Correlation of SOX-2 and NOTCH1 copy numbers with vimentin expression in orthotopic patient-derived xenografts of cardioesophageal cancer in immunodeficient mice.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15034-e15034
Author(s):  
Anna S. Goncharova ◽  
Evgeniy N. Kolesnikov ◽  
Ekaterina V. Zaikina ◽  
A. V. Volkova ◽  
M. V. Mindar ◽  
...  
Keyword(s):  
Nude Mice ◽  
Epithelial Mesenchymal Transition ◽  
Molecular Genetic Analysis ◽  
Distal Esophagus ◽  
Vimentin Expression ◽  
Tissue Samples ◽  
Cardiac Stomach ◽  
Mesenchymal Transition ◽  
Immunodeficient Mice ◽  
Copy Numbers

e15034 Background: Cardioesophageal cancer is one of the most common tumors affecting the mucosa of the cardiac stomach and distal esophagus. Despite the variety of treatment strategies and chemotherapy agents, the prognosis for the patients remains poor. The purpose of the study was to analyze the relative copy numbers of SOX-2 and NOTCH1 and vimentin expression in orthotopic patient-derived xenografts of cardioesophageal cancer. Methods: The model of cardioesophageal cancer was created in Balb/c Nude mice with surgical bioptates of moderately differentiated adenocarcinoma obtained from a donor with infiltrative ulcerative cancer of the lower third of the esophagus with a transition to the cardiac stomach into the distal esophagus of Balb/c Nude mice. The index of proliferative activity in the bioptates was assessed by IHC. The relative copy numbers of SOX-2 and NOTCH1 and vimentin expression were determined by Real-Time qPCR. Results: Expression of vimentin was absent in tissues of the donor tumor. The levels of vimentin expression statistically significantly increased in xenografts (1+ and 3+). The SOX-2 and NOTCH1 relative copy numbers were statistically significantly increased in tissues of the donor tumor (0.9 and 0.7), compared to xenografts (1.5±0.03 and 1.7±0.03). Molecular genetic analysis demonstrated an association between an increased vimentin expression and changes in the relative copy numbers of SOX-2 and NOTCH1 (p = 0.013 and p = 0.0001). Conclusions: The relative copy numbers of SOX-2 and NOTCH1 genetic loci was associated with increased expression of the epithelial-mesenchymal transition marker vimentin in tumor tissue samples and changed with each new generation of orthotopic xenografts.

Analysis of the relative copy numbers of TP63, YAP1 and KMT2D genetic loci and EGFR expression in orthotopic patient-derived xenografts of cardioesophageal cancer in immunodeficient mice.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15033-e15033
Author(s):  
Anna S. Goncharova ◽  
Evgeniy N. Kolesnikov ◽  
Ekaterina V. Zaikina ◽  
A. V. Volkova ◽  
M. V. Mindar ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Nude Mice ◽  
Molecular Genetic ◽  
Molecular Genetic Analysis ◽  
Individual Characteristics ◽  
Genetic Loci ◽  
Cardiac Stomach ◽  
Immunodeficient Mice ◽  
Copy Numbers ◽  
Egfr Expression

e15033 Background: Cardioesophageal cancer is a common tumor affecting the cardiac stomach and lower esophagus. Tumor heterogeneity is important, since it can cause the ineffectiveness of chemotherapy and radiotherapy due to individual characteristics of the neoplasm in different patients, as well as the intensification of invasion and metastasis. Our purpose was to analyze the relative copy numbers of TP63, YAP1 and KMT2D genetic loci and EGFR expression in orthotopic patient-derived xenografts of cardioesophageal cancer. Methods: The model of cardioesophageal cancer was created in Balb/c Nude mice with surgical bioptates of adenocarcinoma obtained from donors. The relative copy numbers of TP63, YAP1 and KMT2D genetic loci and EGFR expression were determined by Real-Time qPCR. Results: A PDX model of cardioesophageal cancer was successfully created by transplanting a moderately differentiated adenocarcinoma from a patient diagnosed with infiltrative ulcerative cancer of the lower third of the esophagus with a transition to the cardiac stomach into the distal esophagus of Balb/c Nude mice. The EGFR expression was elevated in patient tumor samples, compared to healthy tissues (p = 0.021) and gastric cancer xenografts (p = 0.07). Molecular genetic analysis demonstrated an association between an increased EGFR expression and changes in the relative copy numbers of TP63, YAP1, and KMT2D in donor samples compared to gastric cancer xenografts (p = 0.02, p = 0.026 and p = 0.042). Conclusions: The relative copy numbers of TP63, YAP1, and KMT2D were associated with intensified EGFR expression and changed with each new generation of orthotopic xenografts.

scholarly journals MiRNA-200C expression in Fanconi anemia pathway functionally deficient lung cancers

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Wenrui Duan ◽  
Shirley Tang ◽  
Li Gao ◽  
Kathleen Dotts ◽  
Andrew Fink ◽  
...  
Keyword(s):  
Fanconi Anemia ◽  
Epithelial Mesenchymal Transition ◽  
Micro Rna ◽  
Negative Regulator ◽  
Migration And Invasion ◽  
Pcr Analysis ◽  
Tissue Samples ◽  
Lung Cancers ◽  
Mesenchymal Transition ◽  
Micro Rnas

AbstractThe Fanconi Anemia (FA) pathway is essential for human cells to maintain genomic integrity following DNA damage. This pathway is involved in repairing damaged DNA through homologous recombination. Cancers with a defective FA pathway are expected to be more sensitive to cross-link based therapy or PARP inhibitors. To evaluate downstream effectors of the FA pathway, we studied the expression of 734 different micro RNAs (miRNA) using NanoString nCounter miRNA array in two FA defective lung cancer cells and matched control cells, along with two lung tumors and matched non-tumor tissue samples that were deficient in the FA pathway. Selected miRNA expression was validated with real-time PCR analysis. Among 734 different miRNAs, a cluster of microRNAs were found to be up-regulated including an important cancer related micro RNA, miR-200C. MiRNA-200C has been reported as a negative regulator of epithelial-mesenchymal transition (EMT) and inhibits cell migration and invasion by promoting the upregulation of E-cadherin through targeting ZEB1 and ZEB2 transcription factors. miRNA-200C was increased in the FA defective lung cancers as compared to controls. AmpliSeq analysis showed significant reduction in ZEB1 and ZEB2 mRNA expression. Our findings indicate the miRNA-200C potentially play a very important role in FA pathway downstream regulation.

scholarly journals CD73 facilitates EMT progression and promotes lung metastases in triple-negative breast cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Nataliia Petruk ◽  
Sanni Tuominen ◽  
Malin Åkerfelt ◽  
Jesse Mattsson ◽  
Jouko Sandholm ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Epithelial Mesenchymal Transition ◽  
Lung Metastases ◽  
Vimentin Expression ◽  
Mesenchymal Transition ◽  
Cell Protrusion

AbstractCD73 is a cell surface ecto-5′-nucleotidase, which converts extracellular adenosine monophosphate to adenosine. High tumor CD73 expression is associated with poor outcome among triple-negative breast cancer (TNBC) patients. Here we investigated the mechanisms by which CD73 might contribute to TNBC progression. This was done by inhibiting CD73 with adenosine 5′-(α, β-methylene) diphosphate (APCP) in MDA-MB-231 or 4T1 TNBC cells or through shRNA-silencing (sh-CD73). Effects of such inhibition on cell behavior was then studied in normoxia and hypoxia in vitro and in an orthotopic mouse model in vivo. CD73 inhibition, through shRNA or APCP significantly decreased cellular viability and migration in normoxia. Inhibition of CD73 also resulted in suppression of hypoxia-induced increase in viability and prevented cell protrusion elongation in both normoxia and hypoxia in cancer cells. Sh-CD73 4T1 cells formed significantly smaller and less invasive 3D organoids in vitro, and significantly smaller orthotopic tumors and less lung metastases than control shRNA cells in vivo. CD73 suppression increased E-cadherin and decreased vimentin expression in vitro and in vivo, proposing maintenance of a more epithelial phenotype. In conclusion, our results suggest that CD73 may promote early steps of tumor progression, possibly through facilitating epithelial–mesenchymal transition.

scholarly journals RON Mediates Tumor-Promoting Effects in Endometrial Adenocarcinoma

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Qin Yu ◽  
Jianzhang Wang ◽  
Tiantian Li ◽  
Xinxin Xu ◽  
Xinyue Guo ◽  
...  
Keyword(s):  
Nude Mice ◽  
Reproductive Tract ◽  
Epithelial Mesenchymal Transition ◽  
Endometrial Adenocarcinoma ◽  
Female Reproductive Tract ◽  
Migration And Invasion ◽  
Smad Pathway ◽  
Mesenchymal Transition ◽  
Adenocarcinoma Cells

Endometrial adenocarcinoma is one of the most prevalent female reproductive tract cancers in the world, and the development of effective treatment is still the main goal of its current research. Epithelial-mesenchymal transition (EMT) plays a significant part in the occurrence and development of epithelial carcinoma, including endometrial adenocarcinoma. Recepteur d’origine nantais (RON) induces EMT and promotes proliferation, migration, and invasion in various epithelial-derived cancers, but its role in endometrial adenocarcinoma is still poorly studied. The purpose of this study is to verify the overexpression of RON in endometrial adenocarcinoma and to explore its specific roles. RON expression in tumor lesions was verified by immunohistochemical staining, HEC-1B cells were used to construct stable cell lines with RON overexpression or knockdown to investigate the effects of RON on the function of endometrial adenocarcinoma cells, and xenotransplantation experiment was carried out in nude mice to explore the effect of RON on the growth of endometrial adenocarcinoma in vivo. This study revealed that RON could promote the proliferation, migration, and invasion of HEC-1B cells and induce EMT, and these effects were regulated through the Smad pathway. RON overexpression could promote growth of endometrial adenocarcinoma cells in nude mice, while its inhibitor BMS777607 could restrict this role. RON played an important role in endometrial adenocarcinoma and had a potential to become a new therapeutic target for endometrial adenocarcinoma.

scholarly journals Pleckstrin-2 as a Prognostic Factor and Mediator of Gastric Cancer Progression

2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Jun Wang ◽  
Zhigang He ◽  
Bo Sun ◽  
Wenhai Huang ◽  
Jianbin Xiang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Patients ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
In Vivo Studies ◽  
Vimentin Expression ◽  
Mesenchymal Transition ◽  
Gastric Cancer Patients

Pleckstrin-2 (PLEK2) is a crucial mediator of cytoskeletal reorganization. However, the potential roles of PLEK2 in gastric cancer are still unknown. PLEK2 expression in gastric cancer was examined by western blotting and real-time PCR. Survival analysis was utilized to test the clinical impacts of the levels of PLEK2 in gastric cancer patients. In vitro and in vivo studies were used to estimate the potential roles played by PLEK2 in modulating gastric cancer proliferation, self-renewal, and tumourigenicity. Bioinformatics approaches were used to monitor the effect of PLEK2 on epithelial-mesenchymal transition (EMT) signalling pathways. PLEK2 expression was significantly upregulated in gastric cancer as compared with nontumour samples. Kaplan-Meier plotter analysis revealed that gastric cancer patients with higher PLEK2 levels had substantially poorer overall survival compared with gastric cancer patients with lower PLEK2 levels. The upregulation or downregulation of PLEK2 in gastric cancer cell lines effectively enhanced or inhibited cell proliferation and proinvasive behaviour, respectively. Additionally, we also found that PLEK2 enhanced EMT through downregulating E-cadherin expression and upregulating Vimentin expression. Our findings demonstrated that PLEK2 plays a potential role in gastric cancer and may be a novel therapeutic target for gastric cancer.

scholarly journals Heterogeneity in Circulating Tumor Cells: The Relevance of the Stem-Cell Subset

Cancers ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 483 ◽  
Author(s):  
Chiara Agnoletto ◽  
Fabio Corrà ◽  
Linda Minotti ◽  
Federica Baldassari ◽  
Francesca Crudele ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Epithelial Mesenchymal Transition ◽  
Cell Subset ◽  
Intermediate Phenotype ◽  
Current Evidence ◽  
Early Event ◽  
Tumor Type ◽  
Mesenchymal Transition ◽  
Immunodeficient Mice

The release of circulating tumor cells (CTCs) into vasculature is an early event in the metastatic process. The analysis of CTCs in patients has recently received widespread attention because of its clinical implications, particularly for precision medicine. Accumulated evidence documents a large heterogeneity in CTCs across patients. Currently, the most accepted view is that tumor cells with an intermediate phenotype between epithelial and mesenchymal have the highest plasticity. Indeed, the existence of a meta-stable or partial epithelial–mesenchymal transition (EMT) cell state, with both epithelial and mesenchymal features, can be easily reconciled with the concept of a highly plastic stem-like state. A close connection between EMT and cancer stem cells (CSC) traits, with enhanced metastatic competence and drug resistance, has also been described. Accordingly, a subset of CTCs consisting of CSC, present a stemness profile, are able to survive chemotherapy, and generate metastases after xenotransplantation in immunodeficient mice. In the present review, we discuss the current evidence connecting CTCs, EMT, and stemness. An improved understanding of the CTC/EMT/CSC connections may uncover novel therapeutic targets, irrespective of the tumor type, since most cancers seem to harbor a pool of CSCs, and disclose important mechanisms underlying tumorigenicity.

scholarly journals The Cuban Propolis Component Nemorosone Inhibits Proliferation and Metastatic Properties of Human Colorectal Cancer Cells

2020 ◽  
Vol 21 (5) ◽  
pp. 1827 ◽  
Author(s):  
Yahima Frión-Herrera ◽  
Daniela Gabbia ◽  
Michela Scaffidi ◽  
Letizia Zagni ◽  
Osmany Cuesta-Rubio ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Epithelial Mesenchymal Transition ◽  
Metastatic Potential ◽  
Migration And Invasion ◽  
Dependent Manner ◽  
Vimentin Expression ◽  
Mesenchymal Transition ◽  
Colorectal Cancer Cells ◽  
Folk Remedies ◽  
Main Component

The majority of deaths related to colorectal cancer (CRC) are associated with the metastatic process. Alternative therapeutic strategies, such as traditional folk remedies, deserve attention for their potential ability to attenuate the invasiveness of CRC cells. The aim of this study is to investigate the biological activity of brown Cuban propolis (CP) and its main component nemorosone (NEM) and to describe the molecular mechanism(s) by which they inhibit proliferation and metastatic potential of 2 CRC cell lines, i.e., HT-29 and LoVo. Our results show that CP and NEM significantly decreased cell viability and inhibited clonogenic capacity of CRC cells in a dose and time-dependent manner, by arresting the cell cycle in the G0/G1 phase and inducing apoptosis. Furthermore, CP and NEM downregulated BCL2 gene expression and upregulated the expression of the proapoptotic genes TP53 and BAX, with a consequent activation of caspase 3/7. They also attenuated cell migration and invasion by inhibiting MMP9 activity, increasing E-cadherin and decreasing β-catenin and vimentin expression, proteins involved in the epithelial–mesenchymal transition (EMT). In conclusion NEM, besides displaying antiproliferative activity on CRC cells, is able to decrease their metastatic potential by modulating EMT-related molecules. These finding provide new insight about the mechanism(s) of the antitumoral properties of CP, due to NEM content.

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