title: CDH1 and IL1-beta expression dictates FAK and MAPKK-dependent cross-talk between cancer cells and human mesenchymal stem cells.
abstract: BACKGROUND
  Tumor microenvironment conferred by stromal (mesenchymal) stem cells (MSCs) plays a key role in tumor development, progression, and response to therapy. Defining the role of MSCs in tumorigenesis is crucial for their safe utilization in regenerative medicine. Herein, we conducted comprehensive investigation of the cross-talk between human MSCs (hMSCs) and 12 cancer cell lines derived from breast, prostate, colon, head/neck and skin.
  
  
  METHODS
  Human bone marrow-derived MSC line expressing green fluorescence protein (GFP) (hMSC-GFP) were co-cultured with the following cancer cell lines: (MCF7, BT-20, BT-474, MDA-MB-468, T-47D, SK-BR-3, MDA-MB-231, PC-3, HT-29, MDA-MB-435s, and FaDu) and changes in their morphology were assessed using fluorescent microscopy. For cellular tracking, cells were labeled with Vybrant DiO, DiL, and DiD lipophilic dyes. Time-lapse microscopy was conducted using Nikon BioStation IM-Q. Stable expression of mCherry, and luciferase genes was achieved using lentiviral technology. IL1-Beta neutralizing experiments were conducted using soluble recombinant IL-1R (srIL-1R). Changes in gene expression in sorted hMSCs were assessed using Agilent microarray platform while data normalization and bioinformatics were conducted using GeneSpring software.
  
  
  RESULTS
  We observed a dynamic interaction between cancer cells and hMSCs. High CDH1 (E-cadherin) and low IL1-Beta expression by cancer cells promoted reorganization of hMSCs into a niche-like formation, which was dependent on direct cell-cell contact. Our data also revealed transfer of cellular components between cancer cells and hMSCs as one possible mechanism for intercellular communication. Global gene expression analysis of sorted hMSCs following co-culturing with MCF7 and BT-20 cells revealed enrichment in signaling pathways related to bone formation, FAK and MAPKK signaling. Co-culturing hMSCs with MCF7 cells increased their growth evidenced by increase in Ki67 and PCNA staining in tumor cells in direct contact with hMSCs niche. On the other hand, co-culturing hMSCs with FaDu, HT-29 or MDA-MB-231 cells led remarkable decline in their cell growth.
  
  
  CONCLUSIONS
  Dynamic interaction exists between hMSCs and cancer cells. CDH1 and IL1-Beta expression by cancer cells mediates the crosstalk between hMSCs and cancer cells. We propose a model where hMSCs act as the first line of defense against cancer cell growth and spread.
authors.affiliation: Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, 11461, Kingdom of Saudi Arabia. al-toub@hotmail.com.
authors.forename: Mashael
authors.initials: M
authors.lastname: Al-toub
authors.affiliation: Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, 11461, Kingdom of Saudi Arabia. vishnubalaji.lr@gmail.com.
authors.forename: Radhakrishnan
authors.initials: R
authors.lastname: Vishnubalaji
authors.affiliation: Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, 11461, Kingdom of Saudi Arabia. rimih@hotmail.com.
authors.forename: Rimi
authors.initials: R
authors.lastname: Hamam
authors.affiliation: Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, 11461, Kingdom of Saudi Arabia. mkassem@health.sdu.dk.|KMEB, Department of Endocrinology, University Hospital of Odense and University of Southern Denmark, 5000, Odense C, Denmark. mkassem@health.sdu.dk.|DanStem, Danish Stem Cell Center, Panum Institute, University of Copenhagen, 2200, Copenhagen N, Denmark. mkassem@health.sdu.dk.
authors.forename: Moustapha
authors.initials: M
authors.lastname: Kassem
authors.affiliation: Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, 11461, Kingdom of Saudi Arabia. editorial@stemcellres.com.|Prince Naif Health Research Center, King Saud University, Riyadh, 11461, Kingdom of Saudi Arabia. editorial@stemcellres.com.
authors.forename: Abdullah
authors.initials: A
authors.lastname: Aldahmash
authors.affiliation: Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, 11461, Kingdom of Saudi Arabia. nalajez@ksu.edu.sa.
authors.forename: Nehad M
authors.initials: NM
authors.lastname: Alajez
mesh_terms: D064200:Cdh1 Proteins / Q000235:genetics / Q000378:metabolism*; D002450:Cell Communication / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D018920:Coculture Techniques; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D061986:MCF-7 Cells; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D064200:Cdh1 Proteins; D017472:Receptors, Interleukin-1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D020929:Mitogen-Activated Protein Kinase Kinases