Rapamycin Suppresses Self-Renewal and Vasculogenic Potential of Stem Cells Isolated from Infantile Hemangioma

Abstract

Infantile hemangioma (IH) is a common childhood vascular tumor. Although benign, some hemangiomas cause deformation and destruction of features or endanger life. The current treatments, corticosteroid or propranolol, are administered for several months and can have adverse effects for the infant. We designed a high-throughput screen to identify FDA-approved drugs that could be used to treat this tumor. Rapamycin, an mTOR inhibitor, was identified based on its ability to inhibit proliferation of a hemangioma-derived stem cell population, human vasculogenic cells we had previously discovered. In vitro and in vivo studies show that Rapamycin reduces the self-renewal capacity of the hemangioma stem cells, diminishes differentiation potential, and inhibits the vasculogenic activity of these cells in vivo. Longitudinal in vivo imaging of blood flow through vessels formed with hemangioma stem cells shows that Rapamycin also leads to regression of hemangioma blood vessels, consistent with its known anti-angiogenic activity. Finally, we demonstrate that Rapamycin-induced loss of stemness can work in concert with corticosteroid, the current standard therapy for problematic hemangioma, to block hemangioma formation in vivo. Our studies reveal that Rapamycin targets the self-renewal and vascular differentiation potential in patient-derived hemangioma stem cells and suggests a novel therapeutic strategy to prevent formation of this disfiguring and endangering childhood tumor.

Vincristine for Successful Treatment of Steroid-Dependent Infantile Hemangiomas

“…19,20 Interferon therapy is complicated by treatment-related toxicities including fever, irritability, malaise, liver function abnormalities, and neutropenia, although the potential for irreversible neurotoxicity (including several reports of spastic diplegia 21,22 ) substantially limits its consideration as second-line therapy. It remains to be demonstrated which of these therapies is most appropriate; however, this report suggests vincristine to be a viable option that carries a tolerable side-effect profile.…”

Vascular tumors have increased p70 S6-kinase activation and are inhibited by topical rapamycin

“…28 Although the clinical efficacy of rapamycin in patients with infantile hemangioma has not been reported, rapamycin has been shown to reduce the self-renewal capacity and vasculogenic activity of hemangioma stem cells. 27 The drug also reduces the proliferation of hemangioma EC, as well as VEGF and hypoxia-inducible factor-1a levels in these cells. 26 Rapamycin, however, is a potent immunosuppressant, and the long-term effects of systemic drug exposure would be deemed deleterious in individuals with a normal immune system.…”

“…It suppresses the self-renewal and vascular differentiation potential of infantile hemangioma stem cells, and reduces VEGF and hypoxia-inducible factor-1a levels in hemangioma EC. 26,27 Rapamycin and rapalogs have shown promising results in clinical trials for other types of vascular lesions, including Kaposi's sarcoma, kidney angiomyolipoma and complicated vascular anomalies. 17,28,29 As rapamycin is an immunosuppressive drug, it can cause significant negative side effects in healthy individuals when taken systemically.…”

Current Concepts in the Pathogenesis and Management of Vascular Lesions - A Brief Review.

“…Lasers such flashlamp pulsed dye lasers have also been used. (34) Occasionally, selective embolization techniques followed by surgical excision is the optimal therapeutic intervention. The goal is to obstruct or reduce the blood flow to the lesion-so that it can be excised with minimal blood loss.…”