Regular article
Tumorigenesis and neoplastic progression
Intussusceptive Angiogenesis in Human Metastatic Malignant Melanoma

https://doi.org/10.1016/j.ajpath.2021.07.009Get rights and content
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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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Supported by the Swedish state under the agreement between the Swedish government and the county councils, the Avtal om Läkarutbildning och Forskning (ALF) agreement (M.L., M.O.B., J.A.N., and S.B.), Jubileumsklinikens Cancerfond, Lions Cancerfond, Stiftelsen Tornspiran, Kungliga och Hvitfeldtska Stiftelsen, Stiftelsen Assar Gabrielssons Fond, Wilhelm och Martina Lundgrens Vetenskapsfond, Serena Ehrenströms Fond, Torsten och Sara Janssons Fond, and NIH National Institute of Diabetes and Digestive and Kidney Diseases grant R01DK74398 (K.E.M.).

Disclosures: None declared.