scholarly journals Activation of the GPR35 pathway drives angiogenesis in the tumour microenvironment

Gut ◽  
2021 ◽  
pp. gutjnl-2020-323363
Author(s):  
Ester Pagano ◽  
Joshua E Elias ◽  
Georg Schneditz ◽  
Svetlana Saveljeva ◽  
Lorraine M Holland ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Tumour Growth ◽  
Tumour Microenvironment ◽  
Tube Formation ◽  
Tissue Remodelling ◽  
Colon Cancers ◽  
Inflammatory Bowel ◽  
Ion Pumping ◽  
G Protein Coupled

ObjectivePrimary sclerosing cholangitis (PSC) is in 70% of cases associated with inflammatory bowel disease. The hypermorphic T108M variant of the orphan G protein-coupled receptor GPR35 increases risk for PSC and ulcerative colitis (UC), conditions strongly predisposing for inflammation-associated liver and colon cancer. Lack of GPR35 reduces tumour numbers in mouse models of spontaneous and colitis associated cancer. The tumour microenvironment substantially determines tumour growth, and tumour-associated macrophages are crucial for neovascularisation. We aim to understand the role of the GPR35 pathway in the tumour microenvironment of spontaneous and colitis-associated colon cancers.DesignMice lacking GPR35 on their macrophages underwent models of spontaneous colon cancer or colitis-associated cancer. The role of tumour-associated macrophages was then assessed in biochemical and functional assays.ResultsHere, we show that GPR35 on macrophages is a potent amplifier of tumour growth by stimulating neoangiogenesis and tumour tissue remodelling. Deletion of Gpr35 in macrophages profoundly reduces tumour growth in inflammation-associated and spontaneous tumour models caused by mutant tumour suppressor adenomatous polyposis coli. Neoangiogenesis and matrix metalloproteinase activity is promoted by GPR35 via Na/K-ATPase-dependent ion pumping and Src activation, and is selectively inhibited by a GPR35-specific pepducin. Supernatants from human inducible-pluripotent-stem-cell derived macrophages carrying the UC and PSC risk variant stimulate tube formation by enhancing the release of angiogenic factors.ConclusionsActivation of the GPR35 pathway promotes tumour growth via two separate routes, by directly augmenting proliferation in epithelial cells that express the receptor, and by coordinating macrophages’ ability to create a tumour-permissive environment.

Role of MicroRNAs in Colon Cancer Progression and Metastasis

2020 ◽  
Vol 20 ◽  
Author(s):  
Shruthi Sanjitha Sampath ◽  
Sivaramakrishnan Venkatabalsubramanian ◽  
Satish Ramalingam
Keyword(s):  
Colon Cancer ◽  
Cancer Progression ◽  
Target Genes ◽  
Tumour Progression ◽  
Intestinal Barrier ◽  
Colon Cancer Progression ◽  
Bowel Diseases ◽  
Inflammatory Bowel ◽  
Novel Therapeutic Strategies

: MicroRNAs regulate gene expression at the posttranscriptional level by binding to the mRNA of their target genes. The dysfunction of miRNAs is strongly associated with the inflammation of the colon. Besides, some microRNAs are shown to suppress tumours while others promote tumour progression and metastasis. Inflammatory bowel diseases include Crohn’s disease and Ulcerative colitis which increase the risk factor for inflammation-associated colon cancer. MicroRNAs are shown to be involved in gastrointestinal pathologies, by targeting the transcripts encoding proteins of the intestinal barrier and their regulators that are associated with inflammation and colon cancer. Detection of these microRNAs in the blood, serum, tissues, faecal matter, etc will enable us to use these microRNAs as biomarkers for early detection of the associated malignancies and design novel therapeutic strategies to overcome the same. Information on MicroRNAs can be applied for the development of targeted therapies against inflammation-mediated colon cancer.

scholarly journals Correlation Between Immune Lymphoid Cells and Plasmacytoid Dendritic Cells in Human Colon Cancer

2020 ◽  
Author(s):  
Jing Wu ◽  
Hang Cheng ◽  
Tete Li ◽  
Helei Wang ◽  
Guoxia Zang ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Dendritic Cells ◽  
Rna Sequencing ◽  
Immune Cells ◽  
Human Colon ◽  
Tumour Microenvironment ◽  
Plasmacytoid Dendritic Cells ◽  
Lymphoid Cells ◽  
Human Colon Cancer

Abstract Background: Innate lymphoid cells (ILCs), so far studied mostly in mouse models, are important tissue-resident innate immune cells that play important roles in the colorectal cancer microenvironment and maintain the mucosal tissue homeostasis. Plasmacytoid dendritic cells (pDCs) present complexity in various tumour types and are correlated with poor prognosis. pDCs can promote HIV-1–induced group 3 ILC (ILC3) depletion through the CD95 pathway. However, the role of ILC3s in human colon cancer and their correlation with other immune cells, especially pDCs, remain unclear. Methods: We characterised ILCs and pDCs in the tumour microenvironment of 58 colon cancer patients by flow cytometry and selected three patients for RNA sequencing. Results: ILC3s were negatively correlated, and pDCs were positively correlated, with cancer pathological grade. There was a negative correlation between the numbers of ILC3s and pDCs in tumour tissues. RNA sequencing confirmed the correlations between ILC3s and pDCs and highlighted the potential function of many ILC- and pDC-associated differentially expressed genes in the regulation of tumour immunity. pDCs can induce apoptosis of ILC3s through the CD95 pathway in the tumour microenvironment. Conclusions: One of the interactions between ILC3s and pDCs is via the CD95 pathway, which may help explain the role of ILC3s in colon cancer.

The Multifaceted Role of Natural Agents in Colitis-Associated Cancer Prevention and Therapy

2021 ◽  
pp. 220-239
Author(s):  
Ashok Kumar Kumar Pandurangan ◽  
Suresh Kumar Anandasadagopan ◽  
Neesar Ahmed
Keyword(s):  
Oxidative Stress ◽  
Ulcerative Colitis ◽  
Inflammatory Bowel Disease ◽  
Colon Cancer ◽  
The Other ◽  
Preclinical Model ◽  
Natural Agents ◽  
Inflammatory Bowel ◽  
Prevention And Therapy

Inflammatory bowel disease (IBD) is comprised of ulcerative colitis (UC) and Crohn's disease (CD) that was recognized by the inflammation in the colon. There are no proper medications are available to control the IBD in patients. NASIDs such as Aspirin, diclofenac, and ibuprofen are widely used to control the inflammation. On the other hand, the untreated prolonged inflammation leads to the development of cancer in the colon termed as colitis-associated cancer or inflammation-driven colon cancer. Oxidative stress and inflammation play key roles in the pathogenesis of colitis-associated cancer. Single dose of azozymethane (AOM) and three cycles of 2% dextran sodium sulfate (DSS) induces colitis-associated cancer (CAC) in mouse. Hence, many natural products were tested in the preclinical model of colitis-associated cancer. Each of these natural agents modulate important signaling pathway to control the colitis-associated cancer (CAC). In this review, the authors tabulated all the natural agents that culminate the colitis-associated cancer in the preclinical models.

scholarly journals THE ROLE OF ADIPOCYTOKINES IN COLON CANCER AND ADENOMAS / ULOGA ADIPOCITOKINA U KANCERU I ADENOMIMA DEBELOG CREVA

2013 ◽  
Vol 33 (2) ◽  
pp. 135-142 ◽  
Author(s):  
Feti Tulubas ◽  
Rafet Mete ◽  
Meltem Oznur ◽  
Birol Topcu
Keyword(s):  
Colon Cancer ◽  
Pearson Correlation ◽  
Continuous Variables ◽  
Colon Adenoma ◽  
Bowel Diseases ◽  
Inflammatory Bowel ◽  
And Control ◽  
The Relationship ◽  
Insulin Insensitivity

Summary Metabolic changes resulting from obesity, insulin insensitivity, and imbalances in hormones such as adiponectin, leptin, resistin, apelin and visfatin, which are derived from white adipose tissue-derived hormone, are directly linked to both colon cancer (CC) and inflammatory bowel diseases increasing tissue-derived risk. We conducted this study to evaluate the relationship between the circulating concentrations of adiponectin, leptin, resistin, apelin and visfatin and colon adenoma and CC. Our study included 90 participants aged >18 years who were divided into three groups: colon cancer, adenoma and control. The serum concentrations of the investigated adipohormones were measured with ELISA in 30 patients with colon adenoma, 30 with CC and 30 controls with no colon pathology. Demographic, anthropometric, metabolic and hormonal parameters were also recorded. The group means were compared by using one-way analysis of variance (ANOVA). Dual comparisons between groups were analyzed with the Tukey test. Pearson correlation coefficient was used to determine the relation between continuous variables. Adiponectin and leptin levels in patients with adenomas (p<0.000; p<0.000, respectively) and CC (p<0.000; p<0.000, respectively) were lower than in controls. Apelin level in patients with CC (p<0.000; p<0.000, respectively) was lower than in patients with adenomas and in controls. Resistin and visfatin levels in patients with CC (p<0.000; p<0.000, respectively) were higher than in patients with adenomas and in controls.

scholarly journals The EBI2-oxysterol axis promotes the development of intestinal lymphoid structures and colitis

2018 ◽  
Author(s):  
Annika Wyss ◽  
Tina Raselli ◽  
Gérard Schmelczer ◽  
Glynis Klinke ◽  
Nathan Perkins ◽  
...  
Keyword(s):  
Immune System ◽  
Gene Encoding ◽  
Barr Virus ◽  
Dss Colitis ◽  
Inflammatory Bowel ◽  
Epstein Barr ◽  
Lymphoid Structures ◽  
G Protein Coupled ◽  
Colitis Model

AbstractThe gene encoding for Epstein-Barr virus-induced G-protein coupled receptor 2 (EBI2) is a risk gene for inflammatory bowel disease (IBD). Together with its oxysterol ligand 7α,25-dihydroxycholesterol, EBI2 mediates migration and differentiation of immune cells. However, the role of EBI2 in the colonic immune system remains insufficiently studied.We found increased mRNA expression of EBI2 and oxysterol synthesizing enzymes (CH25H, CYP7B1) in the inflamed colon of patients with ulcerative colitis and mice with acute or chronic dextran sulfate sodium (DSS) colitis. Accordingly, we detected elevated extraintestinal levels of 25-hydroxylated oxysterols, including 7α,25-dihydroxycholesterol in mice with acute colonic inflammation. Knockout of EBI2 or CH25H did not affect severity of DSS colitis; however, inflammation was decreased in male EBI2-/- mice in the IL-10 colitis model.The colonic immune system comprises mucosal lymphoid structures, which accumulate upon chronic inflammation in IL-10-deficient mice and in chronic DSS colitis. However, EBI2-/- mice formed significantly less colonic lymphoid structures at baseline and showed defects in inflammation-induced accumulation of lymphoid structures.In summary, we report induction of the EBI2-7α,25-dihydroxycholesterol axis in colitis and a role of EBI2 for the accumulation of lymphoid tissue during homeostasis and inflammation. These data implicate the EBI2-7α,25-dihydroxycholesterol axis in IBD pathogenesis.

scholarly journals Multifunctional role of GPCR signaling in epithelial tube formation

2022 ◽  
Author(s):  
Vishakha Vishwakarma ◽  
Thao Phuong Le ◽  
SeYeon Chung
Keyword(s):  
Rho Kinase ◽  
Tube Formation ◽  
Dependent Manner ◽  
Cortical Actin ◽  
Apical Constriction ◽  
Gpcr Signaling ◽  
Epithelial Tube ◽  
Cellular Forces ◽  
G Protein Coupled

Epithelial tube formation requires Rho1-dependent actomyosin contractility to generate the cellular forces that drive cell shape changes and rearrangement. Rho1 signaling is activated by G protein-coupled receptor (GPCR) signaling at the cell surface. During Drosophila embryonic salivary gland (SG) invagination, the GPCR ligand Folded gastrulation (Fog) activates Rho1 signaling to drive apical constriction. The SG receptor that transduces the Fog signal into Rho1-dependent myosin activation has not been identified. Here, we reveal that the Smog GPCR transduces Fog signal to regulate Rho kinase accumulation and myosin activation in the apicomedial region of cells to control apical constriction during SG invagination. We also report on unexpected Fog-independent roles for Smog in maintaining epithelial integrity and organizing cortical actin. Our data supports a model wherein Smog regulates distinct myosin pools and actin cytoskeleton in a ligand-dependent manner during epithelial tube formation.

Mo1385 Role of the Colon Cancer Screening Programme on Inflammatory Bowel Disease New Diagnosis. One Year Experience in an Italian North-East Area

2013 ◽  
Vol 144 (5) ◽  
pp. S-652
Author(s):  
Tiziana Slongo ◽  
Roberto Marcello ◽  
Francesco Ferrara ◽  
Alberto Furlanetto ◽  
Helena Heras Salvat ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Colon Cancer ◽  
Screening Programme ◽  
Colon Cancer Screening ◽  
North East ◽  
Cancer Screening Programme ◽  
Inflammatory Bowel ◽  
One Year ◽  
New Diagnosis

scholarly journals Intersection of Brain Development and Paediatric Diffuse Midline Gliomas: Potential Role of Microenvironment in Tumour Growth

2018 ◽  
Vol 8 (11) ◽  
pp. 200 ◽  
Author(s):  
Katie Loveson ◽  
Helen Fillmore
Keyword(s):  
Tumour Growth ◽  
Median Overall Survival ◽  
Tumour Microenvironment ◽  
Diffuse Intrinsic Pontine Glioma ◽  
The Body ◽  
Paediatric Brain Tumour ◽  
Molecular Aberrations ◽  
The Brain ◽  
Complex Organ

Diffuse intrinsic pontine glioma (DIPG) is a devastating and incurable paediatric brain tumour with a median overall survival of 9 months. Until recently, DIPGs were treated similarly to adult gliomas, but due to the advancement in molecular and imaging technologies, our understanding of these tumours has increased dramatically. While extensive research is being undertaken to determine the function of the molecular aberrations in DIPG, there are significant gaps in understanding the biology and the influence of the tumour microenvironment on DIPG growth, specifically in regards to the developing pons. The precise orchestration and co-ordination of the development of the brain, the most complex organ in the body, is still not fully understood. Herein, we present a brief overview of brainstem development, discuss the developing microenvironment in terms of DIPG growth, and provide a basis for the need for studies focused on bridging pontine development and DIPG microenvironment. Conducting investigations in the context of a developing brain will lead to a better understanding of the role of the tumour microenvironment and will help lead to identification of drivers of tumour growth and therapeutic resistance.

scholarly journals Anterior Gradient-2 (AGR2) overexpression in colon cancer: a potential prognostic biomarker

2021 ◽  
Author(s):  
Delphine Fessart ◽  
Isabelle Mahouche ◽  
Veronique Brouste ◽  
Valerie Velasco ◽  
Isabelle Soubeyran ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Protein Expression ◽  
Cancer Patients ◽  
Causes Of Death ◽  
Early Stage ◽  
Tumour Microenvironment ◽  
Tissue Samples ◽  
Colon Cancers ◽  
Mrna And Protein Expression ◽  
Protein Disulfide

AbstractAimsColon cancer is one of the most common leading causes of death worldwide. Prognostic at an early stage is an efficient way to decrease mortality. The Endoplasmic Reticulum (ER)-resident protein anterior gradient-2 (AGR2), a Protein Disulfide Isomerase (PDI) is highly expressed in various solid tumours and is involved in tumour microenvironment-associated processes such as tumour growth, invasion and metastasis. This study aims at examining the expression of AGR2 protein in colon cancer as its prognostic value in such cancer remains inconclusive.MethodsAGR2 protein expression was determined using immunohistochemistry on human tissue samples issued from a cohort of 82 colorectal carcinomas (Institut Bergonié, Bordeaux, France).ResultsAGR2 protein expression was significantly higher in tumours than in adjacent non-tumour controls. AGR2 expression subgroup analyses indicated that AGR2 low expression in colon cancer patients was significantly associated with worse overall survival. Mucinous colon cancers exhibited higher AGR2 expression levels than non-mucinous cancers. Additionally, tumours with microsatellite instability (MSI) were characterised by a strong upregulation of AGR2 mRNA and protein expression despite an absence of MLH1/MSH2 mutations.ConclusionOur findings indicate that high AGR2 protein expression is correlated with longer patient survival and that AGR2 overexpression is associated with MSI and mucinous-type colorectal cancers. Overall, AGR2 might serve as a biomarker to stratify colon tumours and to contribute to the prognosis of colon cancer patients.

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