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.

scholarly journals Thymosin β-4 in colorectal cancer is localized predominantly at the invasion front in tumor cells undergoing epithelial mesenchymal transition

2012 ◽  
Vol 13 (4) ◽  
pp. 191-197 ◽  
Author(s):  
Sonia Nemolato ◽  
Angelo Restivo ◽  
Tiziana Cabras ◽  
Pierpaolo Coni ◽  
Luigi Zorcolo ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Cells ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Invasion Front

scholarly journals LncRNA SNHG16 Facilitates Liver Metastases of Colorectal Cancer by Modulating Circulating Tumor Cells (CTCs) Epithelial-Mesenchymal Transition (EMT) via a Positive Feedback Loop with YAP1/TEAD1 Complex

2020 ◽  
Author(s):  
Zhenxian Xiang ◽  
Guoquan Huang ◽  
Haitao Wu ◽  
Qiuming He ◽  
Chaogang Yang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastasis ◽  
Tumor Progression ◽  
Tumor Cells ◽  
Distant Metastasis ◽  
Feedback Loop ◽  
Epithelial Mesenchymal Transition ◽  
Positive Feedback Loop ◽  
Mesenchymal Transition

Abstract Background: Circulating tumor cells are important precursor of colorectal cancer metastasis, which attributes to the main cause of cancer-related death. The ability to adopt epithelial-mesenchymal transition (EMT) process facilitates CTCs generation, thereby overcoming metastatic bottlenecks and realizing distant metastasis. However, the potential molecular mechanism of CRC EMT remains largely unknown.Methods: RT-qPCR, immunohistochemical staining, and western blot were used to detect the expression of mRNA and protein in CRC. Loss- and gain-of-function approaches were performed to investigate the effect of SNHG16 on CRC cell phenotypes. Function assays, including wounding healing, transwell assay, and clone formation were used to assess the effect of SNHG16 on tumor biological behavior. Then, RNA immunoprecipitation, Chromatin Immunoprecipitation, Co-Immunoprecipitation, GST-pull down, biotin-labeled miR-195-5p pull down, and dual-luciferase assay were performed to uncover the underlying mechanism for molecular interaction. Finally, CRC nude mice xenograft model experiment was performed to evaluate the influence of SNHG16 on tumor progression in vivo Results: Compared with normal tissue and cell line, SNHG16 was significantly upregulated in CRC. Clinical investigation revealed that SNHG16 high expression was correlated with advanced TNM stage, distant metastasis, and poor prognosis of cancer patients. According to Loss- and gain-of-function experiment, SNHG16 could promote CRC proliferation, migration, invasion, EMT, mesenchymal-type CTCs (MCTCs) generation, and liver metastasis through YAP1 in vitro and in vivo. Mechanistic research indicates that, SNHG16 could act as miRNA sponge to sequester miR-195-5p on Ago2, thereby protecting YAP1 from repression and facilitating CRC liver metastasis and tumor progression. Moreover, YAP1 could combine with TEA Domain Transcription Factor 1 (TEAD1) to form a YAP1/TEAD1 complex, which could in turn bind to the promoter of SNHG16 and regulate its transcription. In addition, both of YAP1 and TEAD1 are indispensable during this process. Finally, we demonstrated that YAP1 significantly promoted the tumor progression, and SNHG16 could rescue the effect of YAP1 on tumor progressionConclusion: Herein, we clarified a hitherto unexplored positive feedback loop between SNHG16 and YAP1/TEAD1. These findings provided new sights in CRC liver metastasis, and it may act as a potential candidate in the treatment of CRC.

scholarly journals Membranous S100A10 Involvement in the Tumor Budding of Colorectal Cancer During Oncogenesis: Report of Two Cases with Immunohistochemical Analysis

2020 ◽  
Author(s):  
Kazumori Arai ◽  
Hisato Ishimatsu ◽  
Tomohiro Iwasaki ◽  
Chinatsu Tsuchiya ◽  
Akihiro Sonoda ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Cells ◽  
Epithelial Mesenchymal Transition ◽  
S100 Protein ◽  
Immunohistochemical Analysis ◽  
Tumor Budding ◽  
Plasminogen Activation ◽  
Cell Dynamics ◽  
Regional Lymph Nodes ◽  
Mesenchymal Transition

Abstract Background: Tumor budding (TB) and poorly differentiated clusters (PDCs) are a sequence of histologic findings that predict worse prognosis and node metastasis in colorectal cancer (CRC). TB and PDC (TB/PDC) are caused by cancer cell detachment and are distinguished by the number of cancer cells that constitute a cell cluster. In short, PDC is regarded as the previous step of TB. TB/PDC and epithelial–mesenchymal transition (EMT) are closely linked, but its pathogenic mechanisms are still unclear. S100A10, a member of the S100 protein family, forms a heterocomplex with annexin A2 (ANX A2) and then translocates to cell membrane from the cytoplasm and plays various roles in cell dynamics, including plasminogen activation. S100A10 is the activation modulator of the heterocomplex and promotes cell invasion. S100A10 is involved in the remodeling of both actin and extracellular matrix (ECM), which is also associated with EMT. Case presentation: In two representative cases of conventional advanced CRC, we immunohistochemically examined S100A10 and ANX A2 expressions in which both TB and PDC were prominent. Both CRCs metastasized to multiple regional lymph nodes. In both cases, a membranous positivity for S100A10 was diffusely found in both tumor buds and PDCs and was observed in the tumor cells protruding toward the stroma, giving rise to TB/PDC. However, even in tumor glands with TB/PDC, the tumor cells with a smooth border around the stroma showed either cytoplasmic fine-granular expression or no positivity. The immunoreactivity for ANX A2 was almost the same as that for S100A10. In the main tumor components without TB/PDC, no distinct positivity was detected at their smooth borders. Conclusions: During oncogenesis, membranous S100A10 has the potential to be related to TB of CRC. This may be due to plasminogen activation, actin remodeling, and interaction with an altered ECM. However, further study is required to confirm this hypothesis.

scholarly journals Membranous S100A10 involvement in the tumor budding of colorectal cancer during oncogenesis: report of two cases with immunohistochemical analysis

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Kazumori Arai ◽  
Hisato Ishimatsu ◽  
Tomohiro Iwasaki ◽  
Chinatsu Tsuchiya ◽  
Akihiro Sonoda ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Cells ◽  
Epithelial Mesenchymal Transition ◽  
S100 Protein ◽  
Immunohistochemical Analysis ◽  
Tumor Budding ◽  
Plasminogen Activation ◽  
Cell Dynamics ◽  
Regional Lymph Nodes ◽  
Mesenchymal Transition

Abstract Background Tumor budding (TB) and poorly differentiated clusters (PDCs) are a sequence of histologic findings that predict worse prognosis and node metastasis in colorectal cancer (CRC). TB and PDC (TB/PDC) are caused by cancer cell detachment and are distinguished by the number of cancer cells that constitute a cell cluster. In short, PDC is regarded as the previous step of TB. TB/PDC and epithelial-mesenchymal transition (EMT) are closely linked, but its pathogenic mechanisms are still unclear. S100A10, a member of the S100 protein family, forms a heterocomplex with annexin A2 (ANX A2) and then translocates to cell membrane from the cytoplasm and plays various roles in cell dynamics, including plasminogen activation. S100A10 is the activation modulator of the heterocomplex and promotes cell invasion. S100A10 is involved in the remodeling of both actin and extracellular matrix (ECM), which is also associated with EMT. Case presentation In two representative cases of conventional advanced CRC, we immunohistochemically examined S100A10 and ANX A2 expressions in which both TB and PDC were prominent. Both CRCs metastasized to multiple regional lymph nodes. In both cases, a membranous positivity for S100A10 was diffusely found in both tumor buds and PDCs and was observed in the tumor cells protruding toward the stroma, giving rise to TB/PDC. However, even in tumor glands with TB/PDC, the tumor cells with a smooth border around the stroma showed either cytoplasmic fine-granular expression or no positivity. The immunoreactivity for ANX A2 was almost the same as that for S100A10. In the main tumor components without TB/PDC, no distinct positivity was detected at their smooth borders. Conclusions During oncogenesis, membranous S100A10 has the potential to be related to TB of CRC. This may be due to plasminogen activation, actin remodeling, and interaction with an altered ECM. However, further study is required to confirm this hypothesis.

scholarly journals miR-137 alleviates doxorubicin resistance in breast cancer through inhibition of epithelial-mesenchymal transition by targeting DUSP4

2019 ◽  
Vol 10 (12) ◽  
Author(s):  
Feiya Du ◽  
Ling Yu ◽  
Ying Wu ◽  
Shuqian Wang ◽  
Jia Yao ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Cells ◽  
Epithelial Mesenchymal Transition ◽  
Acquired Resistance ◽  
Mesenchymal Transition ◽  
Dual Specificity ◽  
Promising Therapeutic Target

AbstractAcquired resistance to chemotherapy is a major obstacle in breast cancer (BC) treatment. Accumulated evidence has uncovered that microRNAs (miRNAs) are vital regulators of chemoresistance in cancer. Growing studies reveal that miR-137 acts as a suppressor in tumor progression. However, it remains obscure the role of miR-137 in modulating the sensitivity of BC cells to doxorubicin (DOX). In this study, we demonstrate that miR-137 exerts a significant effect on repressing the development of chemoresistance of BC cells in response to DOX via attenuating epithelial-mesenchymal transition (EMT) of tumor cells in vitro and in vivo. MiR-137 overexpression dramatically elevated the sensitivity of BC cells to DOX as well as impaired the DOX-promoted EMT of tumor cells. Mechanistically, miR-137 directly targeted dual-specificity phosphatase 4 (DUSP4) to impact on the EMT and chemoresistance of BC cells upon DOX treatment. Consistently, decreased DUSP4 efficiently enhanced the sensitivity of BC cells to DOX while overexpressed DUSP4 significantly diminished the beneficial effect of miR-137 on BC cells chemoresistance. Moreover, the increased miR-137 heightened the sensitivity of BC cells-derived tumors to DOX through targeting DUSP4 in vivo. Together, our results provide a novel insight into the DOX resistance of BC cells and miR-137 may serve as a new promising therapeutic target for overcoming chemoresistance in BC.

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 Membranous S100A10 Involvement in the Tumor Budding of Colorectal Cancer During Oncogenesis: Report of Two Cases with Immunohistochemical Analysis

2020 ◽  
Author(s):  
Kazumori Arai ◽  
Hisato Ishimatsu ◽  
Tomohiro Iwasaki ◽  
Chinatsu Tsuchiya ◽  
Akihiro Sonoda ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Cells ◽  
Epithelial Mesenchymal Transition ◽  
S100 Protein ◽  
Immunohistochemical Analysis ◽  
Tumor Budding ◽  
Plasminogen Activation ◽  
Cell Dynamics ◽  
Regional Lymph Nodes ◽  
Mesenchymal Transition

Abstract Background Tumor budding (TB) and poorly differentiated clusters (PDCs) are a sequence of histologic findings that predict worse prognosis and node metastasis in colorectal cancer (CRC). TB and PDC (TB/PDC) are caused by cancer cell detachment and are distinguished by the number of cancer cells that constitute a cell cluster. In short, PDC is regarded as the previous step of TB. TB/PDC and epithelial–mesenchymal transition (EMT) are closely linked, but its pathogenic mechanisms are still unclear. S100A10, a member of the S100 protein family, forms a heterocomplex with annexin A2 (ANX A2) and then translocates to cell membrane from the cytoplasm and plays various roles in cell dynamics, including plasminogen activation. S100A10 is the activation modulator of the heterocomplex and promotes cell invasion. S100A10 is involved in the remodeling of both actin and extracellular matrix (ECM), which is also associated with EMT. Recently, the involvement of S100A10 in EMT has been reported. Furthermore, a recent study suggested that S100A10 and ANX A2 are related to the budding of a special type of CRC cells.Case presentation In two representative cases of conventional advanced CRC, we immunohistochemically examined S100A10 and ANX A2 expressions in which both TB and PDC were prominent. Both CRCs metastasized to multiple regional lymph nodes. In both cases, a membranous positivity for S100A10 was diffusely found in both tumor buds and PDCs and was observed in the tumor cells protruding toward the stroma, which originates from TB/PDC. However, even in tumor glands with TB/PDC, the tumor cells with a smooth border around the stroma showed either cytoplasmic fine-granular expression or no positivity. The immunoreactivity for ANX A2 was almost the same as that for S100A10. In the main tumor components without TB/PDC, no distinct positivity was detected at their smooth borders.Conclusions Membranous S100A10 is related to the TB of CRC during oncogenesis. This is possibly due to plasminogen activation, actin remodeling, and interaction with an altered ECM. However, further study is required to confirm this hypothesis.

Aspirin to inhibit the formation and EMT of circulating tumor cells in patients with metastatic colorectal cancer but not breast cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e23024-e23024
Author(s):  
Chao Ni ◽  
Liu Yang
Keyword(s):  
Breast Cancer ◽  
Colorectal Cancer ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Epithelial Mesenchymal Transition ◽  
Underlying Mechanism ◽  
Base Line ◽  
Mesenchymal Transition ◽  
Clinical Trial Information

e23024 Background: High circulating tumor cells (CTCS) have been acknowledged as a poor indication in malignant disease. Besides, platelets are found play crucial role in tumor cells’ epithelial – mesenchymal transition and metastasis, so here we test if disruption of platelet function with aspirin, could decrease the number and inhibit the EMT of CTCs in metastatic colorectal (MCC) or breast cancer (MBC). Methods: Patients with MCC or MBC who were not receiving cytotoxic chemotherapy currently (except for capecitabine maintenance), while endocrine therapy, bisphosphonate or molecular targeted therapy were accepted. Base line of Platelet aggregation rate (PAR), CTCs’ number and molecular phenotype were recorded. Patients whose CTCs ≥ 5 cells/7.5ml peripheral blood were included and receive aspirin 100mg/day for the following 8 weeks. Then the phlebotomy was performed at 4, 8 weeks thereafter to obtain specimen and assess PAR, CTCs’ number and phenotype. The phenotypes of CTCs were classified into epithelial (E+), mesenchymal(M+) and middle type(express both E+ and M+ markers) with fluorescence in situ hybridization assay. Results: Forty patients (19 MBC and 21 MCC patients ) were enrolled. Base line CTC numbers were 8.7± 3.4 in MBC patients, the ratio of E+ and M+ type were 48.2 ± 22.4% and 25.1 ± 14.9% respectively; the base line CTC numbers were 10.7 ± 4.8 in MCC patients, and the ratio of E+ and M+ type were 45.3 ± 27.3% and 22.0 ± 18.5% respectively. Despite adequate platelets inhibition in both groups, CTC numbers were similar in MBC patients in the following 8 weeks ( p= 0.0532 ), while the fraction of E+ or M+ CTCs were also unchanged (E+ CTCs p= 0.305; M+ CTCs p= 0.09); however, both CTC numbers and fraction of M+CTCs were markedly decreased in MCC patients (total numbers: p< 0.01; E+ CTCs p= 0.031; M+ CTCs p= 0.013) . Conclusions: Aspirin could decreased the number of CTCs and block EMT transition in MCC patients, and our results provide potential explanation of how aspirin impede the metastasis of colorectal cancer. But this effect could not be observed in MBC patients. Future studies evaluating the underlying mechanism of this differences remain of interest, and they may be informed by our results. Clinical trial information: NCT02602938.

scholarly journals Prognostic and Therapeutic Significance of Circulating Tumor Cell Phenotype Detection Based on Epithelial-Mesenchymal Transition Markers in Early and Midstage Colorectal Cancer First-Line Chemotherapy

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Guang Lu ◽  
Zhiwen Lu ◽  
Caixia Li ◽  
Xianping Huang ◽  
Qiang Luo
Keyword(s):  
Colorectal Cancer ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Epithelial Mesenchymal Transition ◽  
Progression Free Survival ◽  
Cell Phenotype ◽  
Survival Prognosis ◽  
Free Survival ◽  
Mesenchymal Transition

Purpose. Epithelial-mesenchymal transition (EMT) is related to the process of metastasis and challenges the detection of circulating tumor cells (CTCs) based on epithelial cell adhesion molecules. Circulating tumor cells (CTCs) have been proven to be a prognostic indicator of colorectal cancer (CRC). Although there is evidence that CTC heterogeneity based on EMT markers is associated with disease progression, no standard recommendations have been established for clinical practice. This study is aimed at evaluating the prognostic significance of dynamic CTC detection based on EMT for early and midstage colorectal cancer patients. Methods. 101 patients with early to midterm CRC were admitted from January 2016 to September 2018. All patients underwent CRC radical surgery and standard chemotherapy. Patients in the postchemotherapy were able to epithelial mesenchymal transformed (EMT) CTC testing in peripheral blood using the CanPatrol™ system. Multiple CTC tests were performed according to patient’s own condition and different follow-up time points. Based on patient’s basic information and follow-up data, the Kaplan-Meier method was utilized to establish the progression-free survival model, and the log-rank test was utilized to compare the survival rates between the two groups. Result. Total CTC change of the patient is the best method to predict whether progression-free survival progresses in tumor patients ( Area = 0.857 ). The second detection of total number of CTCs ( P < 0.01 ) detected after chemotherapy, epithelial CTCs ( P = 0.032 ), the increased total number of CTCs ( P < 0.01 ), and the increased number of mesenchymal CTCs ( P = 0.015 ) are significantly related with patient’s poor progression-free survival. Conclusion. Analysis of the second CTC count and classification after follow-up are more related to the survival prognosis of the tumor. The joint analysis of CTC dynamic monitoring data is a good tool to judge patient’s survival prognosis.

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