Down syndrome iPSC model: endothelial perspective on tumor development.

Igor P. Beletsky,Yekaterina Galat,Philip M. Iannaccone,Mariana Perepitchka,Vasiliy Galat

doi:10.18632/oncotarget.27712

Igor P. Beletsky, Yekaterina Galat + Show 3 more

Open Access

https://doi.org/10.18632/oncotarget.27712

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Abstract

Trisomy 21 (T21), known as Down syndrome (DS), is a widely studied chromosomal abnormality. Previous studies have shown that DS individuals have a unique cancer profile. While exhibiting low solid tumor prevalence, DS patients are at risk for hematologic cancers, such as acute megakaryocytic leukemia and acute lymphoblastic leukemia. We speculated that endothelial cells are active players in this clinical background. To this end, we hypothesized that impaired DS endothelial development and functionality, impacted by genome-wide T21 alterations, potentially results in a suboptimal endothelial microenvironment with the capability to prevent solid tumor growth.To test this hypothesis, we assessed molecular and phenotypic differences of endothelial cells differentiated from Down syndrome and euploid iPS cells. Microarray, RNA-Seq, and bioinformatic analyses revealed that most significantly expressed genes belong to angiogenic, cytoskeletal rearrangement, extracellular matrix remodeling, and inflammatory pathways. Interestingly, the majority of these genes are not located on Chromosome 21. To substantiate these findings, we carried out functional assays. The obtained phenotypic results correlated with the molecular data and showed that Down syndrome endothelial cells exhibit decreased proliferation, reduced migration, and a weak TNF-α inflammatory response. Based on this data, we provide a set of genes potentially associated with Down syndrome’s elevated leukemic incidence and its unfavorable solid tumor microenvironment—highlighting the potential use of these genes as therapeutic targets in translational cancer research.

Highlights

Down syndrome (DS) is commonly evaluated on the basis of physical and clinical traits resulting from genomic alterations caused by a trisomy of Chromosome 21 (T21) [1]
The Down syndrome phenotype is characterized by angiogenic, extracellular matrix (ECM)-associated, and immune response imbalances [18, 64]. All of these factors, which rely on endothelial functionality, are key agents that tumors employ to create a favorable niche for growth, and metastasis
Previous studies have shown that T21 has the potential to induce endothelial dysfunction as early as the progenitor stage, but the extent of this biological impact varies between DS individuals [65, 66]

Summary

Introduction

Down syndrome (DS) is commonly evaluated on the basis of physical and clinical traits resulting from genomic alterations caused by a trisomy of Chromosome 21 (T21) [1]. Suggest that there are potentially many causative genes in DS distributed over larger regions of Chromosome 21 [4], and such gene dysregulation may www.oncotarget.com impact up to one-third of disomic genes [5]. Transcriptome and protein analyses have shown that this Chromosome 21 dosage effect can induce gene overexpression and/or underexpression on a genome-wide level [6]. Such genome-wide expression dysregulation in DS was noted in a study on fetal fibroblasts of monozygotic twins discordant for T21 [7]

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