title: Insulinlike growth factor-I-mediated migration and invasion of human colon carcinoma cells requires activation of c-Met and urokinase plasminogen activator receptor.
abstract: OBJECTIVE
  To determine whether insulinlike growth factor-I (IGF-I) and hepatocyte growth factor (HGF) cooperate to induce migration and invasion of human colorectal carcinoma (CRC) cells and whether the effects of IGF-I and/or HGF are mediated through activation of the urokinase plasminogen activator (uPA)/uPA receptor (uPAR) system, a central mediator of tumor-cell migration and invasion.
  
  
  BACKGROUND
  CRC cells must invade through the basement membrane of the colon and migrate to form metastases. CRC cells are known to overexpress IGF-I receptor (IGF-IR), c-Met, and uPAR, 3 cell-surface receptors known to mediate cell migration and invasion. We hypothesized that IGF-IR and c-Met cooperate to induce migration and invasion in CRC cells and that this signaling is dependent on uPAR.
  
  
  METHODS
  KM12L4 human CRC cells were treated with IGF-I, HGF, or IGF-I + HGF in transwell migration and invasion chambers; cells that had migrated or invaded were counted. To determine the role of c-Met in IGF-I-induced migration and invasion, c-Met was inhibited by infection of cells with an adenovirus containing a c-Met ribozyme; transwell assays were then repeated. To determine the role of the uPA/uPAR system in IGF-I-induced CRC cell migration and invasion, transwell assays were repeated after pretreating cells with the uPA inhibitor amiloride or with neutralizing antibodies to uPA and uPAR.
  
  
  RESULTS
  IGF-I and HGF, alone or in combination, increased cell migration and invasion. The c-Met ribozyme inhibited IGF-I- and HGF-mediated migration and invasion, indicating that c-Met is essential for these processes. uPA and uPAR inhibition blocked IGF-I- and HGF-mediated migration and invasion, suggesting that uPAR is downstream of IGF/IGF-IR and HGF/c-Met in the signaling pathways that mediate cell migration and invasion.
  
  
  CONCLUSIONS
  IGF-I and HGF cooperate to induce migration and invasion of CRC cells, and c-Met and uPA/uPAR are required for IGF-I-mediated migration and invasion. In our in vitro model of CRC migration and invasion, uPA and uPAR appear to be downstream of IGF-IR and c-Met and are required for migration and invasion. Elucidation of the pathways that contribute to tumor progression and metastasis should provide a foundation for the rational development and use of targeted therapies for CRC.
authors.affiliation: Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77230-1420, USA.
authors.forename: Todd W
authors.initials: TW
authors.lastname: Bauer
authors.forename: Fan
authors.initials: F
authors.lastname: Fan
authors.forename: Wenbiao
authors.initials: W
authors.lastname: Liu
authors.forename: Marjorie
authors.initials: M
authors.lastname: Johnson
authors.forename: Nila U
authors.initials: NU
authors.lastname: Parikh
authors.forename: Graham C
authors.initials: GC
authors.lastname: Parry
authors.forename: Jennifer
authors.initials: J
authors.lastname: Callahan
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Mazar
authors.forename: Gary E
authors.initials: GE
authors.lastname: Gallick
authors.forename: Lee M
authors.initials: LM
authors.lastname: Ellis
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D015179:Colorectal Neoplasms / Q000473:pathology*; D017228:Hepatocyte Growth Factor / Q000502:physiology; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D009361:Neoplasm Invasiveness; D019859:Proto-Oncogene Proteins c-met / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000502:physiology*; D055293:Receptors, Urokinase Plasminogen Activator; D015398:Signal Transduction / Q000502:physiology; D014568:Urokinase-Type Plasminogen Activator / Q000502:physiology
chemical_list: C524898:PLAUR protein, human; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D017228:Hepatocyte Growth Factor; D007334:Insulin-Like Growth Factor I; D019859:Proto-Oncogene Proteins c-met; D014568:Urokinase-Type Plasminogen Activator