Successful Treatment of Infantile Hemangiomas with Interferon-α-2b

Chang, Eun-Ha; Boyd, Anne J; Nelson, Christine C.; Crowley, Dennis C.; Law, Terence; Keough, Karen; Folkman, Judah; Ezekowitz, R. A. B.; Castle, Valerie P.

doi:10.1097/00043426-199705000-00011

Cited by 187 publications

(102 citation statements)

References 33 publications

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“…The transcriptional effects of these cytokines on EC, however, have been only partially addressed (31) despite the broad evidence for their antiangiogenic effects (32)(33)(34). The aim of this work was to compare the in vitro effects of type I and type II IFNs on the transcriptional profile of EC of different origins and sources.…”

Section: Discussionmentioning

confidence: 99%

Identification of Genes Selectively Regulated by IFNs in Endothelial Cells

Indraccolo

Pfeffer

Minuzzo

et al. 2007

The Journal of Immunology

148

120

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IFNs are highly pleiotropic cytokines also endowed with marked antiangiogenic activity. In this study, the mRNA expression profiles of endothelial cells (EC) exposed in vitro to IFN-α, IFN-β, or IFN-γ were determined. We found that in HUVEC as well as in other EC types 175 genes were up-regulated (>2-fold increase) by IFNs, including genes involved in the host response to RNA viruses, inflammation, and apoptosis. Interestingly, 41 genes showed a >5-fold higher induction by IFN-α in EC compared with human fibroblasts; among them, the gene encoding the angiostatic chemokine CXCL11 was selectively induced by IFN-α in EC along with other genes associated with angiogenesis regulation, including CXCL10, TRAIL, and guanylate-binding protein 1. These transcriptional changes were confirmed and extended by quantitative PCR analysis and ELISA; whereas IFN-α and IFN-β exerted virtually identical effects on transcriptome modulation, a differential gene regulation by type I and type II IFN emerged, especially as far as quantitative aspects were concerned. In vivo, IFN-α-producing tumors overexpressed murine CXCL10 and CXCL11, guanylate-binding protein 1, and TRAIL, with evidence of CXCL11 production by tumor-associated EC. Overall, these findings improve our understanding of the antiangiogenic effects of IFNs by showing that these cytokines trigger an antiangiogenic transcriptional program in EC. Moreover, we suggest that quantitative differences in the magnitude of the transcriptional activation of IFN-responsive genes could form the basis for cell-specific transcriptional signatures.

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Section: Discussionmentioning

confidence: 99%

Identification of Genes Selectively Regulated by IFNs in Endothelial Cells

Indraccolo

Pfeffer

Minuzzo

et al. 2007

The Journal of Immunology

148

120

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“…Recombinant IGF-2 protein (Calbiochem; ED 50 ϭ 10 ng͞ml) was added at 50 ng͞ml to the cultures daily, and medium was changed every 5 days. Sprouting cells were stained with isolectin IB 4 from Griffonia simplicifolia conjugated with Alexa Flour 594 (Molecular Probes).…”

Section: Methodsmentioning

confidence: 99%

“…However, side effects such as delayed skeletal growth, depressed immune function, and personality changes limit their usefulness, particularly when long-term treatment is required. In lifethreatening cases that have not responded to corticosteroids, IFN-␣ has been used as an alternative (3,4). IFN-␣ is believed to inhibit proliferation of endothelial cells; however, its use has been limited by reports of severe and irreversible neurotoxicity in as many as 20% of patients treated (5,6).…”

mentioning

confidence: 99%

Insulin-like growth factor 2 and potential regulators of hemangioma growth and involution identified by large-scale expression analysis

Ritter

Dorrell

Edmonds

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

155

120

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Hemangiomas are benign tumors of the vascular endothelium and are the most common tumors of infancy. These tumors are characterized by an initial phase of rapid proliferation, which is followed, in most cases, by spontaneous involution. Although most lesions resolve without complication, there are some cases in which hemangiomas can be life threatening when occurring near a vital structure. Treatment for these aggressive tumors represents an unmet clinical need. In addition, this characteristic progression of hemangiomas through distinct phases provides a unique opportunity for studying endothelial cell biology and angiogenesis. Using DNA microarrays representing approximately 10,000 human genes, we identified insulin-like growth factor 2 (IGF-2) as a potentially important regulator of hemangioma growth. IGF-2 was highly expressed during the proliferative phase and substantially decreased during involution. This finding was confirmed at the message level by quantitative reverse transcription-PCR and at the protein level by immunohistochemistry. IGF-2 protein was localized primarily to tumor vessels or vascular channels. Using a human hemangioma explant model, we show that IGF-2 promotes sprouting from intact hemangioma tissue. In addition, several angiogenesis-related factors, including integrins ␣v␤3 and ␣5␤1, are present in proliferating hemangiomas. During the involuting phase, an increase in several IFN-induced genes was observed. These studies identify potential regulators of hemangioma growth and involution and provide a foundation on which to build further mechanistic investigations into angiogenesis, using hemangiomas as a model.

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“…Children with endangering or lifethreatening hemangiomas are treated with corticosteroid or interferon-␣. 3,4 However, not all hemangiomas respond to these drugs and neurological toxicity has been associated with interferon-␣ administration. 5,6 The recent demonstration of ectopic expression of type 3 iodothyronine deiodinase in hemangioma, which in at least one child caused hypothyroidism, 7 underscores the need for novel therapy.…”

mentioning

confidence: 99%

Increased Tie2 Expression, Enhanced Response to Angiopoietin-1, and Dysregulated Angiopoietin-2 Expression in Hemangioma-Derived Endothelial Cells

Varughese

Brown

et al. 2001

The American Journal of Pathology

142

108

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Infantile hemangiomas are endothelial tumors that grow rapidly in the first year of life and regress slowly during early childhood. Although hemangiomas are well-known vascular lesions, little is known about the mechanisms that cause the excessive endothelial cell proliferation in these most common tumors of infancy. To investigate the molecular basis of hemangioma, we isolated endothelial cells from several proliferative-phase lesions and showed that these cells are clonal and exhibit abnormal properties in vitro

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Successful Treatment of Infantile Hemangiomas with Interferon-α-2b

Abstract: Interferon-alpha-2b therapy is an effective, well-tolerated treatment for complicated hemangiomas. Measurement of urinary bFGF levels may provide an objective method for monitoring treatment response.

Cited by 187 publications

References 33 publications

Identification of Genes Selectively Regulated by IFNs in Endothelial Cells

Identification of Genes Selectively Regulated by IFNs in Endothelial Cells

Insulin-like growth factor 2 and potential regulators of hemangioma growth and involution identified by large-scale expression analysis

Increased Tie2 Expression, Enhanced Response to Angiopoietin-1, and Dysregulated Angiopoietin-2 Expression in Hemangioma-Derived Endothelial Cells

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