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      Pathobiology of Hemangiosarcoma in Dogs: Research Advances and Future Perspectives

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          Abstract

          Hemangiosarcoma (HSA) is an aggressive and common cancer in dogs. While cutaneous masses are often treatable by tumor excision, visceral tumors are almost always incurable. Treatment advances for this disease have been limited due to a poor understanding of the overall tumor biology. Based upon its histological appearance, HSA has been presumed to originate from transformed endothelial cells; however, accumulating data now suggest a pluripotent bone marrow progenitor as the cell of origin for this disease. More recently, the identification of a novel subclassification of HSAs has provided a foundation to further our understanding of the cellular characteristics of HSA tumor cells, along with those of the cells comprising the tumor microenvironment. These discoveries hold promise for the development of new approaches to improve treatments for canine HSA, as well as to establish the utility of this disease as a spontaneous model to understand the pathogenesis and develop new treatments for vascular tumors of humans. In this review, we will provide a brief historical perspective and pathobiology of canine HSA, along with a focus on the recent advances in the molecular and cellular understanding of these tumors. In addition, future directions that should continue to improve our understanding of HSA pathogenesis will be discussed.

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          Cancer etiology. Variation in cancer risk among tissues can be explained by the number of stem cell divisions.

          Some tissue types give rise to human cancers millions of times more often than other tissue types. Although this has been recognized for more than a century, it has never been explained. Here, we show that the lifetime risk of cancers of many different types is strongly correlated (0.81) with the total number of divisions of the normal self-renewing cells maintaining that tissue's homeostasis. These results suggest that only a third of the variation in cancer risk among tissues is attributable to environmental factors or inherited predispositions. The majority is due to "bad luck," that is, random mutations arising during DNA replication in normal, noncancerous stem cells. This is important not only for understanding the disease but also for designing strategies to limit the mortality it causes. Copyright © 2015, American Association for the Advancement of Science.
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            Sphingosine-1-phosphate: an enigmatic signalling lipid.

            The evolutionarily conserved actions of the sphingolipid metabolite, sphingosine-1-phosphate (S1P), in yeast, plants and mammals have shown that it has important functions. In higher eukaryotes, S1P is the ligand for a family of five G-protein-coupled receptors. These S1P receptors are differentially expressed, coupled to various G proteins, and regulate angiogenesis, vascular maturation, cardiac development and immunity, and are important for directed cell movement.
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              Transcriptome Sequencing to Detect Gene Fusions in Cancer

              Recurrent gene fusions, typically associated with hematological malignancies and rare bone and soft tissue tumors1, have been recently described in common solid tumors2–9. Here we employ an integrative analysis of high-throughput long and short read transcriptome sequencing of cancer cells to discover novel gene fusions. As a proof of concept we successfully utilized integrative transcriptome sequencing to “re-discover” the BCR-ABL1 10 gene fusion in a chronic myelogenous leukemia cell line and the TMPRSS2-ERG 2,3 gene fusion in a prostate cancer cell line and tissues. Additionally, we nominated, and experimentally validated, novel gene fusions resulting in chimeric transcripts in cancer cell lines and tumors. Taken together, this study establishes a robust pipeline for the discovery of novel gene chimeras using high throughput sequencing, opening up an important class of cancer-related mutations for comprehensive characterization.
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                Author and article information

                Contributors
                Role: Academic Editor
                Role: Academic Editor
                Journal
                Vet Sci
                Vet Sci
                vetsci
                Veterinary Sciences
                MDPI
                2306-7381
                06 November 2015
                December 2015
                : 2
                : 4
                : 388-405
                Affiliations
                [1 ]Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA; E-Mails: ajgraef@ 123456umn.edu (A.J.G.); edickers@ 123456umn.edu (E.B.D.); modiano@ 123456umn.edu (J.F.M.)
                [2 ]Animal Cancer Care and Research Program, University of Minnesota, St. Paul, MN 55108, USA
                [3 ]Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
                [4 ]Stem Cell Institute, University of Minnesota, Minneapolis, MN 55455, USA
                [5 ]Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA
                Author notes
                [* ]Author to whom correspondence should be addressed; E-Mail: jhkim@ 123456umn.edu ; Tel.: +1-612-626-6890; Fax: +1-612-626-4915.
                Article
                vetsci-02-00388
                10.3390/vetsci2040388
                5644642
                29061949
                ecb12295-d94f-4738-bed3-65161c562231
                © 2015 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 27 August 2015
                : 20 October 2015
                Categories
                Review

                animal model,dog,hemangiosarcoma,tumor microenvironment
                animal model, dog, hemangiosarcoma, tumor microenvironment

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