Different pathways of macromolecule extravasation from hyperpermeable tumor vessels

Area of Science:

• Oncology
• Vascular Biology
• Cell Biology

Background:

• Tumor microvessels exhibit hyperpermeability to plasma proteins, driven by tumor-secreted vascular permeability factor/vascular endothelial growth factor (VPF/VEGF).
• The precise pathways for macromolecule extravasation from tumor vessels remain incompletely understood.

Purpose of the Study:

• To characterize tumor vasculature in VPF/VEGF-secreting carcinomas.
• To elucidate the mechanisms of macromolecule extravasation from these tumor vessels.

Main Methods:

• Studied two murine carcinomas (MOT and TA3/St) known to secrete VPF/VEGF.
• Utilized a plasma protein tracer (ferritin) to track extravasation pathways.
• Examined endothelial cell morphology, including vesiculo-vacuolar organelles (VVOs) and fenestrae.

Main Results:

• MOT tumors induced large, pericyte-poor "mother" vessels with fenestrae (1.8-5.6% surface area) and reduced VVOs.
• TA3/St tumors, despite higher VPF/VEGF secretion, developed mother vessels without fenestrae and with unchanged VVOs.
• Ferritin extravasated via VVOs in both tumor types; MOT tumors also showed extravasation through fenestrae.
• No endothelial gaps were observed in either tumor type.

Conclusions:

• VPF/VEGF secretion does not universally lead to fenestrated endothelium in all tumors.
• Vesiculo-vacuolar organelles (VVOs) serve as a membrane source for mother vessel formation in MOT tumors.
• Endothelial cell division, rather than VVO-derived membrane transfer, facilitated mother vessel formation in TA3/St tumors.