Identification of Signaling Systems in Proliferating and Involuting Phase Infantile Hemangiomas by Genome-Wide Transcriptional Profiling

Abstract

Infantile hemangiomas are characterized by rapid capillary growth during the first year of life followed by involution during early childhood. The natural history of these lesions creates a unique opportunity to study the changes in gene expression that occur in the vessels of these tumors as they proliferate and regress. Here we use laser capture microdissection and genome-wide transcriptional profiling of vessels from proliferating and involuting hemangiomas to identify differentially expressed genes. Relative to normal placental vessels, proliferating hemangiomas were characterized by increased expression of genes involved in endothelial-pericyte interactions, such as angiopoietin-2 (ANGPT2), jagged-1 (JAG1), and notch-4 (NOTCH4), as well as genes involved in neural and vascular patterning, such as neuropilin-2 (NETO2), a plexin domain containing receptor (plexinC1), and an ephrin receptor (EPHB3). Insulin-like growth factor binding protein-3 (IGFBP3) was down-regulated in proliferating hemangiomas. Involuting hemangiomas were characterized by the expression of chronic inflammatory mediators, such as the chemokine, stromal cellderived factor-1 (SDF-1), and factors that may attenuate the angiogenic response, such as a member of the Down syndrome critical region (DSCR) family. The identification of genes differentially expressed in proliferating and involuting hemangiomas in vivo will contribute to our understanding of this vascular lesion, which remains a leading cause of morbidity in newborn children.

Jagged1/Notch3 Signaling Modulates Hemangioma-Derived Pericyte Proliferation and Maturation

“…Previous studies have demonstrated that the IH life-cycle is associated with clear spatialtemporal changes in the expression of Notch members [14,15]. We analyzed the expression levels of Jagged1, Notch3, Hes1 and HEYL in proliferating and involuting IHs using real-time PCR (Fig.…”

“…Current data suggest that several Notch components are involved in the pathogenesis of IH [14][15][16][17]. Remarkably, recent studies have revealed that endothelial-derived Jagged1 can induce hemangioma-derived stem cells (HemSCs) to acquire a pericyte-like phenotype, which is a crucial step in the vasculogenesis of IH.…”

Wnt3a Expression is Associated with MMP-9 Expression in Primary Tumor and Metastatic Site in Recurrent or Stage IV Colorectal Cancer

“…A reduction of VEGFR-1 expression has been implicated in the proliferation of infantile HemECs and tissue [40,52]. The mechanism for this low expression in HemECs was shown to be the sequestration of β1-inergrin in a multiprotein complex composed of tumor endothelial marker-8 (TEM8) and VEGFR-2, which inhibits nuclear factor in activated T cells (NFAT)-mediated VEGFR-1 transcription [40].…”

Pyogenic granuloma, an impaired wound healing process, linked to vascular growth driven by FLT4 and the nitric oxide pathway

“…Our statistical analyses were not designed to unravel the differences between the stages of infantile hemangiomas but, studies that did, determined them to differ with regard to the genes of the chronic inflammatory response and of the NOTCH pathway. 4,27 For pyogenic granuloma, correspondence analysis and analysis of variance revealed only dissimilarities with the other tissues tested. Such specific genetic behavior of vessels from pyogenic granuloma was not surprising, although not previously described.…”

“…4 Array Hybridization RNA was extracted and amplified using the Paradise Reagent System Kit according to the manufacturer's recommendations (Paradise Reagent System Kit, Applied Biosystems). The amplified and purified cDNAs were then submitted to the Harvard-Partner Center for Genetics and Genomics Facility (www.hpcgg.org).…”