title: Mesenchymal stem cells promote formation of colorectal tumors in mice.
abstract: OBJECTIVE
  Tumor-initiating cells are a subset of tumor cells with the ability to form new tumors; however, they account for less than 0.001% of the cells in colorectal or other types of tumors. Mesenchymal stem cells (MSCs) integrate into the colorectal tumor stroma; we investigated their involvement in tumor initiation.
  
  
  METHODS
  Human colorectal cancer cells, MSCs, and a mixture of both cell types were injected subcutaneously into immunodeficient mice. We compared the ability of each injection to form tumors and investigated the signaling pathway involved in tumor initiation.
  
  
  RESULTS
  A small number (≤ 10) of unsorted, CD133⁻, CD166⁻, epithelial cell adhesion molecule⁻(EpCAM⁻), or CD133⁻/CD166⁻/EpCAM⁻ colorectal cancer cells, when mixed with otherwise nontumorigenic MSCs, formed tumors in mice. Secretion of interleukin (IL)-6 by MSCs increased the expression of CD133 and activation of Janus kinase 2-signal transducer and activator of transcription 3 (STAT3) in the cancer cells, and promoted sphere and tumor formation. An antibody against IL-6 or lentiviral-mediated transduction of an interfering RNA against IL-6 in MSCs or STAT3 in cancer cells prevented the ability of MSCs to promote sphere formation and tumor initiation.
  
  
  CONCLUSIONS
  IL-6, secreted by MSCs, signals through STAT3 to increase the numbers of colorectal tumor-initiating cells and promote tumor formation. Reagents developed to disrupt this process might be developed to treat patients with colorectal cancer.
authors.affiliation: Institute of Anatomy and Cell Biology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Kuo-Shu
authors.initials: KS
authors.lastname: Tsai
authors.forename: Shung-Haur
authors.initials: SH
authors.lastname: Yang
authors.forename: Yen-Ping
authors.initials: YP
authors.lastname: Lei
authors.forename: Chih-Chien
authors.initials: CC
authors.lastname: Tsai
authors.forename: Hsin-Wei
authors.initials: HW
authors.lastname: Chen
authors.forename: Chih-Yuan
authors.initials: CY
authors.lastname: Hsu
authors.forename: Ling-Lan
authors.initials: LL
authors.lastname: Chen
authors.forename: Hsei-Wei
authors.initials: HW
authors.lastname: Wang
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Miller
authors.forename: Shih-Hwa
authors.initials: SH
authors.lastname: Chiou
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
authors.forename: Shih-Chieh
authors.initials: SC
authors.lastname: Hung
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D006801:Humans; D007279:Injections, Subcutaneous; D015850:Interleukin-6 / Q000378:metabolism; D053614:Janus Kinase 2 / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014183:Transplantation, Heterologous / Q000473:pathology*
chemical_list: D015850:Interleukin-6; D050796:STAT3 Transcription Factor; D053614:Janus Kinase 2