scholarly journals Development of an Inflammation-Associated Colorectal Cancer Model and Its Application for Research on Carcinogenesis and Chemoprevention

2012 ◽  
Vol 2012 ◽  
pp. 1-16 ◽  
Author(s):  
Takuji Tanaka
Keyword(s):  
Colorectal Cancer ◽  
Large Bowel ◽  
Human Cancer ◽  
Colon Carcinogenesis ◽  
Human Colorectal Cancer ◽  
Immune System Dysfunction ◽  
Molecular Events ◽  
Increased Risk ◽  
Intestinal Immune System ◽  
Inflammatory Bowel

Chronic inflammation is a well-recognized risk factor for development of human cancer in several tissues, including large bowel. Inflammatory bowel disease, including ulcerative colitis and Crohn’s disease, is a longstanding inflammatory disease of intestine with increased risk for colorectal cancer development. Several molecular events involved in chronic inflammatory process may contribute to multistep carcinogenesis of human colorectal cancer in the inflamed colon. They include overproduction of reactive oxygen and nitrogen species, overproduction and upregulation of productions and enzymes of arachidonic acid biosynthesis pathway and cytokines, and intestinal immune system dysfunction. In this paper, I will describe several methods to induce colorectal neoplasm in the inflamed colon. First, I will introduce a protocol of a novel inflammation-associated colon carcinogenesis in mice. In addition, powerful tumor-promotion/progression activity of dextran sodium sulfate in the large bowel ofApcMin/+mice will be described. Finally, chemoprevention of inflammation-associated colon carcinogenesis will be mentioned.

Dysplastic Lesions in Inflammatory Bowel Disease: Molecular Pathogenesis to Morphology

2013 ◽  
Vol 137 (3) ◽  
pp. 338-350 ◽  
Author(s):  
Kristina A. Matkowskyj ◽  
Zongming E. Chen ◽  
M. Sambasiva Rao ◽  
Guang-Yu Yang
Keyword(s):  
Colorectal Cancer ◽  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Human Cancer ◽  
Significant Risk ◽  
Molecular Pathogenesis ◽  
Field Cancerization ◽  
Molecular Events ◽  
Increased Risk ◽  
Inflammatory Bowel

Context.—Inflammatory bowel disease (IBD) is a long-standing chronic active inflammatory process in the bowel with increased risk for the development of colorectal carcinoma. Several molecular events involved in chronic active inflammatory processes contribute to multistage progression of human cancer development, including reactive oxygen and nitrogen species, aberrant arachidonic acid metabolites and cytokines/growth factors, and immune dysfunction. These molecular events in IBD lead to genetic abnormality and promote aberrant cell proliferation, which further lead to epithelial changes encompassing a broad spectrum from inflammation-induced hyperplasia to dysplasia. Objective.—To review the (1) epidemiologic and molecular pathogenesis of the risk for colorectal cancer in IBD, (2) morphologic characterization, biomarker(s), and classification of dysplastic lesions, and (3) clinical management of dysplastic lesions arising in IBD. Data Sources.—The different IBD-related dysplastic lesions are illustrated by using morphology in conjunction with molecular pathways, and the “field cancerization” theory and its potential significance are discussed with a review of the literature. Conclusions.—Patients with IBD are at increased risk of developing colorectal cancer. The risk of developing carcinoma is related to the extent/duration/activity of the patient's disease. There is no consensus regarding the extent of carcinoma risk associated with IBD; however, all would agree that patients with IBD represent a group at significant risk for developing carcinoma and as such, warrant adequate surveillance and prevention. With better screening modalities and detection/characterization of dysplastic lesions, IBD-associated serrated lesions, and “field cancerization,” we will improve our understanding of and approach to risk stratification.

37 Monitoring the evolution of inflammatory bowel disease (IBD) in pediatric and adult cohorts of patients to identify biomarkers to predict cancer risk

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A38-A38
Author(s):  
Shilpa Ravindran ◽  
Heba Sidahmed ◽  
Harshitha Manjunath ◽  
Rebecca Mathew ◽  
Tanwir Habib ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Colorectal Cancer ◽  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Mesenchymal Transition ◽  
Increased Risk ◽  
Hamad Medical Corporation ◽  
Inflammatory Bowel ◽  
Left And Right

BackgroundPatients with inflammatory bowel disease (IBD) have increased risk of developing colorectal cancer (CRC), depending on the duration and severity of the disease. The evolutionary process in IBD is driven by chronic inflammation leading to epithelial-to-mesenchymal transition (EMT) events in colonic fibrotic areas. EMT plays a determinant role in tumor formation and progression, through the acquisition of ‘stemness’ properties and the generation of neoplastic cells. The aim of this study is to monitor EMT/cancer initiating tracts in IBD in association with the deep characterization of inflammation in order to assess the mechanisms of IBD severity and progression towards malignancy.Methods10 pediatric and 20 adult IBD patients, admitted at Sidra Medicine (SM) and Hamad Medical Corporation (HMC) respectively, have been enrolled in this study, from whom gut tissue biopsies (from both left and right side) were collected. Retrospectively collected tissues (N=10) from patients with malignancy and history of IBD were included in the study. DNA and RNA were extracted from fresh small size (2–4 mm in diameter) gut tissues using the BioMasher II (Kimble) and All Prep DNA/RNA kits (Qiagen). MicroRNA (miRNA; N=700) and gene expression (N=800) profiling have been performed (cCounter platform; Nanostring) as well as the methylation profiling microarray (Infinium Methylation Epic Bead Chip kit, Illumina) to interrogate up to 850,000 methylation sites across the genome.ResultsDifferential miRNA profile (N=27 miRNA; p<0.05) was found by the comparison of tissues from pediatric and adult patients. These miRNAs regulate: i. oxidative stress damage (e.g., miR 99b), ii. hypoxia induced autophagy; iii. genes associated with the susceptibility to IBD (ATG16L1, NOD2, IRGM), iv. immune responses, such as TH17 T cell subset (miR 29). N=6 miRNAs (miR135b, 10a196b, 125b, let7c, 375) linked with the regulation of Wnt/b-catenin, EM-transaction, autophagy, oxidative stress and play role also in cell proliferation and mobilization and colorectal cancer development were differentially expressed (p<0.05) in tissues from left and right sides of gut. Gene expression signature, including genes associated with inflammation, stemness and fibrosis, has also been performed for the IBD tissues mentioned above. Methylation sites at single nucleotide resolution have been analyzed.ConclusionsAlthough the results warrant further investigation, differential genomic profiling suggestive of altered pathways involved in oxidative stress, EMT, and of the possible stemness signature was found. The integration of data from multiple platforms will provide insights of the overall molecular determinants in IBD patients along with the evolution of the disease.Ethics ApprovalThis study was approved by Sidra Medicine and Hamad Medical Corporation Ethics Boards; approval number 180402817 and MRC-02-18-096, respectively.

scholarly journals Overview of Inositol and Inositol Phosphates on Chemoprevention of Colitis-Induced Carcinogenesis

Molecules ◽  
2020 ◽  
Vol 26 (1) ◽  
pp. 31
Author(s):  
Samuel E. Weinberg ◽  
Le Yu Sun ◽  
Allison L. Yang ◽  
Jie Liao ◽  
Guang Yu Yang
Keyword(s):  
Inositol Phosphates ◽  
Human Cancer ◽  
Energy Transduction ◽  
Nutritional Deficiencies ◽  
Increased Risk ◽  
Rna Export ◽  
Inflammatory Bowel ◽  
And Function ◽  
Biologic Function ◽  
Atp Regeneration

Chronic inflammation is one of the most common and well-recognized risk factors for human cancer, including colon cancer. Inflammatory bowel disease (IBD) is defined as a longstanding idiopathic chronic active inflammatory process in the colon, including ulcerative colitis and Crohn’s disease. Importantly, patients with IBD have a significantly increased risk for the development of colorectal carcinoma. Dietary inositol and its phosphates, as well as phospholipid derivatives, are well known to benefit human health in diverse pathologies including cancer prevention. Inositol phosphates including InsP3, InsP6, and other pyrophosphates, play important roles in cellular metabolic and signal transduction pathways involved in the control of cell proliferation, differentiation, RNA export, DNA repair, energy transduction, ATP regeneration, and numerous others. In the review, we highlight the biologic function and health effects of inositol and its phosphates including the nature and sources of these molecules, potential nutritional deficiencies, their biologic metabolism and function, and finally, their role in the prevention of colitis-induced carcinogenesis.

scholarly journals Colorectal Cancer in Inflammatory Bowel Disease

2020 ◽  
Vol 33 (05) ◽  
pp. 305-317
Author(s):  
Martina Nebbia ◽  
Nuha A. Yassin ◽  
Antonino Spinelli
Keyword(s):  
Colorectal Cancer ◽  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Severe Disease ◽  
Critical Role ◽  
Mucosal Inflammation ◽  
Surgical Approaches ◽  
Increased Risk ◽  
Significant Difference ◽  
Inflammatory Bowel

AbstractPatients with inflammatory bowel disease (IBD) are at an increased risk for developing colorectal cancer (CRC). However, the incidence has declined over the past 30 years, which is probably attributed to raise awareness, successful CRC surveillance programs and improved control of mucosal inflammation through chemoprevention. The risk factors for IBD-related CRC include more severe disease (as reflected by the extent of disease and the duration of poorly controlled disease), family history of CRC, pseudo polyps, primary sclerosing cholangitis, and male sex. The molecular pathogenesis of inflammatory epithelium might play a critical role in the development of CRC. IBD-related CRC is characterized by fewer rectal tumors, more synchronous and poorly differentiated tumors compared with sporadic cancers. There is no significant difference in sex distribution, stage at presentation, or survival. Surveillance is vital for the detection and subsequently management of dysplasia. Most guidelines recommend initiation of surveillance colonoscopy at 8 to 10 years after IBD diagnosis, followed by subsequent surveillance of 1 to 2 yearly intervals. Traditionally, surveillance colonoscopies with random colonic biopsies were used. However, recent data suggest that high definition and chromoendoscopy are better methods of surveillance by improving sensitivity to previously “invisible” flat dysplastic lesions. Management of dysplasia, timing of surveillance, chemoprevention, and the surgical approaches are all areas that stimulate various discussions. The aim of this review is to provide an up-to-date focus on CRC in IBD, from laboratory to bedside.

Surveillance in inflammatory bowel disease: an overview

2019 ◽  
Vol 17 (8) ◽  
pp. 32-37
Author(s):  
Sara Koo ◽  
Jignesh Jatania ◽  
Colin Rees
Keyword(s):  
Colorectal Cancer ◽  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Disease Duration ◽  
The Other ◽  
Surveillance Colonoscopy ◽  
Targeted Biopsy ◽  
White Light Endoscopy ◽  
Increased Risk ◽  
Inflammatory Bowel

Patients with inflammatory bowel disease (IBD), including both ulcerative colitis and Crohn's disease, are at an increased risk of developing colorectal cancer. It is well accepted that this risk increases after 8–10 years of disease duration. Patients should be offered a surveillance colonoscopy after this time. Previously, white-light endoscopy with random biopsies every 10 cm was undertaken for surveillance, but recent evidence suggests that chromoendoscopy along with targeted biopsy is superior to this and the other available methods. This article reviews the available evidence for IBD surveillance, surveillance guidelines and the evidence for chromoendoscopy. Additionally, an overview of the assessment, reporting of any visible abnormal lesions and management of subsequently proven dysplastic lesions is given.

Increased risk of high-grade dysplasia and colorectal cancer in inflammatory bowel disease patients with recurrent low-grade dysplasia

2020 ◽  
Vol 91 (6) ◽  
pp. 1334-1342.e1 ◽  
Author(s):  
Michiel E. de Jong ◽  
Heleen Kanne ◽  
Loes H.C. Nissen ◽  
Joost P.H. Drenth ◽  
Lauranne A.A. P. Derikx ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
High Grade Dysplasia ◽  
Low Grade ◽  
High Grade ◽  
Increased Risk ◽  
Inflammatory Bowel ◽  
Low Grade Dysplasia

scholarly journals IBD-Associated Dysplastic Lesions Show More Chromosomal Instability Than Sporadic Adenomas

2019 ◽  
Vol 26 (2) ◽  
pp. 167-180 ◽  
Author(s):  
Linda K Wanders ◽  
Martijn Cordes ◽  
Quirinus Voorham ◽  
Daoud Sie ◽  
Sara D de Vries ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Chromosomal Instability ◽  
Precursor Lesions ◽  
Increased Risk ◽  
Inflammatory Bowel

Inflammatory bowel disease (IBD) patients are at increased risk of developing colorectal cancer. However, histologically, it is challenging to distinguish between IBD-associated dysplasia from sporadic adenomas. We have molecularly characterized these precursor lesions and show that IBD-associated dysplasia lesions are genomically much more unstable.

scholarly journals PDEδ inhibition impedes the proliferation and survival of human colorectal cancer cell lines harboring oncogenic KRas

2018 ◽  
Author(s):  
Christian H. Klein ◽  
Dina C. Truxius ◽  
Holger A. Vogel ◽  
Jana Harizanova ◽  
Sandip Murarka ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Lines ◽  
Human Cancer ◽  
Ductal Adenocarcinoma ◽  
Ras Proteins ◽  
Human Colorectal Cancer ◽  
Braf Mutations ◽  
Kras Mutations ◽  
Human Colorectal Cancer Cell ◽  
Colorectal Cancer Cell Lines

Novelty and ImpactThe ‘undruggable’ KRas is a prevalent oncogene in CRC with poor prognosis. In hPDAC cells pharmacological targeting of PDEδ affects oncogenic KRas signaling, but it remained unclear whether this approach is transferable to other cancer cells. Here, we show that genetic and pharmacologic PDEδ inhibition also impedes the proliferation of oncogenic, but not wild-type KRas bearing CRC cells indicating that PDEδ inhibition is a specific tool for targeting growth of oncogenic KRas bearing CRC.AbstractRas proteins, most notably KRas, are prevalent oncogenes in human cancer. Plasma membrane localization and thereby signaling of KRas is regulated by the prenyl-binding protein PDEδ. Recently, we have reported the specific anti-proliferative effects of PDEδ inhibition in KRas-dependent human pancreatic ductal adenocarcinoma cell lines. Here, we investigated the proliferative dependence on the solubilizing activity of PDEδ of human colorectal cancer (CRC) cell lines with or without oncogenic KRas mutations. Our results show that genetic and pharmacologic interference with PDEδ specifically inhibits proliferation and survival of CRC cell lines harboring oncogenic KRas mutations whereas isogenic cell lines in which the KRas oncogene has been removed, or cell lines with oncogenic BRaf mutations or EGFR overexpression are not dependent on PDEδ. Pharmacological PDEδ inhibition is therefore a possible new avenue to target oncogenic KRas bearing CRC.

K-rasandp16Aberrations Confer Poor Prognosis in Human Colorectal Cancer

2001 ◽  
Vol 19 (2) ◽  
pp. 299-304 ◽  
Author(s):  
M. Esteller ◽  
S. González ◽  
R. A. Risques ◽  
E. Marcuello ◽  
R. Mangues ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Human Cancer ◽  
Methylation Status ◽  
Distant Metastases ◽  
Genetic Alterations ◽  
P53 Mutations ◽  
Human Colorectal Cancer ◽  
Ras Gene ◽  
Reading Frame ◽  
Cox Analysis

PURPOSE: Mutations in the K-ras gene are frequent in human cancer. ras activation in primary cells results in a cellular senescence phenotype that is precluded by inactivation of p16. At the clinical level, this may imply a differential behavior for tumors with alternative or cooperative activation of K-ras function and impairment of p16 pathways.PATIENTS AND METHODS: We have determined the presence of mutations in the K-ras gene and the methylation status of p16 promoter in a series of 119 prospectively collected colorectal carcinomas. p53 mutations and p14 alternative reading frame methylation status were also assessed. Associations with survival were investigated.RESULTS: K-ras mutations were present in 44 (38%) of 115 cases, and p16 methylation was present in 42 (37%) of 113 cases. p53 mutations were detected in 50% (56 of 115) and p14 methylation in 29% (32 of 112) of cases. K-ras and p16 alterations were independent genetic events. Presence of K-ras or p16 genetic alterations (analyzed independently) was associated with shorter survival, although differences were not statistically significant. Cox analysis of the two variables combined showed a diminished survival as the results of an interaction between p16 and K-ras. Alternative alteration of K-ras and p16 genes was an independent prognostic factor in human colorectal cancer in univariate and multivariate analysis. Differences were maintained when cases undergoing radical surgery and without distant metastases were considered.CONCLUSION: These results suggest that the combined K-ras and p16 analyses may be of prognostic use in human colorectal cancer.

Lipidomics As Tools For Finding Biomarkers Of Intestinal Pathology: From Irritable Bowel Syndrome To Colorectal Cancer

2021 ◽  
Vol 22 ◽  
Author(s):  
Lorena Ortega Moreno ◽  
Pilar Navarro Sánchez ◽  
Raquel Abalo
Keyword(s):  
Colorectal Cancer ◽  
Inflammatory Bowel Disease ◽  
Irritable Bowel Syndrome ◽  
Bowel Disease ◽  
Screening Methods ◽  
Intestinal Diseases ◽  
Non Invasive ◽  
Increased Risk ◽  
Inflammatory Bowel ◽  
Irritable Bowel

: Lipidomics is an emerging and promising branch that analyses the different lipid mole-cules in a biological sample. It is considered a branch of metabolomics, which is defined as the comprehensive analysis of metabolites in a biological specimen. Nonetheless, in recent years lipidomics is becoming a distinct discipline in the biomedicine field. Lipids play important roles in many biological pathways and can work as biomarkers of disease or therapeutic targets for the treatment of diseases. The major lipidomics strategies are shotgun lipidomics and liquid chromatography coupled with mass spectrometry. Gastro-intestinal diseases, such as irritable bowel syndrome or inflammatory bowel disease, are chronic diseases that need non-invasive biomarkers for prognosis and diagnosis. Even more, patients with inflammatory bowel disease are at significantly increased risk of colorectal cancer, principally resulting from the pro-neoplastic effects of chronic intesti-nal inflammation. Current screening methods utilized globally include sigmoidoscopy or standard colonoscopy, but it is important to develop non-invasive and accurate screen-ing tools to facilitate early detection and precise staging of colorectal cancer. Disease progression and response to treatment may also benefit from the application of these potential new tools. This review focuses on studies that use lipidomics approaches to discover potential biomarkers for monitoring the mentioned intestinal diseases and, par-ticularly, tumor progression.

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