scholarly journals Modeling the effects of EMT-immune dynamics on epithelial cancer progression

2019 ◽  
Author(s):  
Daniel R. Bergman ◽  
Matthew K. Karikomi ◽  
Min Yu ◽  
Qing Nie ◽  
Adam L. MacLean
Keyword(s):  
Tumor Cell ◽  
Cancer Progression ◽  
Uterine Cancer ◽  
Cell Phenotype ◽  
Specific Gene ◽  
Epithelial Cancer ◽  
Free Survival ◽  
Mesenchymal Transition ◽  
New Genes

During progression from carcinoma in situ to an invasive tumor, the immune system is engaged in complex sets of interactions with various tumor cells. Tumor cell plasticity also alters disease trajectories via epithelial-to-mesenchymal transition (EMT). Several of the same pathways that regulate EMT are involved in tumor-immune interactions, yet little is known about the mechanisms and consequences of crosstalk between these regulatory processes. Here we introduce a multiscale evolutionary model to describe tumor-immune-EMT interactions and their impact on epithelial cancer progression from in situ to invasive disease. Through in silico analyses of large patient cohorts, we find controllable regions that maximize invasion-free survival. We identify that delaying tumor progression depends crucially on properties of the mesenchymal tumor cell phenotype: its growth rate and its immune-evasiveness. Through analysis of EMT-inflammation-associated data from The Cancer Genome Atlas, we find that association with EMT significantly worsens invasion-free survival probabilities in support of our model, and we predict new genes influencing outcomes in bladder and uterine cancer, including FGF pathway members. These results offer novel means to delay disease progression by regulating properties of EMT through specific gene interactions, and demonstrate the importance of studying cancer-immune interactions in light of EMT.

scholarly journals Modeling the effects of EMT-immune dynamics on carcinoma disease progression

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Daniel R. Bergman ◽  
Matthew K. Karikomi ◽  
Min Yu ◽  
Qing Nie ◽  
Adam L. MacLean
Keyword(s):  
Tumor Cell ◽  
Disease Progression ◽  
Cancer Progression ◽  
Epithelial To Mesenchymal Transition ◽  
Uterine Cancer ◽  
The Cancer Genome Atlas ◽  
Cell Phenotype ◽  
Free Survival ◽  
Mesenchymal Transition

AbstractDuring progression from carcinoma in situ to an invasive tumor, the immune system is engaged in complex sets of interactions with various tumor cells. Tumor cell plasticity alters disease trajectories via epithelial-to-mesenchymal transition (EMT). Several of the same pathways that regulate EMT are involved in tumor-immune interactions, yet little is known about the mechanisms and consequences of crosstalk between these regulatory processes. Here we introduce a multiscale evolutionary model to describe tumor-immune-EMT interactions and their impact on epithelial cancer progression from in situ to invasive disease. Through simulation of patient cohorts in silico, the model predicts that a controllable region maximizes invasion-free survival. This controllable region depends on properties of the mesenchymal tumor cell phenotype: its growth rate and its immune-evasiveness. In light of the model predictions, we analyze EMT-inflammation-associated data from The Cancer Genome Atlas, and find that association with EMT worsens invasion-free survival probabilities. This result supports the predictions of the model, and leads to the identification of genes that influence outcomes in bladder and uterine cancer, including FGF pathway members. These results suggest new means to delay disease progression, and demonstrate the importance of studying cancer-immune interactions in light of EMT.

scholarly journals Cell-free DNA promotes malignant transformation in non-tumor cells

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Aline Gomes de Souza ◽  
Victor Alexandre F. Bastos ◽  
Patricia Tieme Fujimura ◽  
Izabella Cristina C. Ferreira ◽  
Letícia Ferro Leal ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Tumor Cells ◽  
Malignant Transformation ◽  
Cancer Progression ◽  
Biological Fluids ◽  
Cellular Migration ◽  
Cell Phenotype ◽  
Cell Free Dna ◽  
Prostate Cell ◽  
Free Dna

AbstractCell-free DNA is present in different biological fluids and when released by tumor cells may contribute to pro-tumor events such as malignant transformation of cells adjacent to the tumor and metastasis. Thus, this study analyzed the effect of tumor cell-free DNA, isolated from the blood of prostate cancer patients, on non-tumor prostate cell lines (RWPE-1 and PNT-2). To achieve this, we performed cell-free DNA quantification and characterization assays, evaluation of gene and miRNA expression profiling focused on cancer progression and EMT, and metabolomics by mass spectrometry and cellular migration. The results showed that tumor-free cell DNA was able to alter the gene expression of MMP9 and CD44, alter the expression profile of nine miRNAs, and increased the tryptophan consumption and cell migration rates in non-tumor cells. Therefore, tumor cell-free DNA was capable of altering the receptor cell phenotype, triggering events related to malignant transformation in these cells, and can thus be considered a potential target for cancer diagnosis and therapy.

scholarly journals Expression of E-cadherin and specific CXCR3 isoforms impact each other in prostate cancer

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Bo Ma ◽  
Ahmad Khazali ◽  
Hanshuang Shao ◽  
Yuhan Jiang ◽  
Alan Wells
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Surface Expression ◽  
Cell Phenotype ◽  
Reciprocal Regulation ◽  
Mesenchymal Transition ◽  
Protein Levels ◽  
E Cadherin

Abstract Background Carcinoma cells shift between epithelial and mesenchymal phenotypes during cancer progression, as defined by surface presentation of the cell-cell cohesion molecule E-cadherin, affecting dissemination, progression and therapy responsiveness. Concomitant with the loss of E-cadherin during the mesenchymal transition, the predominant receptor isoform for ELR-negative CXC ligands shifts from CXCR3-B to CXCR3-A which turns this classical G-protein coupled receptor from an inhibitor to an activator of cell migration, thus promoting tumor cell invasiveness. We proposed that CXCR3 was not just a coordinately changed receptor but actually a regulator of the cell phenotype. Methods Immunoblotting, immunofluorescence, quantitative real-time PCR and flow cytometry assays investigated the expression of E-cadherin and CXCR3 isoforms. Intrasplenic inoculation of human prostate cancer (PCa) cells with spontaneous metastasis to the liver analyzed E-cadherin and CXCR3-B expression during cancer progression in vivo. Results We found reciprocal regulation of E-cadherin and CXCR3 isoforms. E-cadherin surface expression promoted CXCR3-B presentation on the cell membrane, and to a lesser extent increased its mRNA and total protein levels. In turn, forced expression of CXCR3-A reduced E-cadherin expression level, whereas CXCR3-B increased E-cadherin in PCa. Meanwhile, a positive correlation of E-cadherin and CXCR3-B expression was found both in experimental PCa liver micro-metastases and patients’ tissue. Conclusions CXCR3-B and E-cadherin positively correlated in vitro and in vivo in PCa cells and liver metastases, whereas CXCR3-A negatively regulated E-cadherin expression. These results suggest that CXCR3 isoforms may play important roles in cancer progression and dissemination via diametrically regulating tumor’s phenotype.

scholarly journals Epithelial-to-mesenchymal transition lowers the cholesterol pathway, wich influences colon tumors differentiation.

2021 ◽  
Author(s):  
Anais Aulas ◽  
Maria-Lucia Liberatoscioli ◽  
Pascal Finetti ◽  
Olivier Cabaud ◽  
David J Birnbaum ◽  
...  
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Disease Evolution ◽  
Mesenchymal Transition ◽  
New Genes ◽  
Mesenchymal To Epithelial Transition ◽  
Vitro Model ◽  
New Biomarkers ◽  
Cancer Tissues

Colorectal cancer (CRC) is the second cause of death worldwide. Up to 70% of CRC patients will metastasize at one point. Understanding the chain of events that lead to metastasis occurrence is urgent to identify new biomarkers of progression or new targets to prevent and delay disease evolution. Epithelial to mesenchymal transition (EMT) is a major program engaged during metastasis. EMT is extremely complex to analyze in situ due to the broad involvement of its transcription factors. We hypothesized that a relevant and dynamic in vitro model of pure cancer cells will reveal a combination of new genes that might further identify signs of EMT in cancer tissues. We treated HT-29 cells grown in 3D with an EMT-inducing factor, but also looked at reverse changes after EMT-inducing factor removal. For each condition, pan-transcriptomic analyses were done. Genes that were both induced upon EMT induction and inhibited upon EMT release (mesenchymal to epithelial transition or MET) were selected. Consistent with our hypothesis, we identified new genes for the EMT-MET programs. These genes were used to build a metagene that, when applied to a large database of transcriptomic data from primary colorectal tumors (n= 2,239), had an independent prognosis value. Finally, we submitted this metagene to CMap and identified drugs that might affect EMT-MET programs. Statins, well-known inhibitors of cholesterol synthesis, were among them and effectively delayed MET in vitro. These data show that cholesterol and EMT pathways are opposite regulators and impact differently tumors differentiation and outcome.

Combining Multiplex SERS Nanovectors and Multivariate Analysis for In Situ Profiling of Circulating Tumor Cell Phenotype Using a Microfluidic Chip

Small ◽  
2018 ◽  
Vol 14 (20) ◽  
pp. 1704433 ◽  
Author(s):  
Yizhi Zhang ◽  
Zhuyuan Wang ◽  
Lei Wu ◽  
Shenfei Zong ◽  
Binfeng Yun ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Tumor Cell ◽  
Microfluidic Chip ◽  
Circulating Tumor Cell ◽  
Cell Phenotype

scholarly journals Extracellular Vesicles: A New Perspective in Tumor Therapy

2018 ◽  
Vol 2018 ◽  
pp. 1-7 ◽  
Author(s):  
Yan-Zi Sun ◽  
Jun-Shan Ruan ◽  
Zong-Sheng Jiang ◽  
Ling Wang ◽  
Shao-Ming Wang
Keyword(s):  
Cell Growth ◽  
Tumor Microenvironment ◽  
Tumor Cell ◽  
Extracellular Vesicles ◽  
Cancer Progression ◽  
Immune Therapy ◽  
Tumor Therapy ◽  
Critical Role ◽  
Mesenchymal Transition

In recent years, the study of extracellular vesicles has been booming across various industries. Extracellular vesicles are considered one of the most important physiological endogenous carriers for the specific delivery of molecular information (nucleonic acid, cytokines, enzymes, etc.) between cells. It has been discovered that they perform a critical role in promoting tumor cell growth, proliferation, tumor cell invasion, and metastatic ability and regulating the tumor microenvironment to promote tumor cell communication and metastasis. In this review, we will discuss (1) the mechanism of extracellular vesicles generation, (2) their role in tumorigenesis and cancer progression (cell growth and proliferation, tumor microenvironment, epithelial-mesenchymal transition (EMT), invasion, and metastasis), (3) the role of extracellular vesicles in immune therapy, (4) extracellular vesicles targeting in tumor therapy, and (5) the role of extracellular vesicles as biomarkers. It is our hope that better knowledge and understanding of the extracellular vesicles will offer a wider range of effective therapeutic targets for experimental tumor research.

MicroRNA regulation of radiation sensitivity in colorectal cancers.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 608-608
Author(s):  
Shushan Rajesh Rana ◽  
Katherine Kelley ◽  
Rebecca Ruhl ◽  
Charles R. Thomas ◽  
Vassiliki Liana Tsikitis ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Cancer Progression ◽  
Epithelial To Mesenchymal Transition ◽  
Locally Advanced ◽  
Radiation Sensitivity ◽  
Colorectal Cancers ◽  
Specific Gene ◽  
Mesenchymal Transition

608 Background: Patients with locally advanced colorectal cancer (T3/T4/Node positive) receive neoadjuvant chemoradiation therapy (CRT) and subsequent surgery. While 10-25% of patients have complete response to CRT, the remaining patients undergo extensive tumor excision that leads to quality of life issues. Response to CRT is an independent predictor of overall survival highlighting the importance of improving CRT response rates. Several tumor intrinsic factors govern responses to CRT including specific gene expression programs. Emerging evidence suggests that microRNAs (miRs) modulate gene expression programs in response to radiation. Moreover, miR-processing machinery is frequently mutated in colorectal cancers (TCGA, 2016 provisional). miRs have been implicated in several pathological processes associated with colorectal cancer progression including cancer stemness and epithelial-to-mesenchymal transition (EMT). In this context, we hypothesized that differential expression of miRs regulates colorectal cancer radiation sensitivity and therefore can be used as a biomarker to predict therapeutic responses to radiation. Methods: To investigate the differences in miR profiles between rectal cancer patients that had either a pathological partial response (PR) or no response (NR), we isolated RNA from FFPE biopsies using the miRvana microRNA isolation kit (Life Technologies). We used the Nanostring miR profiling platform and obtained absolute counts for > 700 human miRs of which ~500 miRs were expressed above detection limits (cut-off of 20 counts after normalization to the top-100 miRs). We performed in vitro gain and loss of studies with miR transfections in human CRC cell lines with RNAimax reagent and used a luminescence-based assay for proliferation (Cell titer glo, Promega). We performed surviving fraction assays by seeding cells on 6 well plate and counting colonies stained with Methylene Blue. Results: We identified seventeen miRs that were differentially expressed. Among the most upregulated in this group, miR-451a, inhibited proliferation and colony formation in 2D and 3D assays in the presence of radiation. Conclusions: Our data suggests miRs may alter cell survival pathways and affect tumor radiosensitivity.

scholarly journals Context Matters: NOTCH Signatures and Pathway in Cancer Progression and Metastasis

Cells ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 94
Author(s):  
Julia O. Misiorek ◽  
Alicja Przybyszewska-Podstawka ◽  
Joanna Kałafut ◽  
Beata Paziewska ◽  
Katarzyna Rolle ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Notch Signaling ◽  
Cancer Cells ◽  
Cell Fate ◽  
Cancer Progression ◽  
Human Cancer ◽  
Tumor Biology ◽  
Solid Cancer ◽  
Term Survival ◽  
Mesenchymal Transition

The Notch signaling pathway is a critical player in embryogenesis but also plays various roles in tumorigenesis, with both tumor suppressor and oncogenic activities. Mutations, deletions, amplifications, or over-expression of Notch receptors, ligands, and a growing list of downstream Notch-activated genes have by now been described for most human cancer types. Yet, it often remains unclear what may be the functional impact of these changes for tumor biology, initiation, and progression, for cancer therapy, and for personalized medicine. Emerging data indicate that Notch signaling can also contribute to increased aggressive properties such as invasion, tumor heterogeneity, angiogenesis, or tumor cell dormancy within solid cancer tissues; especially in epithelial cancers, which are in the center of this review. Notch further supports the “stemness” of cancer cells and helps define the stem cell niche for their long-term survival, by integrating the interaction between cancer cells and the cells of the tumor microenvironment (TME). The complexity of Notch crosstalk with other signaling pathways and its roles in cell fate and trans-differentiation processes such as epithelial-to-mesenchymal transition (EMT) point to this pathway as a decisive player that may tip the balance between tumor suppression and promotion, differentiation and invasion. Here we not only review the literature, but also explore genomic databases with a specific focus on Notch signatures, and how they relate to different stages in tumor development. Altered Notch signaling hereby plays a key role for tumor cell survival and coping with a broad spectrum of vital issues, contributing to failed therapies, poor patient outcome, and loss of lives.

scholarly journals Primary Anaplastic Large-Cell Lymphoma in Adults: Clinical Presentation, Immunophenotype, and Outcome

Blood ◽  
1997 ◽  
Vol 90 (9) ◽  
pp. 3727-3734 ◽  
Author(s):  
Hervé Tilly ◽  
Philippe Gaulard ◽  
Eric Lepage ◽  
Charles Dumontet ◽  
Jacques Diebold ◽  
...  
Keyword(s):  
Overall Survival ◽  
Tumor Cell ◽  
Anaplastic Large Cell Lymphoma ◽  
Cell Lymphoma ◽  
Large Cell ◽  
Cell Phenotype ◽  
Event Free Survival ◽  
Free Survival ◽  
Response To Chemotherapy ◽  
Large Cell Lymphoma

Abstract Anaplastic, CD30+, large-cell lymphoma is now a well-recognized pathologic entity that accounts for 2% to 8% of all lymphomas. Recent progress has been made in the understanding of certain biologic features found in anaplastic large-cell lymphoma, but information about its clinical behavior, in comparison to other large-cell lymphomas, is limited. The pathologic review of a large multicenter study of the treatment of aggressive lymphoma identified 146 cases of anaplastic large-cell lymphoma (ALCL) on the basis of morphology and CD30 expression. We compared initial presentation, immunophenotype, and clinical outcome of these cases with those of the 1,695 nonanaplastic diffuse large-cell lymphomas (non-ALCL) included in the same trial. Patients with ALCL were more likely to be male (P = .018) and were younger (P < .0001) than those with non-ALCL. B symptoms were more frequent in ALCL (P = .006). Skin (P < .0001) and lung (P < .05) involvement was also more frequent in ALCL, but frequency of bone marrow involvement was identical (P = .5). Tumor cell phenotype was B in 56 cases (38%), T in 49 cases (34%), and null in 33 cases (22%). Response to chemotherapy (P = .001), event-free survival (P = .006), and overall survival (P = .0004) were better for ALCL than for non-ALCL. Multivariate analyses identified anaplastic character as an independent factor that predicted a longer survival. Tumor cell phenotype did not influence event-free survival (P = .72) or overall survival (P = .83). ALCL in adults is a clinicopathologic entity which, independent of its phenotypic characteristics, has a better outcome than other diffuse large-cell lymphomas.

scholarly journals Circulating Tumor Cells and Fibronectin 1 in the Prognosis of Nasopharyngeal Carcinoma

2020 ◽  
Vol 19 ◽  
pp. 153303382090991
Author(s):  
Ying Yu ◽  
Zhi-Xiu Lin ◽  
Hai-Wen Li ◽  
Hai-Qing Luo ◽  
Dong-Hong Yang ◽  
...  
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Messenger Rna ◽  
Progression Free Survival ◽  
Circulating Tumor Cell ◽  
Free Survival ◽  
Rna In Situ Hybridization

Objective: Nasopharyngeal carcinoma is highly endemic in Southeast China. Circulating tumor cell is an important biomarker in the prognosis of variety kinds of cancers. Overexpression of fibronectin 1 was observed in variety kinds of malignancies and may contribute to progress and metastasis of the cancers. The current study was aimed to investigate phenotypes of circulating tumor cell in nasopharyngeal carcinoma blood and fibronectin 1 expression in the circulating tumor cell, and their clinical application in predicting nasopharyngeal carcinoma prognosis. Methods: Blood samples were obtained from nasopharyngeal carcinoma patients before and after treatment. CanPatrol circulating tumor cell enrichment and RNA in situ hybridization were applied to identify circulating tumor cell and its phenotypes. Fibronectin 1 messenger RNA expression in the cells of circulating tumors was examined by messenger RNA-in situ hybridization. Results: Circulating tumor cell was not associated with tumor characteristics or lymph node metastasis. Patients with >9 circulating tumor cells or >5 mesenchymal phenotype circulating tumor cell per 5-mL blood had poorer progression-free survival ( P < .05). Multivariable analysis demonstrated that 2 or more mesenchymal phenotype circulating tumor cells with high fibronectin 1 messenger RNA expression predicted shorter progression-free survival ( P < .05). Conclusions: Circulating tumor cells with high-level fibronectin 1 expression was associated with poor survival in patients with nasopharyngeal carcinoma and could be an independent prognostic factor for nasopharyngeal carcinoma.

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