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BiomaterialsVolume 98, 1 August 2016, Pages 152-162

CD44 alternative splicing in gastric cancer cells is regulated by culture dimensionality and matrix stiffness(Article)

  • Branco da Cunha, C.,
  • Klumpers, D.D.,
  • Koshy, S.T.,
  • Weaver, J.C.,
  • Chaudhuri, O.,
  • Seruca, R.,
  • Carneiro, F.,
  • Granja, P.L.,
  • Mooney, D.J.
  • View Correspondence (jump link)
  • aSchool of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, United States
  • bWyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, United States
  • cInstitute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, 4200-465, Portugal
  • dInstituto de Engenharia Biomédica da Universidade do Porto (INEB), Porto, 4150-180, Portugal
  • eInstituto de Investigação e, Inovação em Saúde da Universidade do Porto (i3S), Porto, 4200-135, Portugal
  • fFaculdade de Medicina da Universidade do Porto (FMUP)/Hospital S. João, Porto, 4200-319, Portugal
  • gDept. Orthopedic Surgery, Research Institute MOVE, VU University Medical Center, Amsterdam, 1081 HV, Netherlands
  • hHarvard-MIT Division of Health Sciences and Technology, Cambridge, MA 02139, United States
  • iDepartment of Mechanical Engineering, Stanford University, Stanford, CA 94305, United States
  • jDepartamento de Engenharia Metalúrgica e Materiais, Faculdade de Engenharia da Universidade do Porto (FEUP), Porto, 4200-465, Portugal

Abstract

Two-dimensional (2D) cultures often fail to mimic key architectural and physical features of the tumor microenvironment. Advances in biomaterial engineering allow the design of three-dimensional (3D) cultures within hydrogels that mimic important tumor-like features, unraveling cancer cell behaviors that would not have been observed in traditional 2D plastic surfaces. This study determined how 3D cultures impact CD44 alternative splicing in gastric cancer (GC) cells. In 3D cultures, GC cells lost expression of the standard CD44 isoform (CD44s), while gaining CD44 variant 6 (CD44v6) expression. This splicing switch was reversible, accelerated by nutrient shortage and delayed at lower initial cell densities, suggesting an environmental stress-induced response. It was further shown to be dependent on the hydrogel matrix mechanical properties and accompanied by the upregulation of genes involved in epithelial-mesenchymal transition (EMT), metabolism and angiogenesis. The 3D cultures reported here revealed the same CD44 alternative splicing pattern previously observed in human premalignant and malignant gastric lesions. These findings indicate that fundamental features of 3D cultures - such as soluble factors diffusion and mechanical cues - influence CD44 expression in GC cells. Moreover, this study provides a new model system to study CD44 dysfunction, whose role in cancer has been in the spotlight for decades. © 2016 Elsevier Ltd.

Author keywords

Alternative splicingCD44Culture dimensionalityExtracellular matrix (ECM)Matrix stiffness

Indexed keywords

Engineering controlled terms:BiomechanicsCell engineeringCytologyDiseasesEnzyme activityHydrogelsStiffnessStiffness matrixTumors
Engineering uncontrolled termsAlternative splicingBiomaterial engineeringsCD44Epithelial-mesenchymal transitionExtracellular matricesThreedimensional (3-d)Tumor microenvironmentTwo Dimensional (2 D)
Engineering main heading:Cells
EMTREE drug terms:CD44v6 antigenHermes antigenCD44 protein, humanhyaluronic acid binding protein
EMTREE medical terms:alternative RNA splicingangiogenesisantigen expressionapoptosisArticlebasement membranecancer cellcell culturecell densitycell encapsulationcell metabolismcell proliferationcell subpopulationclinical articleenvironmental stressepithelial mesenchymal transitionflow cytometrygene controlhumanhuman cellhuman tissuehydrogelmatrix stiffnessoxidative stresspriority journalprotein depletionquantitative analysisreal time polymerase chain reactionreverse transcription polymerase chain reactionrigiditystomach cancerstomach lesionsurface propertyupregulationalternative RNA splicinganimalcell culture techniqueextracellular matrixgeneticsmetabolismnuclear reprogrammingpathologyproceduresratstomach tumortumor cell lineYoung modulus
MeSH:Alternative SplicingAnimalsCell Culture TechniquesCell Line, TumorCell ProliferationCellular ReprogrammingElastic ModulusExtracellular MatrixHumansHyaluronan ReceptorsOxidative StressRatsStomach Neoplasms

Chemicals and CAS Registry Numbers:

CD44 protein, human; Hyaluronan Receptors

Funding details

Funding sponsor Funding number Acronym
Fundação para a Ciência e a Tecnologia
See opportunities
Fundação Calouste Gulbenkian
Fundação para a Ciência e a Tecnologia
See opportunities		SFRH/BD/44982/2008
Fundação Luso-Americana para o DesenvolvimentoPTDC/CTM-NAN/120958/2010

  • 1

    We thank Patricia Rogers and Mandy Tam (Harvard University) for assistance with FACS, Anabela Ribeiro Nunes (from the Office for Science Communication at IBMC.INEB) for designing Fig. 7 , and Bárbara Gomes (IPATIMUP/FMUP) for immunohistochemistry of gastric tumor samples. C.B.C. had research fellowships by the Portuguese Fundação para a Ciência e a Tecnologia (FCT) (ref.: SFRH/BD/44982/2008 ), Calouste Gulbenkian Foundation (FCG) and Luso-American Development Foundation (FLAD). The work herein reported was funded by FCT ( PTDC/CTM-NAN/120958/2010 ) . Appendix A

  • ISSN: 01429612
  • CODEN: BIMAD
  • Source Type: Journal
  • Original language: English
  • DOI: 10.1016/j.biomaterials.2016.04.016
  • PubMed ID: 27187279
  • Document Type: Article
  • Publisher: Elsevier Ltd

  Mooney, D.J.; School of Engineering and Applied Sciences, Harvard University 29 Oxford St., 319 Pierce Hall, Cambridge, MA, United States;
© Copyright 2017 Elsevier B.V., All rights reserved.

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