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      Vascular dysfunction and increased metastasis of B16F10 melanomas in Shb deficient mice as compared with their wild type counterparts

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          Abstract

          Background

          Shb is a signaling protein downstream of vascular endothelial growth factor receptor-2 and Shb deficiency has been found to restrict tumor angiogenesis. The present study was performed in order to assess metastasis in Shb deficiency using B16F10 melanoma cells.

          Methods

          B16F10 melanoma cells were inoculated subcutaneously on wild type or Shb +/− mice. Primary tumors were resected and lung metastasis determined after tumor relapse. Lung metastasis was also assessed after bone marrow transplantation of wild type bone marrow to Shb +/− recipients and Shb +/− bone marrow to wild type recipients. Primary tumors were subject to immunofluorescence staining for CD31, VE-cadherin, desmin and CD8, RNA isolation and isolation of vascular fragments for further RNA isolation. RNA was used for real-time RT-PCR and microarray analysis.

          Results

          Numbers of lung metastases were increased in Shb +/− or −/− mice and this coincided with reduced pericyte coverage and increased vascular permeability. Gene expression profiling of vascular fragments isolated from primary tumors and total tumor RNA revealed decreased expression of different markers for cytotoxic T cells in tumors grown on Shb +/− mice, suggesting that vascular aberrations caused altered immune responses.

          Conclusions

          It is concluded that a unique combinatorial response of increased vascular permeability and reduced recruitment of cytotoxic CD8+ cells occurs as a consequence of Shb deficiency in B16F10 melanomas. These changes may promote tumor cell intravasation and metastasis.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s12885-015-1269-y) contains supplementary material, which is available to authorized users.

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          Most cited references40

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          Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis.

          Herein we report that the VEGFR/PDGFR kinase inhibitor sunitinib/SU11248 can accelerate metastatic tumor growth and decrease overall survival in mice receiving short-term therapy in various metastasis assays, including after intravenous injection of tumor cells or after removal of primary orthotopically grown tumors. Acceleration of metastasis was also observed in mice receiving sunitinib prior to intravenous implantation of tumor cells, suggesting possible "metastatic conditioning" in multiple organs. Similar findings with additional VEGF receptor tyrosine kinase inhibitors implicate a class-specific effect for such agents. Importantly, these observations of metastatic acceleration were in contrast to the demonstrable antitumor benefits obtained when the same human breast cancer cells, as well as mouse or human melanoma cells, were grown orthotopically as primary tumors and subjected to identical sunitinib treatments.
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            Melanoma.

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              Signal transduction by vascular endothelial growth factor receptors.

              VEGFs (vascular endothelial growth factors) control vascular development during embryogenesis and the function of blood vessels and lymphatic vessels in the adult. There are five related mammalian ligands, which act through three receptor tyrosine kinases. Signalling is modulated through neuropilins, which act as VEGF co-receptors. Heparan sulfate and integrins are also important modulators of VEGF signalling. Therapeutic agents that interfere with VEGF signalling have been developed with the aim of decreasing angiogenesis in diseases that involve tissue growth and inflammation, such as cancer. The present review will outline the current understanding and consequent biology of VEGF receptor signalling.
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                Author and article information

                Contributors
                guangxiang.zang@medbio.umu.se
                Karin.gustafsson@mcb.uu.se
                Maria.jamalpour@mcb.uu.se
                Jong.hong@ki.se
                Guillem.genove@ki.se
                Michael.welsh@mcb.uu.se
                Journal
                BMC Cancer
                BMC Cancer
                BMC Cancer
                BioMed Central (London )
                1471-2407
                8 April 2015
                8 April 2015
                2015
                : 15
                : 234
                Affiliations
                [ ]Department of Medical Cell Biology, Uppsala University, Box 571, Husargatan 3, 75123 Uppsala, Sweden
                [ ]Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institutet, Stockholm, Sweden
                [ ]Present address: Department of Medical Bioscience, Umeå University, Umeå, Sweden
                Article
                1269
                10.1186/s12885-015-1269-y
                4392795
                9af6f190-4e8e-492d-a62f-97689382cb4f
                © Zang et al.; licensee BioMed Central. 2015

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. 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
                : 9 December 2014
                : 25 March 2015
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2015

                Oncology & Radiotherapy
                shb,melanoma,vascular permeability,metastasis,cd8+ cells,pericytes
                Oncology & Radiotherapy
                shb, melanoma, vascular permeability, metastasis, cd8+ cells, pericytes

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