title: Vascular dysfunction and increased metastasis of B16F10 melanomas in Shb deficient mice as compared with their wild type counterparts.
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.
authors.affiliation: Department of Medical Cell Biology, Uppsala University, Box 571, Husargatan 3, 75123, Uppsala, Sweden. guangxiang.zang@medbio.umu.se.|Present address: Department of Medical Bioscience, Umeå University, Umeå, Sweden. guangxiang.zang@medbio.umu.se.
authors.forename: Guangxiang
authors.initials: G
authors.lastname: Zang
authors.affiliation: Department of Medical Cell Biology, Uppsala University, Box 571, Husargatan 3, 75123, Uppsala, Sweden. Karin.gustafsson@mcb.uu.se.
authors.forename: Karin
authors.initials: K
authors.lastname: Gustafsson
authors.affiliation: Department of Medical Cell Biology, Uppsala University, Box 571, Husargatan 3, 75123, Uppsala, Sweden. Maria.jamalpour@mcb.uu.se.
authors.forename: Maria
authors.initials: M
authors.lastname: Jamalpour
authors.affiliation: Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institutet, Stockholm, Sweden. Jong.hong@ki.se.
authors.forename: JongWook
authors.initials: J
authors.lastname: Hong
authors.affiliation: Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institutet, Stockholm, Sweden. Guillem.genove@ki.se.
authors.forename: Guillem
authors.initials: G
authors.lastname: Genové
authors.affiliation: Department of Medical Cell Biology, Uppsala University, Box 571, Husargatan 3, 75123, Uppsala, Sweden. Michael.welsh@mcb.uu.se.
authors.forename: Michael
authors.initials: M
authors.lastname: Welsh
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D002199:Capillary Permeability / Q000235:genetics; D004195:Disease Models, Animal; D015870:Gene Expression; D005838:Genotype; D008175:Lung Neoplasms / Q000556:secondary; D008546:Melanoma, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000378:metabolism; D020286:Pericytes / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics*; D047368:Tumor Burden
chemical_list: D011518:Proto-Oncogene Proteins; C085634:Shb protein, mouse