Journal Article
. 2020 Sep; 11(36):3387-3404.
doi: 10.18632/oncotarget.27712.

Down syndrome iPSC model: endothelial perspective on tumor development

Mariana Perepitchka 1 Yekaterina Galat 1 Igor P Beletsky 2 Philip M Iannaccone 1 Vasiliy Galat 3 
  • PMID: 32934781
  •     77 References


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.

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

Carcinogenesis in Down syndrome: what can be learned from trisomy 21?
Daniel Satgé, Jean Bénard.
Semin Cancer Biol, 2008 May 06; 18(5). PMID: 18455928
Vessel co-option in cancer.
Elizabeth A Kuczynski, Peter B Vermeulen, +2 authors, Andrew R Reynolds.
Nat Rev Clin Oncol, 2019 Mar 01; 16(8). PMID: 30816337
Highly Cited. Review.
The evolution of the cancer niche during multistage carcinogenesis.
Mary Helen Barcellos-Hoff, David Lyden, Timothy C Wang.
Nat Rev Cancer, 2013 Jun 14; 13(7). PMID: 23760023
Highly Cited. Review.
Role of tissue factor in cancer.
Raj S Kasthuri, Mark B Taubman, Nigel Mackman.
J Clin Oncol, 2009 Sep 10; 27(29). PMID: 19738116    Free PMC article.
Highly Cited. Review.
Myeloid leukemia in Down syndrome.
Irum Khan, Sébastien Malinge, John Crispino.
Crit Rev Oncog, 2011 Dec 14; 16(1-2). PMID: 22150305    Free PMC article.
Cytokine-free directed differentiation of human pluripotent stem cells efficiently produces hemogenic endothelium with lymphoid potential.
Yekaterina Galat, Svetlana Dambaeva, +4 authors, Vasiliy Galat.
Stem Cell Res Ther, 2017 Mar 18; 8(1). PMID: 28302184    Free PMC article.
Extracellular Vesicles in Cancer: Cell-to-Cell Mediators of Metastasis.
Annette Becker, Basant Kumar Thakur, +3 authors, David Lyden.
Cancer Cell, 2016 Dec 14; 30(6). PMID: 27960084    Free PMC article.
Highly Cited. Review.
A Genome-wide Analysis of Human Pluripotent Stem Cell-Derived Endothelial Cells in 2D or 3D Culture.
Jue Zhang, Michael P Schwartz, +11 authors, William L Murphy.
Stem Cell Reports, 2017 Mar 28; 8(4). PMID: 28343999    Free PMC article.
Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal.
Jianjiong Gao, Bülent Arman Aksoy, +10 authors, Nikolaus Schultz.
Sci Signal, 2013 Apr 04; 6(269). PMID: 23550210    Free PMC article.
Highly Cited.
Solid malignancies in individuals with Down syndrome: a case presentation and literature review.
Scott V Bratman, Kathleen C Horst, Robert W Carlson, Daniel S Kapp.
J Natl Compr Canc Netw, 2014 Nov 02; 12(11). PMID: 25361800
Highly penetrant myeloproliferative disease in the Ts65Dn mouse model of Down syndrome.
Gina Kirsammer, Sarah Jilani, +4 authors, John D Crispino.
Blood, 2007 Sep 29; 111(2). PMID: 17901249    Free PMC article.
Molecular and cellular alterations in Down syndrome: toward the identification of targets for therapeutics.
Nicole Créau.
Neural Plast, 2012 Aug 01; 2012. PMID: 22848846    Free PMC article.
Transgene Reactivation in Induced Pluripotent Stem Cell Derivatives and Reversion to Pluripotency of Induced Pluripotent Stem Cell-Derived Mesenchymal Stem Cells.
Vasiliy Galat, Yekaterina Galat, +3 authors, Mary J C Hendrix.
Stem Cells Dev, 2016 May 20; 25(14). PMID: 27193052    Free PMC article.
Domains of genome-wide gene expression dysregulation in Down's syndrome.
Audrey Letourneau, Federico A Santoni, +25 authors, Stylianos E Antonarakis.
Nature, 2014 Apr 18; 508(7496). PMID: 24740065
Highly Cited.
Emerging Roles of Vascular Cell Adhesion Molecule-1 (VCAM-1) in Immunological Disorders and Cancer.
Deok-Hoon Kong, Young Kwan Kim, +2 authors, Sukmook Lee.
Int J Mol Sci, 2018 Apr 05; 19(4). PMID: 29614819    Free PMC article.
Concise review: new paradigms for Down syndrome research using induced pluripotent stem cells: tackling complex human genetic disease.
James A Briggs, Elizabeth A Mason, +2 authors, Ernst J Wolvetang.
Stem Cells Transl Med, 2013 Feb 16; 2(3). PMID: 23413375    Free PMC article.
Stem and progenitor cell dysfunction in human trisomies.
Binbin Liu, Sarah Filippi, Anindita Roy, Irene Roberts.
EMBO Rep, 2014 Dec 19; 16(1). PMID: 25520324    Free PMC article.
The endothelin axis in urologic tumors: mechanisms of tumor biology and therapeutic implications.
Edwin Herrmann, Martin Bögemann, +3 authors, Christian Wülfing.
Expert Rev Anticancer Ther, 2005 Dec 27; 6(1). PMID: 16375646
Trisomy 21 causes changes in the circulating proteome indicative of chronic autoinflammation.
Kelly D Sullivan, Donald Evans, +8 authors, Thomas Blumenthal.
Sci Rep, 2017 Nov 03; 7(1). PMID: 29093484    Free PMC article.
Metastatic niche functions and therapeutic opportunities.
Toni Celià-Terrassa, Yibin Kang.
Nat Cell Biol, 2018 Jul 28; 20(8). PMID: 30050120
The Role of IL-33/ST2 Pathway in Tumorigenesis.
Kristen M Larsen, Maydelis Karla Minaya, Vivek Vaish, Maria Marjorette O Peña.
Int J Mol Sci, 2018 Sep 13; 19(9). PMID: 30205617    Free PMC article.
Origins of leukaemia in children with Down syndrome.
Johann K Hitzler, Alvin Zipursky.
Nat Rev Cancer, 2005 Jan 05; 5(1). PMID: 15630411
Microenvironmental regulation of tumour angiogenesis.
Michele De Palma, Daniela Biziato, Tatiana V Petrova.
Nat Rev Cancer, 2017 Jul 15; 17(8). PMID: 28706266
Highly Cited. Review.
Chromosome 21 and down syndrome: from genomics to pathophysiology.
Stylianos E Antonarakis, Robert Lyle, +2 authors, Samuel Deutsch.
Nat Rev Genet, 2004 Oct 29; 5(10). PMID: 15510164
Highly Cited. Review.
Hematopoietic defects in the Ts1Cje mouse model of Down syndrome.
Catherine L Carmichael, Ian J Majewski, +4 authors, Hamish S Scott.
Blood, 2008 Dec 26; 113(9). PMID: 19109561
The relationship between tissue factor and cancer progression: insights from bench and bedside.
Yascha W van den Berg, Susanne Osanto, Pieter H Reitsma, Henri H Versteeg.
Blood, 2011 Nov 09; 119(4). PMID: 22065595
Highly Cited. Review.
Down's syndrome suppression of tumour growth and the role of the calcineurin inhibitor DSCR1.
Kwan-Hyuck Baek, Alexander Zaslavsky, +13 authors, Sandra Ryeom.
Nature, 2009 May 22; 459(7250). PMID: 19458618    Free PMC article.
Highly Cited.
Microenvironmental regulation of tumor progression and metastasis.
Daniela F Quail, Johanna A Joyce.
Nat Med, 2013 Nov 10; 19(11). PMID: 24202395    Free PMC article.
Highly Cited. Review.
OncoKB: A Precision Oncology Knowledge Base.
Debyani Chakravarty, Jianjiong Gao, +45 authors, Nikolaus Schultz.
JCO Precis Oncol, 2017 Sep 12; 2017. PMID: 28890946    Free PMC article.
Highly Cited.
A model of early human embryonic stem cell differentiation reveals inter- and intracellular changes on transition to squamous epithelium.
Vasiliy Galat, Sergey Malchenko, +7 authors, Mary J C Hendrix.
Stem Cells Dev, 2011 Aug 25; 21(8). PMID: 21861759    Free PMC article.
Hypoxia-mediated translational activation of ITGB3 in breast cancer cells enhances TGF-β signaling and malignant features in vitro and in vivo.
Marta Sesé, Pedro Fuentes, +5 authors, Santiago Ramón Y Cajal.
Oncotarget, 2018 Feb 01; 8(70). PMID: 29383126    Free PMC article.
Targeting selectins and selectin ligands in inflammation and cancer.
Steven R Barthel, Jacyln D Gavino, Leyla Descheny, Charles J Dimitroff.
Expert Opin Ther Targets, 2007 Nov 22; 11(11). PMID: 18028011    Free PMC article.
Highly Cited. Review.
The utility of stem cells in pediatric urinary bladder regeneration.
Philip M Iannaccone, Vasil Galat, +2 authors, Arun K Sharma.
Pediatr Res, 2017 Sep 16; 83(1-2). PMID: 28915233
Reduced expression of the hyaluronan and proteoglycan link proteins in malignant gliomas.
Hosung Sim, Bin Hu, Mariano S Viapiano.
J Biol Chem, 2009 Jul 28; 284(39). PMID: 19633295    Free PMC article.
Endothelin 1 in cancer: biological implications and therapeutic opportunities.
Laura Rosanò, Francesca Spinella, Anna Bagnato.
Nat Rev Cancer, 2013 Jul 26; 13(9). PMID: 23884378
Highly Cited. Review.
The genetic architecture of Down syndrome phenotypes revealed by high-resolution analysis of human segmental trisomies.
Jan O Korbel, Tal Tirosh-Wagner, +30 authors, Julie R Korenberg.
Proc Natl Acad Sci U S A, 2009 Jul 15; 106(29). PMID: 19597142    Free PMC article.
Highly Cited.
Endothelin-1 promotes vascular endothelial growth factor-dependent angiogenesis in human chondrosarcoma cells.
M-H Wu, C-Y Huang, +4 authors, C-H Tang.
Oncogene, 2013 Apr 16; 33(13). PMID: 23584483
Hypoxia-inducible factor 1 (HIF-1) promotes extracellular matrix remodeling under hypoxic conditions by inducing P4HA1, P4HA2, and PLOD2 expression in fibroblasts.
Daniele M Gilkes, Saumendra Bajpai, +2 authors, Gregg L Semenza.
J Biol Chem, 2013 Feb 21; 288(15). PMID: 23423382    Free PMC article.
Highly Cited.
Structural ECM components in the premetastatic and metastatic niche.
Anette M Høye, Janine T Erler.
Am J Physiol Cell Physiol, 2016 Apr 08; 310(11). PMID: 27053524
Trisomic dose of several chromosome 21 genes perturbs haematopoietic stem and progenitor cell differentiation in Down's syndrome.
S De Vita, C Canzonetta, +10 authors, D Nizetic.
Oncogene, 2010 Aug 11; 29(46). PMID: 20697343    Free PMC article.
Inflammatory and Immunological parameters in adults with Down syndrome.
Maria Bf Trotta, João B Serro Azul, +3 authors, Jorge E Kalil.
Immun Ageing, 2011 Apr 19; 8(1). PMID: 21496308    Free PMC article.
Apolipoprotein E Overexpression Is Associated With Tumor Progression and Poor Survival in Colorectal Cancer.
Zhixun Zhao, Shuangmei Zou, +9 authors, Xishan Wang.
Front Genet, 2019 Jan 12; 9. PMID: 30631342    Free PMC article.
NetworkAnalyst for statistical, visual and network-based meta-analysis of gene expression data.
Jianguo Xia, Erin E Gill, Robert E W Hancock.
Nat Protoc, 2015 May 08; 10(6). PMID: 25950236
Highly Cited.
Extracellular matrix metalloproteinase inducer in interstitial pneumonias.
Nao Odajima, Tomoko Betsuyaku, +4 authors, Masaharu Nishimura.
Hum Pathol, 2006 Jul 27; 37(8). PMID: 16867869
Down syndrome phenotypes: the consequences of chromosomal imbalance.
J R Korenberg, X N Chen, +7 authors, C Disteche.
Proc Natl Acad Sci U S A, 1994 May 24; 91(11). PMID: 8197171    Free PMC article.
Highly Cited.
Mosaicism for trisomy 21: a review.
Paulie Papavassiliou, Chariyawan Charalsawadi, Kelly Rafferty, Colleen Jackson-Cook.
Am J Med Genet A, 2014 Nov 22; 167A(1). PMID: 25412855
Impairment of circulating endothelial progenitors in Down syndrome.
Valerio Costa, Linda Sommese, +16 authors, Claudio Napoli.
BMC Med Genomics, 2010 Sep 15; 3. PMID: 20836844    Free PMC article.
ERK1/2 MAP kinases: structure, function, and regulation.
Robert Roskoski.
Pharmacol Res, 2012 May 10; 66(2). PMID: 22569528
Highly Cited. Review.
Down syndrome and leukemia: insights into leukemogenesis and translational targets.
Marion K Mateos, Draga Barbaric, +2 authors, Glenn M Marshall.
Transl Pediatr, 2016 Feb 03; 4(2). PMID: 26835364    Free PMC article.
Proteomics identification of ITGB3 as a key regulator in reactive oxygen species-induced migration and invasion of colorectal cancer cells.
Yunlong Lei, Kai Huang, +14 authors, Yuquan Wei.
Mol Cell Proteomics, 2011 May 31; 10(10). PMID: 21622897    Free PMC article.
Infections and immunodeficiency in Down syndrome.
G Ram, J Chinen.
Clin Exp Immunol, 2011 Mar 01; 164(1). PMID: 21352207    Free PMC article.
Highly Cited. Review.
The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data.
Ethan Cerami, Jianjiong Gao, +12 authors, Nikolaus Schultz.
Cancer Discov, 2012 May 17; 2(5). PMID: 22588877    Free PMC article.
Highly Cited.
Functional screening of 2 Mb of human chromosome 21q22.2 in transgenic mice implicates minibrain in learning defects associated with Down syndrome.
D J Smith, M E Stevens, +8 authors, E M Rubin.
Nat Genet, 1997 May 01; 16(1). PMID: 9140392
Lefty Glycoproteins in Human Embryonic Stem Cells: Extracellular Delivery Route and Posttranslational Modification in Differentiation.
Zhila Khalkhali-Ellis, Vasiliy Galat, +3 authors, Mary J C Hendrix.
Stem Cells Dev, 2016 Aug 25; 25(21). PMID: 27554431    Free PMC article.
Human embryonic stem cell lines with genetic disorders.
Y Verlinsky, N Strelchenko, +4 authors, A Kuliev.
Reprod Biomed Online, 2005 Feb 12; 10(1). PMID: 15705304
Tissue factor and cell signalling in cancer progression and thrombosis.
W Ruf, J Disse, +2 authors, F Schaffner.
J Thromb Haemost, 2011 Aug 04; 9 Suppl 1. PMID: 21781267    Free PMC article.
Generation, expansion and functional analysis of endothelial cells and pericytes derived from human pluripotent stem cells.
Valeria V Orlova, Francijna E van den Hil, +3 authors, Christine L Mummery.
Nat Protoc, 2014 May 31; 9(6). PMID: 24874816
Highly Cited.
NF-κB, inflammation, immunity and cancer: coming of age.
Koji Taniguchi, Michael Karin.
Nat Rev Immunol, 2018 Jan 31; 18(5). PMID: 29379212
Highly Cited. Review.
Regulation of angiogenesis by hypoxia and hypoxia-inducible factors.
Michele M Hickey, M Celeste Simon.
Curr Top Dev Biol, 2006 Nov 23; 76. PMID: 17118268
Targeting tumor micro-environment for design and development of novel anti-angiogenic agents arresting tumor growth.
Rajesh N Gacche, Rohan J Meshram.
Prog Biophys Mol Biol, 2013 Oct 22; 113(2). PMID: 24139944
SERPINB2 Is a Novel Indicator of Cancer Stem Cell Tumorigenicity in Multiple Cancer Types.
Na-Hee Lee, Se-Ra Park, +7 authors, Hwa-Yong Lee.
Cancers (Basel), 2019 Apr 11; 11(4). PMID: 30965654    Free PMC article.
Application of small molecule CHIR99021 leads to the loss of hemangioblast progenitor and increased hematopoiesis of human pluripotent stem cells.
Yekaterina Galat, Irina Elcheva, +4 authors, Vasiliy Galat.
Exp Hematol, 2018 Jun 08; 65. PMID: 29879440
Hypoxia modulates fibroblastic architecture, adhesion and migration: a role for HIF-1α in cofilin regulation and cytoplasmic actin distribution.
Melanie Vogler, Sabine Vogel, +6 authors, Anke Zieseniss.
PLoS One, 2013 Jul 23; 8(7). PMID: 23874890    Free PMC article.
Induction of pluripotent stem cells from adult human fibroblasts by defined factors.
Kazutoshi Takahashi, Koji Tanabe, +4 authors, Shinya Yamanaka.
Cell, 2007 Nov 24; 131(5). PMID: 18035408
Highly Cited.
Hematoendothelial differentiation of human embryonic stem cells.
Maxim A Vodyanik, Igor I Slukvin.
Curr Protoc Cell Biol, 2008 Jan 30; Chapter 23. PMID: 18228507
A role for CCL2 in both tumor progression and immunosurveillance.
Ming Li, Deborah A Knight, +2 authors, Trina J Stewart.
Oncoimmunology, 2013 Sep 28; 2(7). PMID: 24073384    Free PMC article.
TGF-β Signaling in Cancer.
Viqar Syed.
J Cell Biochem, 2016 Jan 17; 117(6). PMID: 26774024
Highly Cited.
Harnessing Oxidative Stress as an Innovative Target for Cancer Therapy.
Lynne Postovit, Christian Widmann, Peng Huang, Spencer B Gibson.
Oxid Med Cell Longev, 2018 Jul 07; 2018. PMID: 29977457    Free PMC article.
Effect of tumor microenvironment on tumor VEGF during anti-VEGF treatment: systems biology predictions.
Stacey D Finley, Aleksander S Popel.
J Natl Cancer Inst, 2013 May 15; 105(11). PMID: 23670728    Free PMC article.
An aneuploid mouse strain carrying human chromosome 21 with Down syndrome phenotypes.
Aideen O'Doherty, Sandra Ruf, +15 authors, Elizabeth M C Fisher.
Science, 2005 Sep 24; 309(5743). PMID: 16179473    Free PMC article.
Highly Cited.
Immunity, inflammation, and cancer.
Sergei I Grivennikov, Florian R Greten, Michael Karin.
Cell, 2010 Mar 23; 140(6). PMID: 20303878    Free PMC article.
Highly Cited. Review.
Movers and shakers: cell cytoskeleton in cancer metastasis.
C M Fife, J A McCarroll, M Kavallaris.
Br J Pharmacol, 2014 Mar 29; 171(24). PMID: 24665826    Free PMC article.
Highly Cited. Review.
Cell invasion in the spheroid sprouting assay: a spatial organisation analysis adaptable to cell behaviour.
Silvia Blacher, Charlotte Erpicum, +5 authors, Agnès Noel.
PLoS One, 2014 May 09; 9(5). PMID: 24806521    Free PMC article.
The extracellular matrix: a dynamic niche in cancer progression.
Pengfei Lu, Valerie M Weaver, Zena Werb.
J Cell Biol, 2012 Feb 22; 196(4). PMID: 22351925    Free PMC article.
Highly Cited. Review.
Efficient differentiation of human pluripotent stem cells to endothelial progenitors via small-molecule activation of WNT signaling.
Xiaojun Lian, Xiaoping Bao, +6 authors, Sean P Palecek.
Stem Cell Reports, 2014 Nov 25; 3(5). PMID: 25418725    Free PMC article.
Highly Cited.
Cross-talk between apolipoprotein E and cytokines.
Hongliang Zhang, Li-Min Wu, Jiang Wu.
Mediators Inflamm, 2011 Jul 21; 2011. PMID: 21772670    Free PMC article.
The extracellular matrix modulates the hallmarks of cancer.
Michael W Pickup, Janna K Mouw, Valerie M Weaver.
EMBO Rep, 2014 Nov 10; 15(12). PMID: 25381661    Free PMC article.
Highly Cited. Review.