title: Pleiotropic effects of cancer cells' secreted factors on human stromal (mesenchymal) stem cells.
abstract: BACKGROUND
  Studying cancer tumors' microenvironment may reveal a novel role in driving cancer progression and metastasis. The biological interaction between stromal (mesenchymal) stem cells (MSCs) and cancer cells remains incompletely understood. Herein, we investigated the effects of tumor cells' secreted factors as represented by a panel of human cancer cell lines (breast (MCF7 and MDA-MB-231); prostate (PC-3); lung (NCI-H522); colon (HT-29) and head & neck (FaDu)) on the biological characteristics of MSCs.
  
  
  METHODS
  Morphological changes were assessed using fluorescence microscopy. Changes in gene expression were assessed using Agilent microarray and qRT-PCR. GeneSpring 12.1 and DAVID tools were used for bioinformatic and signaling pathway analyses. Cell migration was assessed using a transwell migration system. SB-431542, PF-573228 and PD98059 were used to inhibit transforming growth factor β (TGFβ), focal adhesion kinase (FAK), and mitogen activated protein kinase kinase (MAPKK) pathways, respectively. Interleukin-1β (IL1β) was measured using ELISA.
  
  
  RESULTS
  MSCs exposed to secreted factors present in conditioned media (CM) from FaDu, MDA-MB-231, PC-3 and NCI-H522, but not from MCF7 and HT-29, developed an elongated, spindle-shaped morphology with bipolar processes. In association with phenotypic changes, genome-wide gene expression and bioinformatics analysis revealed an enhanced pro-inflammatory response of those MSCs. Pharmacological inhibitions of FAK and MAPKK severely impaired the pro-inflammatory response of MSCs to tumor CM (approximately 80% to 99%, and 55% to 88% inhibition, respectively), while inhibition of the TGFβ pathway was found to promote the pro-inflammatory response (approximately 3-fold increase). In addition, bioinformatics and pathway analysis of gene expression data from tumor cell lines combined with experimental validation revealed tumor-derived IL1β as one mediator of the pro-inflammatory phenotype observed in MSCs exposed to tumor CM.
  
  
  CONCLUSIONS
  Our data revealed tumor-derived IL1β as one mediator of the pro-inflammatory response in MSCs exposed to tumor CM, which was found to be positively regulated by FAK and MAPK signaling and negatively regulated by TGFβ signaling. Thus, our data support a model where MSCs could promote cancer progression through becoming pro-inflammatory cells within the cancer stroma.
authors.forename: Mashael
authors.initials: M
authors.lastname: Al-toub
authors.forename: Abdulaziz
authors.initials: A
authors.lastname: Almusa
authors.forename: Mohammed
authors.initials: M
authors.lastname: Almajed
authors.forename: May
authors.initials: M
authors.lastname: Al-Nbaheen
authors.forename: Moustapha
authors.initials: M
authors.lastname: Kassem
authors.forename: Abdullah
authors.initials: A
authors.lastname: Aldahmash
authors.forename: Nehad M
authors.initials: NM
authors.lastname: Alajez
mesh_terms: D050156:Adipogenesis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement; D054365:Chemokine CXCL5 / Q000378:metabolism; D054427:Chemokine CXCL6 / Q000378:metabolism; D016000:Cluster Analysis; D017077:Culture Media, Conditioned / Q000494:pharmacology*; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019073:HT29 Cells; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D061986:MCF-7 Cells; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects; D010641:Phenotype; D015398:Signal Transduction / Q000187:drug effects; D059467:Transcriptome; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D054365:Chemokine CXCL5; D054427:Chemokine CXCL6; D017077:Culture Media, Conditioned; D015850:Interleukin-6; D016212:Transforming Growth Factor beta; D051416:Focal Adhesion Protein-Tyrosine Kinases; D020929:Mitogen-Activated Protein Kinase Kinases