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Oncotarget: Down syndrome iPSC model: an endothelial perspective on tumor development


Oncotarget recently published "Down syndrome iPSC model: endothelial perspective on tumor development" which reported that the authors speculated that endothelial cells are active players in this clinical background.

To this end, they 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, an assessment was made of molecular and phenotypic differences of endothelial cells differentiated from Down syndrome and euploid iPS cells.

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, the Oncotarget authors 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.

The Oncotarget authors provide a set of genes potentially associated with Down syndrome's elevated leukemic incidence and its unfavorable solid tumor microenvironment

Dr. Mariana Perepitchka, Dr. Yekaterina Galat, and Dr. Vasiliy Galat said, "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)."

Initially, the dominant perspective was that DS phenotypes resulted from extra gene dosage effects solely relative to T21. Furthermore, even though Chromosome 21 is considered to host approximately 350 genes, research efforts were directed toward a small subset of genes clustered around the DS critical region.

More recent studies, however, suggest that there are potentially many causative genes in DS distributed over larger regions of Chromosome 21, and such gene dysregulation may impact up to one-third of disomic genes.

These authors' previous research, amongst others, has shown that induced pluripotent stem cells progress through major embryonic developmental stages, and by utilizing DS iPSCs, this opens a direct line into investigating DS phenotypic traits and genotypic implications.

Figure 5: Tube formation, spheroid sprouting, and inflammatory response of disomic and trisomic iECs. (A) (i, ii) SR2-iEC and DSV-iEC phase contrast microscopy images of the Tube Formation Assay: prior to and following WimTube software analysis; (iii) SR2-iECs and DSV-iECs stained with cell-permeant dye Calcein-AM. The numerical values, reported in pixels (px), refer to total tube length; (iv) Tube Formation data table showing mean values for loops, branching points, and total number of tubes; (B) (i, ii) Phase contrast microscopy images of the Spheroid Assay: prior to and following WimSprout software analysis; (iii) Spheroid Assay data table showing mean values, which are reported in pixels (px), for total spheroid area, total sprout area, and total sprout length. (C) Representative image: flow cytometry results of iEC response to TNF-α stimulation. The sensitivity of the response was evaluated on the basis of VCAM-1 (CD106) and E-selectin (CD62E) cell surface expression. (D) Inflammatory Assay data incorporating four experimental replicates. Unlike the SR2-iEC line, DSV-iECs have VCAM-1 and E-selectin moderately expressed prior to TNF-α activation. Following the addition of TNF-α, DSV-iECs do not show as significant a difference in VCAM-1 and E-selectin expression like SR2-iECs. All statistical data in the Figure is presented as mean ± SEM.

From a genotypic standpoint, previous studies focusing on DSCR1 and DYRK1A genes, located on the extra copy of Chromosome 21, showed that DS individuals have a unique cancer profile.

Interestingly, the majority of the significantly expressed genes within these pathways were not located on Chromosome 21. These findings, confirmed by functional assays, may prove to be useful in ongoing DS clinical research and provide a new perspective on tumor development, which can aid future cancer-related studies.

The Perepitchka/Galat Research Team concluded in their Oncotarget Research Paper that taking into account all of these aspects, this work identified the following factors that may offer insight into the question of why DS individuals exhibit elevated leukemic precedence and decreased solid tumor growth: decreased proliferative and migratory capability; a potentially prolonged inflammatory state; down-regulation of genome-wide solid tumor-associated oncogenes; and an up-regulation of genome-wide leukemia-associated oncogenes.

These factors also highlight the widespread involvement of the tumor niche during pre-metastatic phases of cancer development and the importance of evaluating the endothelial microenvironment from a variety of molecular perspectives.

The use of iPSCs and directed differentiation protocols provides a new and powerful tool to continue gaining more insight into the biology of DS, endothelial development, the solid tumor niche, and a wide array of human diseases.

As more differentiation models become available, such as hematopoietic stem cells, the types of experiments that can be done and their correct interpretation will grow.

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

Full text - https://www.oncotarget.com/article/27712/text/

Correspondence to - Mariana Perepitchka - mperepitchka@u.northwestern.edu, Yekaterina Galat - ygalat@luriechildrens.org, and Vasiliy Galat - v-galat@northwestern.edu

Keywords - Down syndrome, iPSC-derived endothelial model, T21 genome-wide Implications, meta-analysis, tumor microenvironment

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