Intussusceptive Angiogenesis in Human Metastatic Malignant Melanoma

Area of Science:

• Oncology
• Cancer Biology
• Tumor Microenvironment

Background:

• Angiogenesis is crucial for tumor growth, supplying oxygen and nutrients.
• Vascular endothelial growth factor (VEGF) inhibitors show limited efficacy in many tumors.
• Intussusceptive angiogenesis, distinct from VEGF-driven angiogenesis, may explain this limitation.

Purpose of the Study:

• To investigate the presence and significance of intussusceptive angiogenesis in human melanoma.
• To explore the role of matrix metalloproteinase 9 (MMP9) in this process.
• To evaluate MMP inhibition as a potential anti-angiogenic strategy.

Main Methods:

• Epifluorescence and confocal microscopy to visualize intravascular pillars in human melanoma metastases, patient-derived xenografts (PDXs), and genetically engineered mouse models.
• RNA sequencing for gene expression analysis.
• Multiplex immunostaining for protein expression and immune cell infiltration.

Main Results:

• Intravascular pillars, hallmarks of intussusceptive angiogenesis, were detected in human melanoma metastases but rarely in PDXs and not in BPT mice.
• Higher MMP9 mRNA expression was observed in human metastases compared to PDXs.
• MMP inhibition blocked pillar formation in vitro, but not other angiogenic structures.

Conclusions:

• Intussusceptive angiogenesis may contribute to human melanoma metastasis growth.
• MMP inhibition shows promise in blocking intussusceptive angiogenesis and warrants further investigation as a therapeutic target.