Intussusceptive Angiogenesis in Human Metastatic Malignant Melanoma
| Autor: | Jan Borén, Levent M. Akyürek, Per Fogelstrand, Matias Ekstrand, Joakim Karlsson, Max Levin, Malin Levin, Keith E. Mostov, Lars Ny, Martin O. Bergo, Jonas Nilsson, Sara Bjursten, Zhiyuan Zhao, Kristell Le Gal, Andrew J. Ewald, Ankur Pandita |
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| Rok vydání: | 2021 |
| Předmět: |
Male
Skin Neoplasms Angiogenesis MMP9 Matrix metalloproteinase Medical and Health Sciences Pathology and Forensic Medicine Mice chemistry.chemical_compound 80 and over Genetics Pathology medicine Animals Humans 2.1 Biological and endogenous factors PTEN Tensin Aetiology Intussusceptive angiogenesis Melanoma Neovascularization Aged Cancer Aged 80 and over Pathologic Neovascularization Pathologic biology Regular Article Middle Aged medicine.disease Vascular endothelial growth factor Matrix Metalloproteinase 9 chemistry Cancer research biology.protein Heterografts Female Biotechnology |
| Zdroj: | The American journal of pathology, vol 191, iss 11 Am J Pathol |
| ISSN: | 0002-9440 |
| Popis: | 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, invitro. In conclusion, intussusceptive angiogenesis may contribute to the growth of human melanoma metastases. MMP inhibition blocked pillar formation invitro and should be further investigated as a potential anti-angiogenic drug target in metastatic melanoma. |
| Databáze: | OpenAIRE |
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