A University of Minnesota Medical School-led research team, USA, discovered that a cancer signalling pathway has previously unrecognised roles in the retina and brain blood vessels.
The findings were recently published in Science Signaling.
Blood-CNS barriers serve as a protective boundary between the bloodstream and the central nervous system by regulating the transport of nutrients, hormones, and metabolic waste and preventing retinal and brain swelling.
One of the key mediators of this mechanism is the Norrin/Frizzled4 signalling pathway.
Until now, the link between this pathway and the MDM2–p53 axis — which suppresses tumours — had not been recognised.
“Our findings reveal an unexpected link between the p53 stress response pathway and Norrin signalling in the vasculature of the central nervous system,” said Harald Junge, PhD, an associate professor at the University of Minnesota Medical School.
“This has implications for cancer treatments that target MDM2 and increase p53 abundance. It’s important to consider that these treatments could impact barrier function, which could potentially lead to dysregulated transport between blood and CNS, neuroinflammation, and swelling.”
The study found that p53 — a protein known for protecting against cancer — weakens the Norrin/Frizzled4 signalling system in blood vessels by lowering levels of another protein called NCAPH.
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These findings suggest drugs that boost p53 levels — such as MDM2 inhibitors — may accidentally damage the protective barriers in the brain and eyes.
The study also highlights NCAPH as a new candidate gene linked to familial exudative vitreoretinopathy (FEVR) — a rare, inherited eye condition that affects blood vessel growth in the retina.
Given the critical role of p53 in regulating vascular barrier function, it is essential to assess whether MDM2 inhibitors — currently in clinical trials for cancer — could potentially compromise the blood-retina or blood-brain barriers.
The findings also support further investigation into the role of NCAPH in endothelial cells, both as a downstream effector of p53 and as a potential disease gene in vascular disorders, such as FEVR.
This study was supported by grants from the National Eye Institute and National Institutes of Health [R01EY024261, R01EY03331,6, and 1R21DA056728-01A1].
