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Intussusceptive Angiogenesis in Human Metastatic Malignant Melanoma

  • Ankur Pandita
    Affiliations
    Wallenberg Laboratory for Cardiovascular Research, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden

    Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

    Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden
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  • Matias Ekstrand
    Affiliations
    Wallenberg Laboratory for Cardiovascular Research, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden
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  • Sara Bjursten
    Affiliations
    Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

    Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden
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  • Zhiyuan Zhao
    Affiliations
    Wallenberg Laboratory for Cardiovascular Research, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden

    Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

    Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden
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  • Per Fogelstrand
    Affiliations
    Wallenberg Laboratory for Cardiovascular Research, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden
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  • Kristell Le Gal
    Affiliations
    Sahlgrenska Center for Cancer Research, University of Gothenburg, Gothenburg, Sweden
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  • Lars Ny
    Affiliations
    Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

    Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden

    Sahlgrenska Center for Cancer Research, University of Gothenburg, Gothenburg, Sweden
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  • Martin O. Bergo
    Affiliations
    Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
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  • Joakim Karlsson
    Affiliations
    Sahlgrenska Center for Cancer Research, University of Gothenburg, Gothenburg, Sweden
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  • Jonas A. Nilsson
    Affiliations
    Sahlgrenska Center for Cancer Research, University of Gothenburg, Gothenburg, Sweden
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  • Levent M. Akyürek
    Affiliations
    Department of Pathology, Sahlgrenska University Hospital, Gothenburg, Sweden
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  • Malin C. Levin
    Affiliations
    Wallenberg Laboratory for Cardiovascular Research, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden
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  • Jan Borén
    Affiliations
    Wallenberg Laboratory for Cardiovascular Research, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden
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  • Andrew J. Ewald
    Affiliations
    Department of Cell Biology, Johns Hopkins University, Baltimore, Maryland

    Department of Oncology, Cancer Invasion and Metastasis Program, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland
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  • Keith E. Mostov
    Affiliations
    Departments of Anatomy and Biochemistry/Biophysics, University of California, San Francisco, California
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  • Max Levin
    Correspondence
    Address correspondence to Max Levin, M.D., Department of Oncology, Sahlgrenska University Hospital, Blå Stråket 6, SE-413 45, Göteborg, Sweden.
    Affiliations
    Wallenberg Laboratory for Cardiovascular Research, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden

    Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

    Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden
    Search for articles by this author
      Angiogenesis supplies oxygen and nutrients to growing tumors. Inhibiting angiogenesis may stop tumor growth, but vascular endothelial growth factor inhibitors have limited effect in most tumors. This limited effect may be explained by an additional, less vascular endothelial growth factor–driven form of angiogenesis known as intussusceptive angiogenesis. The importance of intussusceptive angiogenesis in human tumors is not known. Epifluorescence and confocal microscopy was used to visualize intravascular pillars, the hallmark structure of intussusceptive angiogenesis, in tumors. Human malignant melanoma metastases, patient-derived melanoma xenografts in mice (PDX), and genetically engineered v-raf murine sarcoma viral oncogene homolog B1 (BRAF)-induced, phosphatase and TENsin homolog deleted on chromosome 10 (PTEN)-deficient (BPT) mice (BrafCA/+Ptenf/fTyr-Cre+/0-mice) were analyzed for pillars. Gene expression in human melanoma metastases and PDXs was analyzed by RNA sequencing. Matrix metalloproteinase 9 (MMP9) protein expression and T-cell and macrophage infiltration in tumor sections were determined with multiplex immunostaining. Intravascular pillars were detected in human metastases but rarely in PDXs and not in BPT mice. The expression of MMP9 mRNA was higher in human metastases compared with PDXs. High expression of MMP9 protein as well as infiltration of macrophages and T-cells were detected in proximity to intravascular pillars. MMP inhibition blocked formation of pillars, but not tubes or tip cells, in vitro. In conclusion, intussusceptive angiogenesis may contribute to the growth of human melanoma metastases. MMP inhibition blocked pillar formation in vitro and should be further investigated as a potential anti-angiogenic drug target in metastatic melanoma.
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