MOA of steroids in infantile hemangioma elucidated

Infantile hemangioma

Researchers from Children’s Hospital Boston and Harvard Medical School have shed light on the mechanism of action (MOA) of corticosteroid therapy in infantile hemangioma.

By administering dexamethasone in a murine model, the team discovered that the corticosteroid inhibits the vasculogenic potential of VEGF-A expression by stems cells derived from human infantile hemangioma. Silencing VEGF-A also inhibits vasculogenesis in these cells.

Shoshana Greenberger, MD, PhD, and colleagues reported the findings in the March 18 issue of The New England Journal of Medicine.

Infantile hemangioma is generally not harmful. However, 10% of them are destructive, disfiguring, and can threaten vision and life. Infantile hemangioma is usually treated with corticosteroids, and scientists assumed that steroids acted on endothelial cells, which constitute about 30% of cells in the hemangioma.

The researchers implanted human hemangioma-derived stem cells and human cord blood endothelial progenitor cells into immune-deficient mice. They then injected the mice with dexamethasone daily for 7 days.

The researchers observed that the dexamethasone suppressed blood vessel formation compared to mice that they injected with saline. The blood vessel suppression was dose-dependent.

They also treated the hemangioma-derived stem cells and the cord blood endothelial progenitor cells separately with dexamethasone for 3 days. They observed that the hemangioma-derived stem cells had a significant decrease in the number of blood cells in the murine tumors, whereas the cord blood endothelial cells did not.

The team then tested the impact of dexamethasone on the expression of VEGF-A. They found that hemangioma-derived stem cells experience a significant dose-dependent down-regulation of VEGF-A mRNA and protein. They confirmed that prednisone, prednisolone, methylprednisolone, and hydrocortisone have a similar effect on VEGF-A expression.

When the investigators down-regulated VEGF-A using shRNA silencing, they observed that hemangioma-derived stem cells had an 89% reduction in microvessel density.

The investigators also established that VEGF-A is present in actively growing hemangiomas, but not in regressing, or involuting, ones. They also found VEGF-A to be localized in cells outside the blood vessels.

The investigators concluded that silencing VEGF-A expression is sufficient to block the vasculogenic potential of hemangioma-derived stem cells. And dexamethasone specifically suppresses the vasculogenic capability of hemangioma-derived stem cells in part by down-regulating VEGF-A.

They also noticed that dexamethasone down regulates other proangiogenic factors in hemangioma-derived stem cells, including urokinase plasminogen activator receptor, interleukin-6, monocyte chemoattractant protein 1, and matrix metalloproteinase 1.

They believe that this approach could potentially be useful for testing and development of new therapies to treat infantile hemangioma.