Corticosteroid Suppression of VEGF-A in Infantile Hemangioma-Derived Stem Cells

Greenberger, Shoshana; Boscolo, Elisa; Adini, Irit; Mulliken, John B.; Bischoff, Joyce

doi:10.1056/nejmoa0903036

Cited by 230 publications

(233 citation statements)

References 32 publications

(31 reference statements)

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“…Finally, we had the opportunity to study β-adrenoceptor mRNA expression in hemangioma-derived stem cells (9). Again, β 1 -adrenoceptor mRNA was the predominant subtype expressed in the hemangioma-derived stem cells (Figure 4).…”

Section: Resultsmentioning

confidence: 99%

“…Inhibition of this pathway by β-blockers has not been studied in detail with respect to inhibition of cell proliferation. Furthermore, data on inhibition of downstream signaling of β-adrenoceptors in endothelial cells from IH are not available and future studies using hemangiomaderived stem cells are warranted (9). However, models of the antiangiogenic effect of β-blockers by downregulation of angiogenesis factor expression or induction of endothelial cell apoptosis in IH have been postulated (3).…”

Section: Discussionmentioning

confidence: 99%

“…The derivation, sources, and culture conditions for the hemangioma-derived stem cells have been detailed previously (9).…”

Section: Hemangioma Cellsmentioning

confidence: 99%

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β1-Adrenoceptor mRNA level reveals distinctions between infantile hemangioma and vascular malformations

et al. 2013

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Background: Infantile hemangioma (Ih) is the most frequent vascular tumor of early childhood. Recently, propranolol, a nonselective β 1 -and β 2 -adrenoceptor inhibitor, was introduced into the therapy of severe proliferating Ih with excellent results. however, the underlying mechanism of action of propranolol is still unclear. Methods: We performed immunohistochemistry for cluster of differentiation 31 (cD31), D2-40, glucose transporter-1 (GLUT-1), and Ki67 in order to characterize 21 vascular anomalies (nine Ih, seven venous malformations (VMs), and five lymphatic malformations (LMs)). Furthermore, we analyzed the expression of β 1 -, β 2 -, and β 3 -adrenoceptor mRNA in these specimens as well as in hemangioma-derived stem cells by quantitative real-time PcR (qPcR). results: We show that the expression of β 1 -adrenoceptor mRNA is 10.7-fold higher in Ih independent of the proliferative or regressive phase as well as 2.5-fold higher in hemangioma-derived stem cells as compared with β 2 -adrenoceptor mRNA. In LM, the expression of β 2 -adrenoceptor mRNA was ninefold higher than that of β 1 -adrenoceptor mRNA. VM showed low expression levels of all β-adrenoceptor mRNAs, and β 3 -adrenoceptor mRNA was hardly detectable in any specimens examined. conclusion: These results provide the first evidence of distinctions between Ih and vascular malformations with regard to β-adrenoceptor subtype mRNA levels. r ecently, propranolol, a nonselective β-adrenoceptor inhibitor, was introduced into the therapy of severe proliferating infantile hemangioma (IH) (1). Propranolol treatment in IH results in fast growth inhibition and rapid tumor regression within a few days of therapy. This novel medical treatment has not been developed in a classic way; it was accidentally observed during corticosteroid therapy, the so far standard therapy for proliferating IH (2) when cardiac hypertrophy as a side effect is treated by propranolol. The molecular mechanism of propranolol on IH proliferation is unknown at present. A possible method of action could be vasoconstriction or induction of endothelial cell apoptosis (3). Inhibition of β-adrenoceptors has been suggested to have a negative impact on tumor development as well as a direct effect on endothelial cells by downregulation of angiogenesis factors such as vascular endothelial growth factor, matrix metalloproteinase-2, and matrix metalloproteinase-9 (4,5). A possible involvement of the β 2 -adrenoceptor/cyclic adenosine monophosphate pathway has been described in tumor vascularization of glioblastoma (4).IH is the most frequent benign tumor of early childhood that shows specific biological features: after an initial phase of proliferation during the first year of life, a long-lasting period of spontaneous regression over several years is observed (6). The underlying molecular mechanism could not be completely determined because of a lack of models for IH. Until recently, neither IH cell lines nor animal models were available. Endothelial cells from IH show specific expression of glucos...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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β1-Adrenoceptor mRNA level reveals distinctions between infantile hemangioma and vascular malformations

et al. 2013

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“…The mechanism of action of steroids is not entirely clear, though it is postulated to have an inhibitory effect on the production of vascular endothelial growth factor A (VEGF-A) by stem cells in haemangioma. 13,14 This is the study to demonstrate the efficacy of corticosteroids in halting the proliferation of IHs clinically (decrease in hemangioma size and improved visual function) and biologically (decrease in the circulating proangiogenic proteins). The effect, measured over the first year of life, was more pronounced with high-dose, intermittent pulses with methylprednisolone.…”

Section: Resultsmentioning

confidence: 99%

Pulse steroid therapy in infantile facial hemangiomas: the early experience

et al. 2018

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Background: To investigate the efficacy and safety of Pulse steroid therapy in the management of Infantile facial hemangioma in five subjects.Methods: Consecutive patients who presented with facial hemangioma were prospectively enrolled in this study between January 2014 till August 2017. All subjects underwent treatment with 30mg/kg/day I/V methyl prednisolone for 6days and then weekly for 6weeks and then followed by oral daily dosing. All subjects underwent systemic, and radiologic evaluations before treatment and at periodic intervals after starting therapy. Side effects from therapy were also evaluated.Results: Five subjects under 6 months of age, with facial hemangioma were enrolled in this study. After hospital admission, I/V steroid therapy was initiated in all subjects under monitoring by a pediatric cardiologist. Subsequent oral therapy after 6 weeks was performed with periodic out-patient monitoring. All subjects had excellent response to treatment, with regression of facial hemangioma. There were no side effects from therapy.Conclusions: I/V methyl prednisolone pulse steroid therapy for facial hemangioma was effective in all the five subjects.

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“…Additionally, insulin like growth factor-2, which stimulates angiogenesis, is upregulated in proliferating but not involuting blood vessels. (22) Endothelial progenitor cells (EPCs) are vascular stem cells with the capacity to contribute to postnatal vascular development. There is now compelling evidence that these EPCs play an etiologic role in the development of IH.…”

Section: Pathophysiology:-mentioning

confidence: 99%