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      The Inflammatory Microenvironment in Colorectal Neoplasia

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          Abstract

          Colorectal cancer (CRC) is a major cause of mortality and morbidity worldwide. Inflammatory activity within the stroma of invasive colorectal tumours is known to be a key predictor of disease activity with type, density and location of immune cells impacting on patient prognosis. To date, there has been no report of inflammatory phenotype within pre-malignant human colonic adenomas. Assessing the stromal microenvironment and particularly, inflammatory activity within colorectal neoplastic lesions is central to understanding early colorectal carcinogenesis. Inflammatory cell infiltrate was assessed by immunohistochemistry in paired colonic adenoma and adjacent normal colonic mucosa samples, and adenomas exhibiting increasing degrees of epithelial cell dysplasia. Macrophage phenotype was assessed using double stain immunohistochemistry incorporating expression of an intracellular enzyme of function. A targeted array of inflammatory cytokine and receptor genes, validated by RT-PCR, was used to assess inflammatory gene expression. Inflammatory cell infiltrates are a key feature of sporadic adenomatous colonic polyps with increased macrophage, neutrophil and T cell (specifically helper and activated subsets) infiltration in adenomatous colonic polyps, that increases in association with characteristics of high malignant potential, namely, increasing degree of cell dysplasia and adenoma size. Macrophages within adenomas express iNOS, suggestive of a pro-inflammatory phenotype. Several inflammatory cytokine genes ( CXCL1, CXCL2, CXCL3, CCL20, IL8, CCL23, CCL19, CCL21, CCL5) are dysregulated in adenomas. This study has provided evidence of increased inflammation within pre-malignant colonic adenomas. This may allow potential mechanistic pathways in the initiation and promotion of early colorectal carcinogenesis to be identified.

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          Most cited references 49

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          Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method.

          The two most commonly used methods to analyze data from real-time, quantitative PCR experiments are absolute quantification and relative quantification. Absolute quantification determines the input copy number, usually by relating the PCR signal to a standard curve. Relative quantification relates the PCR signal of the target transcript in a treatment group to that of another sample such as an untreated control. The 2(-Delta Delta C(T)) method is a convenient way to analyze the relative changes in gene expression from real-time quantitative PCR experiments. The purpose of this report is to present the derivation, assumptions, and applications of the 2(-Delta Delta C(T)) method. In addition, we present the derivation and applications of two variations of the 2(-Delta Delta C(T)) method that may be useful in the analysis of real-time, quantitative PCR data. Copyright 2001 Elsevier Science (USA).
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            Type, density, and location of immune cells within human colorectal tumors predict clinical outcome.

            The role of the adaptive immune response in controlling the growth and recurrence of human tumors has been controversial. We characterized the tumor-infiltrating immune cells in large cohorts of human colorectal cancers by gene expression profiling and in situ immunohistochemical staining. Collectively, the immunological data (the type, density, and location of immune cells within the tumor samples) were found to be a better predictor of patient survival than the histopathological methods currently used to stage colorectal cancer. The results were validated in two additional patient populations. These data support the hypothesis that the adaptive immune response influences the behavior of human tumors. In situ analysis of tumor-infiltrating immune cells may therefore be a valuable prognostic tool in the treatment of colorectal cancer and possibly other malignancies.
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              A genetic model for colorectal tumorigenesis.

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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2011
                7 January 2011
                : 6
                : 1
                Affiliations
                [1 ]Gastrointestinal Research Group, School of Medicine and Dentistry, Aberdeen University, Aberdeen, United Kingdom
                [2 ]Department of Pathology, Aberdeen University, Aberdeen, United Kingdom
                [3 ]Colorectal Surgery Unit, Western General Hospital, Edinburgh, United Kingdom
                [4 ]Biomathematics and Statistics Scotland, The Rowett Institute of Nutrition and Health, Aberdeen University, Aberdeen, United Kingdom
                [5 ]The Rowett Institute of Nutrition and Health, Aberdeen University, Aberdeen, United Kingdom
                Vanderbilt University Medical Center, United States of America
                Author notes

                Conceived and designed the experiments: MHM EEO GIM. Performed the experiments: MHM KNS JED NF GLH JT MH. Analyzed the data: GN CM MHM EEO GIM JED JT NAGM. Contributed reagents/materials/analysis tools: MHM GIM KNS NF JT JED. Wrote the paper: MHM EEO GIM.

                Article
                PONE-D-10-02300
                10.1371/journal.pone.0015366
                3017541
                21249124
                McLean et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Page count
                Pages: 8
                Categories
                Research Article
                Biology
                Immunology
                Immune Cells
                Medicine
                Gastroenterology and Hepatology
                Colon
                Oncology
                Cancers and Neoplasms
                Gastrointestinal Tumors
                Colonic Polyps

                Uncategorized

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