scholarly journals Downregulation of Immune Response- and External Stimulus-Related Genes in CRC Organoids, and Their Re-Expression by Co-Culturing with CAFs

2020 ◽  
Author(s):  
Mie Naruse ◽  
Masako Ochiai ◽  
Shigeki Sekine ◽  
Hirokazu Taniguchi ◽  
Teruhiko Yoshida ◽  
...  
Keyword(s):  
Immune Response ◽  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Culture System ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
External Stimulus ◽  
Preclinical Model ◽  
Tumor Tissues ◽  
Anti Cancer

Abstract Organoids derived from epithelial tumors have recently been utilized as a preclinical model in basic and translational studies. This model is considered to reproduce the features of cell-cell contacted and differentiated original tumor cells, but not the tumor microenvironment. In this study, we established organoids and paired cancer-associated fibroblasts (CAFs) from surgical specimens of colorectal carcinomas (CRCs), and evaluated gene expression profiles in organoids with and without co-culture with CAFs to assess interactions between tumor cells and CAFs in tumor tissues. We found that the expression levels of several genes, which are highly expressed in original CRC tissues, were downregulated in organoids but re-expressed by co-culturing with CAFs. They comprised immune response- and external stimulus-related genes, e.g., REG family and dual oxidases (DUOXs), which are known to have malignant functions, e.g., cell-proliferation and/or reducing apoptosis of epithelia and drug resistance for anti-cancer drugs in tumors. In addition, the degree of re-production of REG1 and DUOX2 in the co-culture system varied depending on CAFs from each CRC case. In conclusion, the co-culture system of CRC organoids with paired CAFs was able to partially reproduce the tumor microenvironment.

scholarly journals Re-expression of REG family and DUOXs genes in CRC organoids by co-culturing with CAFs

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Mie Naruse ◽  
Masako Ochiai ◽  
Shigeki Sekine ◽  
Hirokazu Taniguchi ◽  
Teruhiko Yoshida ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Culture System ◽  
Expression Profiles ◽  
3D Structure ◽  
Gene Expression Profiles ◽  
Cellular Heterogeneity ◽  
Preclinical Model ◽  
Drug Resistant ◽  
Tumor Tissues

AbstractOrganoids derived from epithelial tumors have recently been utilized as a preclinical model in basic and translational studies. This model is considered to represent the original tumor in terms of 3D structure, genetic and cellular heterogeneity, but not tumor microenvironment. In this study, we established organoids and paired cancer-associated fibroblasts (CAFs) from surgical specimens of colorectal carcinomas (CRCs), and evaluated gene expression profiles in organoids with and without co-culture with CAFs to assess interactions between tumor cells and CAFs in tumor tissues. We found that the expression levels of several genes, which are highly expressed in original CRC tissues, were downregulated in organoids but re-expressed in organoids by co-culturing with CAFs. They comprised immune response- and external stimulus-related genes, e.g., REG family and dual oxidases (DUOXs), which are known to have malignant functions, leading tumor cells to proliferative and/or anti-apoptotic states and drug resistant phenotypes. In addition, the degree of differential induction of REG1 and DUOX2 in the co-culture system varied depending on CAFs from each CRC case. In conclusion, the co-culture system of CRC organoids with paired CAFs was able to partially reproduce the tumor microenvironment.

scholarly journals Semaphorin Signaling in Cancer-Associated Inflammation

2019 ◽  
Vol 20 (2) ◽  
pp. 377 ◽  
Author(s):  
Giulia Franzolin ◽  
Luca Tamagnone
Keyword(s):  
Immune Response ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Disease Progression ◽  
Tumor Cells ◽  
Cross Talk ◽  
Immune Cells ◽  
Major Element ◽  
Inflammatory Cells ◽  
Anti Cancer

The inflammatory and immune response elicited by the growth of cancer cells is a major element conditioning the tumor microenvironment, impinging on disease progression and patients’ prognosis. Semaphorin receptors are widely expressed in inflammatory cells, and their ligands are provided by tumor cells, featuring an intense signaling cross-talk at local and systemic levels. Moreover, diverse semaphorins control both cells of the innate and the antigen-specific immunity. Notably, semaphorin signals acting as inhibitors of anti-cancer immune response are often dysregulated in human tumors, and may represent potential therapeutic targets. In this mini-review, we provide a survey of the best known semaphorin regulators of inflammatory and immune cells, and discuss their functional impact in the tumor microenvironment.

scholarly journals Modulation of the Immune Response by Deferasirox in Myelodysplastic Syndrome Patients

2021 ◽  
Vol 14 (1) ◽  
pp. 41
Author(s):  
Hana Votavova ◽  
Zuzana Urbanova ◽  
David Kundrat ◽  
Michaela Dostalova Merkerova ◽  
Martin Vostry ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Blood Cell ◽  
Myelodysplastic Syndrome ◽  
Molecular Mechanisms ◽  
Expression Profiles ◽  
Adaptive Immune Response ◽  
Gene Expression Profiles ◽  
Iron Chelator ◽  
Multiple Cancer

Deferasirox (DFX) is an oral iron chelator used to reduce iron overload (IO) caused by frequent blood cell transfusions in anemic myelodysplastic syndrome (MDS) patients. To study the molecular mechanisms by which DFX improves outcome in MDS, we analyzed the global gene expression in untreated MDS patients and those who were given DFX treatment. The gene expression profiles of bone marrow CD34+ cells were assessed by whole-genome microarrays. Initially, differentially expressed genes (DEGs) were determined between patients with normal ferritin levels and those with IO to address the effect of excessive iron on cellular pathways. These DEGs were annotated to Gene Ontology terms associated with cell cycle, apoptosis, adaptive immune response and protein folding and were enriched in cancer-related pathways. The deregulation of multiple cancer pathways in iron-overloaded patients suggests that IO is a cofactor favoring the progression of MDS. The DEGs between patients with IO and those treated with DFX were involved predominantly in biological processes related to the immune response and inflammation. These data indicate DFX modulates the immune response mainly via neutrophil-related genes. Suppression of negative regulators of blood cell differentiation essential for cell maturation and upregulation of heme metabolism observed in DFX-treated patients may contribute to the hematopoietic improvement.

scholarly journals P02.10 FocuSCOPE: a single cell, multi-omics solution to simultaneously analyze tumor variants and microenvironment

2021 ◽  
Vol 9 (Suppl 1) ◽  
pp. A12.1-A12
Author(s):  
Y Arjmand Abbassi ◽  
N Fang ◽  
W Zhu ◽  
Y Zhou ◽  
Y Chen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Tumor Microenvironment ◽  
Single Cell ◽  
High Throughput ◽  
Immune Cells ◽  
Genetic Variants ◽  
Expression Profiles ◽  
Single Cells ◽  
Gene Expression Profiles ◽  
Single Cell Sequencing

Recent advances of high-throughput single cell sequencing technologies have greatly improved our understanding of the complex biological systems. Heterogeneous samples such as tumor tissues commonly harbor cancer cell-specific genetic variants and gene expression profiles, both of which have been shown to be related to the mechanisms of disease development, progression, and responses to treatment. Furthermore, stromal and immune cells within tumor microenvironment interact with cancer cells to play important roles in tumor responses to systematic therapy such as immunotherapy or cell therapy. However, most current high-throughput single cell sequencing methods detect only gene expression levels or epigenetics events such as chromatin conformation. The information on important genetic variants including mutation or fusion is not captured. To better understand the mechanisms of tumor responses to systematic therapy, it is essential to decipher the connection between genotype and gene expression patterns of both tumor cells and cells in the tumor microenvironment. We developed FocuSCOPE, a high-throughput multi-omics sequencing solution that can detect both genetic variants and transcriptome from same single cells. FocuSCOPE has been used to successfully perform single cell analysis of both gene expression profiles and point mutations, fusion genes, or intracellular viral sequences from thousands of cells simultaneously, delivering comprehensive insights of tumor and immune cells in tumor microenvironment at single cell resolution.Disclosure InformationY. Arjmand Abbassi: None. N. Fang: None. W. Zhu: None. Y. Zhou: None. Y. Chen: None. U. Deutsch: None.

scholarly journals Circulating tumor cell characterization of lung cancer brain metastasis in the cerebrospinal fluid through single-cell transcriptome analysis

2020 ◽  
Author(s):  
Haoyu Ruan ◽  
Yihang Zhou ◽  
Jie Shen ◽  
Yue Zhai ◽  
Ying Xu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cerebrospinal Fluid ◽  
Single Cell ◽  
Tumor Cells ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Unknown Primary ◽  
Great Promise ◽  
Cell Cycle Gene

AbstractMetastatic lung cancer accounts for about half of the brain metastases (BM). Development of leptomeningeal metastases (LM) are becoming increasingly common, and its prognosis is still poor despite the advances in systemic and local approaches. Cytology analysis in the cerebrospinal fluid (CSF) remains the diagnostic gold standard. Although several previous studies performed in CSF have offered great promise for the diagnostics and therapeutics of LM, a comprehensive characterization of circulating tumor cells (CTCs) in CSF is still lacking. To fill this critical gap of lung adenocarcinoma LM (LUAD-LM), we analyzed the transcriptomes of 1,375 cells from 5 LUAD-LM patient and 3 control samples using single-cell RNA sequencing technology. We defined CSF-CTCs based on abundant expression of epithelial markers and genes with lung origin, as well as the enrichment of metabolic pathway and cell adhesion molecules, which are crucial for the survival and metastases of tumor cells. Elevated expression of CEACAM6 and SCGB3A2 was discovered in CSF-CTCs, which could serve as candidate biomarkers of LUAD-LM. We identified substantial heterogeneity in CSF-CTCs among LUAD-LM patients and within patient among individual cells. Cell-cycle gene expression profiles and the proportion of CTCs displaying mesenchymal and cancer stem cell properties also vary among patients. In addition, CSF-CTC transcriptome profiling identified one LM case as cancer of unknown primary site (CUP). Our results will shed light on the mechanism of LUAD-LM and provide a new direction of diagnostic test of LUAD-LM and CUP cases from CSF samples.

scholarly journals NITUMID: Nonnegative matrix factorization-based Immune-TUmor MIcroenvironment Deconvolution

2019 ◽  
Author(s):  
Daiwei Tang ◽  
Seyoung Park ◽  
Hongyu Zhao
Keyword(s):  
Tumor Microenvironment ◽  
Matrix Factorization ◽  
Nonnegative Matrix Factorization ◽  
Expression Profiles ◽  
Mrna Level ◽  
Nonnegative Matrix ◽  
Gene Expression Profiles ◽  
Cell Types ◽  
Supplementary Information ◽  
Mrna Levels

Abstract Motivation A number of computational methods have been proposed recently to profile tumor microenvironment (TME) from bulk RNA data, and they have proved useful for understanding microenvironment differences among therapeutic response groups. However, these methods are not able to account for tumor proportion nor variable mRNA levels across cell types. Results In this article, we propose a Nonnegative Matrix Factorization-based Immune-TUmor MIcroenvironment Deconvolution (NITUMID) framework for TME profiling that addresses these limitations. It is designed to provide robust estimates of tumor and immune cells proportions simultaneously, while accommodating mRNA level differences across cell types. Through comprehensive simulations and real data analyses, we demonstrate that NITUMID not only can accurately estimate tumor fractions and cell types’ mRNA levels, which are currently unavailable in other methods; it also outperforms most existing deconvolution methods in regular cell type profiling accuracy. Moreover, we show that NITUMID can more effectively detect clinical and prognostic signals from gene expression profiles in tumor than other methods. Availability and implementation The algorithm is implemented in R. The source code can be downloaded at https://github.com/tdw1221/NITUMID. Supplementary information Supplementary data are available at Bioinformatics online.

scholarly journals A Machine Learning Approach for Tracing Tumor Original Sites With Gene Expression Profiles

2020 ◽  
Vol 8 ◽  
Author(s):  
Xin Liang ◽  
Wen Zhu ◽  
Bo Liao ◽  
Bo Wang ◽  
Jialiang Yang ◽  
...  
Keyword(s):  
Machine Learning ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Metastatic Tumor ◽  
Unknown Primary ◽  
Clinical Practices ◽  
Tumor Tissues ◽  
Machine Learning Approach ◽  
Treatment Plans ◽  
Metastatic Sites

Some carcinomas show that one or more metastatic sites appear with unknown origins. The identification of primary or metastatic tumor tissues is crucial for physicians to develop precise treatment plans for patients. With unknown primary origin sites, it is challenging to design specific plans for patients. Usually, those patients receive broad-spectrum chemotherapy, while still having poor prognosis though. Machine learning has been widely used and already achieved significant advantages in clinical practices. In this study, we classify and predict a large number of tumor samples with uncertain origins by applying the random forest and Naive Bayesian algorithms. We use the precision, recall, and other measurements to evaluate the performance of our approach. The results have showed that the prediction accuracy of this method was 90.4 for 7,713 samples. The accuracy was 80% for 20 metastatic tumors samples. In addition, the 10-fold cross-validation is used to evaluate the accuracy of classification, which reaches 91%.

scholarly journals The Human Papillomavirus (HPV) E1 protein regulates the expression of cellular genes involved in immune response

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Leonardo Josué Castro-Muñoz ◽  
Joaquín Manzo-Merino ◽  
J. Omar Muñoz-Bello ◽  
Leslie Olmedo-Nieva ◽  
Alberto Cedro-Tanda ◽  
...  
Keyword(s):  
Immune Response ◽  
Human Papillomavirus ◽  
Defense Mechanisms ◽  
Viral Infections ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Antiviral Immune Response ◽  
E1 Protein ◽  
Cellular Genes ◽  
Proliferation And Differentiation

Abstract The Human Papillomavirus (HPV) E1 protein is the only viral protein with enzymatic activity. The main known function of this protein is the regulation of the viral DNA replication. Nevertheless, it has been demonstrated that the ablation of HPV18 E1 mRNA in HeLa cells promotes a deregulation of several genes, particularly those involved in host defense mechanisms against viral infections; however, the specific contribution of E1 protein in HPV-independent context has not been studied. The aim of this work was to determine the effect of the HPV E1 protein in the regulation of cellular gene expression profiles evaluated through RNA-seq. We found that E1 proteins from HPV16 and 18 induced an overexpression of different set of genes associated with proliferation and differentiation processes, as well as downregulation of immune response genes, including IFNβ1 and IFNλ1 and Interferon-stimulated gene (ISG), which are important components involved in the antiviral immune response. Together, our results indicate that HR-(High-Risk) and LR-(Low-Risk) HPV E1 proteins play an important role in inhibiting the anti-viral immune response.

High-diluted thymulin on Ehrlich tumor growth in mice and the importance of tumor microenvironment

2021 ◽  
Vol 17 (3-4) ◽  
pp. 20-41
Author(s):  
Juliana Gimenez Amaral ◽  
Thayna Neves Cardoso ◽  
Aloísio Cunha De Carvalho ◽  
Cideli de Paula Coelho ◽  
Silvia Waisse ◽  
...  
Keyword(s):  
Immune Response ◽  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Spleen Cell ◽  
Tumor Cells ◽  
Caspase 3 ◽  
Tumor Growth Rate ◽  
Cell Populations ◽  
Ehrlich Tumor ◽  
Systemic Immune Response

Introduction: The aim of the present study was to describe different biological aspects of Ehrlich tumor in mice, such as body weight evolution, tumor growth rate, histological organization and systemic immune response after treatment with high-diluted thymulin (10-9 M, named 5CH). Methods: Tumor assessment was focused on macro- and microscopic aspects; parameters included occurrence of necrosis, embolism and tumor development, in addition to quantitative analysis of apoptosis (caspase-3), cell proliferation (Ki-67) and angiogenesis (vascular endothelial growth factor - VEGF) by means of specific immunohistochemistry markers. Spleen cell populations were evaluated by flow cytometry analysis. Results: Mice treated with thymulin 5CH exhibited changes in the tumor microenvironment, such as reduced micro-embolism incidence and cytokeratin expression, with increased caspase-3 expression in the tumor cells. These findings indicate some apoptotic activity by the tumor cells induced by the treatment, even though no reduction of the macroscopic tumor mass occurred. No changes in the systemic immune response were detected, as the balance among spleen cell populations remained unchanged. Conclusions: The results indicate that treatment of mice bearing Ehrlich tumor with thymulin 5CH induces some specific changes in the tumor environment. However, it did not influence systemic immunity parameters. Adjuvant use of thymulin 5CH in oncological clinical practice is still a matter of discussion.

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