrease cell elasticity in order to facilitate cell motility without affecting the epithelial–mesenchymal transition (EMT) status. Clinically, the miR-210-STMN1 axis was activated in CRC patients with liver metastasis and correlated with a worse clinical outcome. This study elucidates a miRNA-oriented mechanism regulating the deformability of CRCSCs beyond the EMT process.

scholarly journals AKT3 Expression in Mesenchymal Colorectal Cancer Cells Drives Growth and Is Associated with Epithelial-Mesenchymal Transition

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 801
Author(s):  
Joyce Y. Buikhuisen ◽  
Patricia M. Gomez Barila ◽  
Arezo Torang ◽  
Daniëlle Dekker ◽  
Joan H. de Jong ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Surrogate Marker ◽  
High Expression ◽  
Mesenchymal Transition ◽  
High Propensity ◽  
Colorectal Cancer Cells ◽  
Epithelial Compartment ◽  
Selection Of

Colorectal cancer (CRC) is a heterogeneous disease that can currently be subdivided into four distinct consensus molecular subtypes (CMS) based on gene expression profiling. The CMS4 subtype is marked by high expression of mesenchymal genes and is associated with a worse overall prognosis compared to other CMSs. Importantly, this subtype responds poorly to the standard therapies currently used to treat CRC. We set out to explore what regulatory signalling networks underlie the CMS4 phenotype of cancer cells, specifically, by analysing which kinases were more highly expressed in this subtype compared to others. We found AKT3 to be expressed in the cancer cell epithelium of CRC specimens, patient derived xenograft (PDX) models and in (primary) cell cultures representing CMS4. Importantly, chemical inhibition or knockout of this gene hampers outgrowth of this subtype, as AKT3 controls expression of the cell cycle regulator p27KIP1. Furthermore, high AKT3 expression was associated with high expression of epithelial-mesenchymal transition (EMT) genes, and this observation could be expanded to cell lines representing other carcinoma types. More importantly, this association allowed for the identification of CRC patients with a high propensity to metastasise and an associated poor prognosis. High AKT3 expression in the tumour epithelial compartment may thus be used as a surrogate marker for EMT and may allow for a selection of CRC patients that could benefit from AKT3-targeted therapy.

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