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      Early increase in blood supply (EIBS) is associated with tumor risk in the Azoxymethane model of colon cancer

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          Abstract

          Background

          The present study aimed to investigate the role of blood supply in early tumorigenesis in colorectal cancer. We leveraged the renin angiotensin system (RAS) to alter colonic blood supply and determine the effect on tumor initiation and progression.

          Methods

          To test the effect of blood supply on tumorigenesis, 53 male A/J mice were randomly assigned to one of three RAS modulation groups and one of two AOM treatments. The RAS modulation groups were I) water (RAS-unmodulated) as a control group, II) angiotensin-II and III) the angiotensin receptor blocker, Losartan. The mice in each group were then randomly split into either the saline control condition or the AOM-treated condition in which tumors were induced with a standard protocol of serial azoxymethane (AOM) injections. To monitor microvascular changes in the rectal mucosa during the study, we used confocal laser endomicroscopy (CLE) with FITC-Dextran for in-vivo imaging of vessels and polarization-gated spectroscopy (PGS) to quantify rectal hemoglobin concentration ([Hb]) and blood vessel radius (BVR).

          Results

          At 12 weeks post-AOM injections and before tumor formation, CLE images revealed many traditional hallmarks of angiogenesis including vessel dilation, loss of co-planarity, irregularity, and vessel sprouting in the pericryptal capillaries of the rectal mucosa in AOM-Water tumor bearing mice. PGS measurements at the same time-point showed increased rectal [Hb] and decreased BVR. At later time points, CLE images showed pronounced angiogenic features including irregular networks throughout the colon. Notably, the AOM-Losartan mice had significantly lower tumor multiplicity and did not exhibit the same angiogenic features observed with CLE, or the increase in [Hb] or decrease in BVR measured with PGS. The AOM-AngII mice did not have any significant trends.

          Conclusion

          In-vivo PGS measurements of rectal colonic blood supply as well as CLE imaging revealed angiogenic disruptions to the capillary network prior to tumor formation. Losartan demonstrated an effective way to mitigate the changes to blood supply during tumorigenesis and reduce tumor multiplicity. These effects can be used in future studies to understand the early vessel changes observed.

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          Most cited references20

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          A genetic explanation of Slaughter's concept of field cancerization: evidence and clinical implications.

          The concept of "field cancerization" was first introduced by Slaughter et al. [D. P, Slaughter et al., Cancer (Phila.), 6: 963-968, 1953] in 1953 when studying the presence of histologically abnormal tissue surrounding oral squamous cell carcinoma. It was proposed to explain the development of multiple primary tumors and locally recurrent cancer. Organ systems in which field cancerization has been described since then are: head and neck (oral cavity, oropharynx, and larynx), lung, vulva, esophagus, cervix, breast, skin, colon, and bladder. Recent molecular findings support the carcinogenesis model in which the development of a field with genetically altered cells plays a central role. In the initial phase, a stem cell acquires genetic alterations and forms a "patch," a clonal unit of altered daughter cells. These patches can be recognized on the basis of mutations in TP53, and have been reported for head and neck, lung, skin, and breast cancer. The conversion of a patch into an expanding field is the next logical and critical step in epithelial carcinogenesis. Additional genetic alterations are required for this step, and by virtue of its growth advantage, a proliferating field gradually displaces the normal mucosa. In the mucosa of the head and neck, as well as the esophagus, such fields have been detected with dimensions of >7 cm in diameter, whereas they are usually not detected by routine diagnostic techniques. Ultimately, clonal divergence leads to the development of one or more tumors within a contiguous field of preneoplastic cells. An important clinical implication is that fields often remain after surgery of the primary tumor and may lead to new cancers, designated presently by clinicians as "a second primary tumor" or "local recurrence," depending on the exact site and time interval. In conclusion, the development of an expanding preneoplastic field appears to be a critical step in epithelial carcinogenesis with important clinical consequences. Diagnosis and treatment of epithelial cancers should not only be focused on the tumor but also on the field from which it developed.
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            Confocal laser endoscopy for diagnosing intraepithelial neoplasias and colorectal cancer in vivo.

            A confocal laser endoscopy system has recently been developed that may allow subsurface imaging of living cells in colonic tissue in vivo. The aim of the present study was to assess its potential for prediction of histology during screening colonoscopy for colorectal cancer. Twenty-seven patients underwent colonoscopy with the confocal endoscope using acriflavine hydrochloride or fluorescein sodium with blue laser illumination. Furthermore, 42 patients underwent colonoscopy with this system using fluorescein sodium. Standardized locations and circumscript lesions were examined by confocal imaging before taking biopsy specimens. Confocal images were graded according to cellular and vascular changes and correlated with conventional histology in a prospective and blinded fashion. Acriflavine hydrochloride and fluorescein sodium both yielded high-quality images. Whereas acriflavine hydrochloride strongly labeled the superficial epithelial cells, fluorescein sodium offered deeper imaging into the lamina propria. Fluorescein sodium was thus used for the prospective component of the study in which 13,020 confocal images from 390 different locations were compared with histologic data from 1038 biopsy specimens. Subsurface analysis during confocal laser endoscopy allowed detailed analysis of cellular structures. The presence of neoplastic changes could be predicted with high accuracy (sensitivity, 97.4%; specificity, 99.4%; accuracy, 99.2%). Confocal laser endoscopy is a novel diagnostic tool to analyze living cells during colonoscopy, thereby enabling virtual histology of neoplastic changes with high accuracy. These newly discovered diagnostic possibilities may be of crucial importance in clinical practice and lead to an optimized rapid diagnosis of neoplastic changes during ongoing colonoscopy.
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              Angiotensin receptors: a new role in cancer?

              There is increasing evidence that Angiotensin II (AngII), a major regulator of blood pressure and cardiovascular homeostasis, is involved in the regulation of cell proliferation, angiogenesis, inflammation and tissue remodeling, which suggests that this peptide might also play a role in cancer. This review focuses on the expression and function of Angiotensin I-converting enzyme (ACE) and AngII receptors in various aspects of cancer. Recent experimental data suggests that ACE inhibitors and AngII type 1 receptor (AT1R) antagonists have beneficial effects on tumor progression, vascularization and metastasis, and that the AngII type 2 receptor (AT2R) subtype has a potential role in cancer. An overview of the major intracellular signaling pathways associated with AT1R and AT2R activation in cancer cells, as well as in endothelial and inflammatory cells, is presented here.
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                Author and article information

                Contributors
                SarahRuderman2012@u.northwestern.edu
                aeshein@u.northwestern.edu
                vestav@yahoo.com
                udougher@medicine.bsd.uchicago.edu
                dralmoghrabi@gmail.com
                agomes724@gmail.com
                ajay749@gmail.com
                baldeeppabla@gmail.com
                hkroy@bu.edu
                John.Hart@uchospitals.edu
                mbissonn@medicine.bsd.uchicago.edu
                VaniKondaMD@gmail.com
                (847)467-1870 , v-backman@northwestern.edu
                Journal
                BMC Cancer
                BMC Cancer
                BMC Cancer
                BioMed Central (London )
                1471-2407
                13 August 2018
                13 August 2018
                2018
                : 18
                : 814
                Affiliations
                [1 ]ISNI 0000 0001 2299 3507, GRID grid.16753.36, Department of Biomedical Engineering, , Northwestern University, ; Evanston, IL 60208 USA
                [2 ]ISNI 0000 0004 1936 7822, GRID grid.170205.1, Center for Endoscopic Research and Therapeutics, , University of Chicago Medicine, ; Chicago, IL 60637 USA
                [3 ]ISNI 0000000107058297, GRID grid.262743.6, Department of Gastroenterology, , Rush University, ; Chicago, IL 60612 USA
                [4 ]ISNI 0000 0001 2183 6745, GRID grid.239424.a, Department of Gastroenterology, , Boston Medical Center, ; Boston, MA 02118 USA
                Author information
                http://orcid.org/0000-0003-2582-0788
                Article
                4709
                10.1186/s12885-018-4709-7
                6090821
                30103733
                3a14023b-4710-4fb6-bae3-e24a693ee196
                © The Author(s). 2018

                Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 2 January 2018
                : 31 July 2018
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000054, National Cancer Institute;
                Award ID: R01CA183101
                Award ID: R01CA165309
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000070, National Institute of Biomedical Imaging and Bioengineering;
                Award ID: F31EB022414
                Award Recipient :
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2018

                Oncology & Radiotherapy
                colorectal cancer,early increase in blood supply,angiogenesis,renin angiotensin system,field effect of carcinogenesis

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