title: Curcumin suppresses crosstalk between colon cancer stem cells and stromal fibroblasts in the tumor microenvironment: potential role of EMT.
abstract: OBJECTIVE
  Interaction of stromal and tumor cells plays a dynamic role in initiating and enhancing carcinogenesis. In this study, we investigated the crosstalk between colorectal cancer (CRC) cells with stromal fibroblasts and the anti-cancer effects of curcumin and 5-Fluorouracil (5-FU), especially on cancer stem cell (CSC) survival in a 3D-co-culture model that mimics in vivo tumor microenvironment.
  
  
  METHODS
  Colon carcinoma cells HCT116 and MRC-5 fibroblasts were co-cultured in a monolayer or high density tumor microenvironment model in vitro with/without curcumin and/or 5-FU.
  
  
  RESULTS
  Monolayer tumor microenvironment co-cultures supported intensive crosstalk between cancer cells and fibroblasts and enhanced up-regulation of metastatic active adhesion molecules (β1-integrin, ICAM-1), transforming growth factor-β signaling molecules (TGF-β3, p-Smad2), proliferation associated proteins (cyclin D1, Ki-67) and epithelial-to-mesenchymal transition (EMT) factor (vimentin) in HCT116 compared with tumor mono-cultures. High density tumor microenvironment co-cultures synergistically increased tumor-promoting factors (NF-κB, MMP-13), TGF-β3, favored CSC survival (characterized by up-regulation of CD133, CD44, ALDH1) and EMT-factors (increased vimentin and Slug, decreased E-cadherin) in HCT116 compared with high density HCT116 mono-cultures. Interestingly, this synergistic crosstalk was even more pronounced in the presence of 5-FU, but dramatically decreased in the presence of curcumin, inducing biochemical changes to mesenchymal-epithelial transition (MET), thereby sensitizing CSCs to 5-FU treatment.
  
  
  CONCLUSIONS
  Enrichment of CSCs, remarkable activation of tumor-promoting factors and EMT in high density co-culture highlights that the crosstalk in the tumor microenvironment plays an essential role in tumor development and progression, and this interaction appears to be mediated at least in part by TGF-β and EMT. Modulation of this synergistic crosstalk by curcumin might be a potential therapy for CRC and suppress metastasis.
authors.affiliation: Institute of Anatomy, Ludwig-Maximilian-University Munich, Munich, Germany.
authors.forename: Constanze
authors.initials: C
authors.lastname: Buhrmann
authors.affiliation: Institute of Anatomy, Ludwig-Maximilian-University Munich, Munich, Germany.
authors.forename: Patricia
authors.initials: P
authors.lastname: Kraehe
authors.affiliation: German Heart Institute Berlin, Department of Thoracic and Cardiovascular Surgery, Laboratory for Tissue Engineering, Berlin, Germany.
authors.forename: Cora
authors.initials: C
authors.lastname: Lueders
authors.affiliation: Investigating Institute of Molecular Biological System Transfer, Tehran, Iran; Department of Parasitology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran.
authors.forename: Parviz
authors.initials: P
authors.lastname: Shayan
authors.affiliation: Gastrointestinal Cancer Research Laboratory, Division of Gastroenterology, Baylor Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas, United States of America.
authors.forename: Ajay
authors.initials: A
authors.lastname: Goel
authors.affiliation: Institute of Anatomy, Ludwig-Maximilian-University Munich, Munich, Germany.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Shakibaei
mesh_terms: D018920:Coculture Techniques; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology; D003474:Curcumin / Q000494:pharmacology*; D058750:Epithelial-Mesenchymal Transition; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005472:Fluorouracil / Q000494:pharmacology; D045325:HCT116 Cells; D006801:Humans; D015398:Signal Transduction; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000502:physiology; D059016:Tumor Microenvironment
chemical_list: D016212:Transforming Growth Factor beta; D003474:Curcumin; D005472:Fluorouracil