title: Intertumor heterogeneity in vascularity and invasiveness of artificial melanoma brain metastases.
abstract: BACKGROUND
  Patients diagnosed with melanoma brain metastases have few treatment options and poor prognosis, and improved treatment strategies for these patients require detailed understanding of the underlying pathobiology. In this investigation we studied the vascularity and invasiveness of artificial brain metastases established from four human melanoma cell lines.
  
  
  METHODS
  A-07, D-12, R-18, and U-25 cells transfected with GFP were injected intracerebrally and intra-arterially in nude mice. Moribund mice were killed and autopsied, and the brain was evaluated by fluorescence imaging or by histological examination. Expression and secretion of factors involved in angiogenesis and invasion were assessed by quantitative PCR, ELISA, and immunohistochemistry.
  
  
  RESULTS
  The melanoma cells grew preferentially in the meninges and ventricles after intracerebral and intra-arterial injection. Intertumor heterogeneity in the aggressiveness of meningeal tumors reflected differences in angiogenic activity and expression of vascular endothelial growth factor A (VEGF-A) and interleukin 8 (IL-8). In contrast, growth and invasion of the brain parenchyma relied primarily on vascular co-option. The cell lines showed different patterns of invasion from meninges to the scull and from meninges to the brain parenchyma, and these differences were associated with differences in expression of the matrix metalloproteinases MMP-2 and MMP-9. Furthermore, the melanoma cells produced multiple brain lesions after intracerebral implantation by using the meningeal linings of the brain as transport routes.
  
  
  CONCLUSIONS
  The melanoma cell lines showed different growth patterns in the brain, and these differences were associated with differences in expression of the angiogenic factors VEGF-A and IL-8 and the matrix metalloproteinases MMP-2 and MMP-9.
authors.affiliation: Group of Radiation Biology and Tumor Physiology, Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway. trude.golimo.simonsen@rr-research.no.
authors.forename: Trude G
authors.initials: TG
authors.lastname: Simonsen
authors.affiliation: Group of Radiation Biology and Tumor Physiology, Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway. Jon.Vidar.Gaustad@rr-research.no.
authors.forename: Jon-Vidar
authors.initials: JV
authors.lastname: Gaustad
authors.affiliation: Group of Radiation Biology and Tumor Physiology, Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway. Einar.K.Rofstad@rr-research.no.
authors.forename: Einar K
authors.initials: EK
authors.lastname: Rofstad
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology / Q000556:secondary; D015972:Gene Expression Regulation, Neoplastic; D018740:Genetic Heterogeneity; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000235:genetics; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis* / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis* / Q000235:genetics; D008545:Melanoma / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D051379:Mice; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology; D061848:Optical Imaging; D011859:Radiography; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D016209:Interleukin-8; D042461:Vascular Endothelial Growth Factor A; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9