Affordable Access

Access to the full text

Down syndrome iPSC model: endothelial perspective on tumor development

Authors
  • Perepitchka, Mariana
  • Galat, Yekaterina
  • Beletsky, Igor P.
  • Iannaccone, Philip M.
  • Galat, Vasiliy
Type
Published Article
Journal
Oncotarget
Publisher
"Impact Journals, LLC "
Publication Date
Sep 08, 2020
Volume
11
Issue
36
Pages
3387–3404
Identifiers
DOI: 10.18632/oncotarget.27712
PMID: 32934781
PMCID: PMC7486695
Source
PubMed Central
Keywords
License
Green

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.

Report this publication

Statistics

Seen <100 times