Gene expression analysis reveals marked differences in the transcriptome of infantile hemangioma endothelial cells compared to normal dermal microvascular endothelial cells

Abstract

BackgroundInfantile hemangiomas are benign vascular tumors primarily found on the skin in 10% of the pediatric population. The etiology of this disease is largely unknown and while large scale genomic studies have examined the transcriptomes of infantile hemangioma tumors as a whole, no study to date has compared the global gene expression profiles of pure infantile hemangioma endothelial cells (HEMECs) to that of normal human dermal microvascular endothelial cells (HDMVECs).MethodsTo shed light on the molecular differences between these normal and aberrant dermal endothelial cell types, we performed whole genome microarray analysis on purified cultures of HEMECs and HDMVECs. We then utilized qPCR and immunohistochemistry to confirm our microarray results.ResultsOur array analysis identified 125 genes whose expression was upregulated and 104 genes whose expression was downregulated by greater than two fold in HEMECs compared to HDMVECs. Bioinformatics analysis revealed three major classifications of gene functions that were altered in HEMECs including cell adhesion, cell cycle, and arachidonic acid production. Several of these genes have been reported to be critical regulators and/or mutated in cancer, vascular tumors, and vascular malformations. We confirmed the expression of a subset of these differentially expressed genes (ANGPT2, ANTXR1, SMARCE1, RGS5, CTAG2, LTBP2, CLDN11, and KISS1) using qPCR and utilized immunohistochemistry on a panel of paraffin embedded infantile hemangioma tumor tissues to demonstrate that the cancer/testis antigen CTAG2 is highly abundant in vessel-dense proliferating infantile hemangiomas and with significantly reduced levels during tumor involution as vascular density decreases.ConclusionOur data reveal that the transcriptome of HEMECs is reflective of a pro-proliferative cell type with altered adhesive characteristics. Moveover, HEMECs show altered expression of many genes that are important in the progression and prognosis of metastatic cancers.

Competitive endogenous RNA networks: integrated analysis of non-coding RNA and mRNA expression profiles in infantile hemangioma

“…The pathogenesis of hemangioma is largely unknown due to its sophisticated etiology. Although a lot of papers report the RNA networks in IH [ 12 , 14 , 17 – 19 ], those work all used microarrays methods. In this study, we used Ribo-Zero RNA-Seq and HiSeq means to examine the global expression profiles of protein-coding transcripts and non-coding RNAs, including miRNAs and lncRNAs, in IH and matched normal skin controls.…”

Extracellular matrix composition modulates angiosarcoma cell attachment and proliferation

“…Our lab has previously shown that aberrant endothelial cells isolated from the benign vascular tumor, infantile hemangioma, differ in their expression patterns and regulation of ECM components from that of normal endothelial cells [ 17 , 18 ], though it is unclear if similar properties are present in malignant vascular tumors such as angiosarcomas. We demonstrate that multiple ECM proteins and their MMP regulators are detectable in angiosarcoma tissues.…”

Transcriptional activation of Hedgehog pathway components in aggressive haemangioma

“…Infantile hemangiomas consist of immature and disorganized endothelial cells and also contain endothelial progenitor cells . Alterations of VEGF and NOTCH‐signalling, among others, have been found in hemangiomas, and experiments pointing to a placental origin of endothelial cells in hemangiomas have been published . Moreover, FGF2 has been described as a marker for hemangioma, but has been discussed controversially regarding its level of expression during proliferation as compared to involution .…”