title: Mesenchymal stem cells enhance lung cancer initiation through activation of IL-6/JAK2/STAT3 pathway.
abstract: BACKGROUND
  The role of mesenchymal stem cells (MSCs) and IL-6 in lung cancer has not been well-addressed. We aimed to determine if MSCs can enhance the ability of tumor initiation of lung cancer cells, and link MSCs with activation of the IL-6/JAK2/STAT3 signaling pathway.
  
  
  METHODS
  Lung cancer cell lines A549 and CL1-5 were directly or indirectly cocultured with MSCs. Spheres were defined as cell colonies with >50% area showing 3-dimensional structure and blurred cell margins. Cells without and with MSCs were injected into NOD/SCID mice. The percentage of tumor formation was determined. The influence of the IL-6/JAK2/STAT3 signaling pathway in cancer cell sphere formation and tumor growth were investigated.
  
  
  RESULTS
  A very small number of lung cancer cells, when mixed with otherwise non-tumorigenic MSCs, obtained de novo tumorigenicity when injected subcutaneously and allowed to form a tumor xenograft. Secretion of IL-6 from MSCs increased activation of the JAK2/STAT3 pathway in cancer cells, and enhanced sphere formation and tumor initiation. A reduced capacity of tumor formation of A549 and CL1-5 lung cancer cells when IL-6 was inhibited in MSCs or STAT3 was silenced in A549 and CL1-5 admixed with MSCs.
  
  
  CONCLUSIONS
  Culture of A549 or CL1-5 lung cancer cells with MSCs increased sphere formation, drug resistance, and overexpression of pluripotency markers through activation of the IL-6/JAK2/STAT3 pathway. MSCs enhanced the capability of A549 and CL1-5 lung cancer cells to form tumors in immunodeficient mice. Blockade of the IL-6/JAK2/STAT3 pathway attenuated the capability of A549 and CL1-5 cells to form tumors.
authors.affiliation: Institute of Emergency and Critical Care Medicine, National Yang-Ming University School of Medicine, Taiwan. hsuhs@vghtpe.gov.tw
authors.forename: Han-Shui
authors.initials: HS
authors.lastname: Hsu
authors.forename: Jiun-Han
authors.initials: JH
authors.lastname: Lin
authors.forename: Tien-Wei
authors.initials: TW
authors.lastname: Hsu
authors.forename: Kelly
authors.initials: K
authors.lastname: Su
authors.forename: Cheng-Wien
authors.initials: CW
authors.lastname: Wang
authors.forename: Kuang-Yao
authors.initials: KY
authors.lastname: Yang
authors.forename: Shih-Hwa
authors.initials: SH
authors.lastname: Chiou
authors.forename: Shih-Chieh
authors.initials: SC
authors.lastname: Hung
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D006801:Humans; D015850:Interleukin-6 / Q000502:physiology*; D053614:Janus Kinase 2 / Q000502:physiology*; D008175:Lung Neoplasms / Q000209:etiology* / Q000473:pathology; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D051379:Mice; D009368:Neoplasm Transplantation; D050796:STAT3 Transcription Factor / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D014183:Transplantation, Heterologous
chemical_list: D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2