title: An interaction between hepatocyte growth factor and its receptor (c-MET) prolongs the survival of chronic lymphocytic leukemic cells through STAT3 phosphorylation: a potential role of mesenchymal cells in the disease.
abstract: BACKGROUND
  Chronic lymphocytic leukemia cells are characterized by an apparent longevity in vivo which is lost when they are cultured in vitro. Cellular interactions and factors provided by the microenvironment appear essential to cell survival and may protect leukemic cells from the cytotoxicity of conventional therapies. Understanding the cross-talk between leukemic cells and stroma is of interest for identifying signals supporting disease progression and for developing novel therapeutic strategies.
  
  
  METHODS
  Different cell types, sharing a common mesenchymal origin and representative of various bone marrow components, were used to challenge the viability of leukemic cells in co-cultures and in contact-free culture systems. Using a bioinformatic approach we searched for genes shared by lineages prolonging leukemic cell survival and further analyzed their biological role in signal transduction experiments.
  
  
  RESULTS
  Human bone marrow stromal cells, fibroblasts, trabecular bone-derived cells and an osteoblast-like cell line strongly enhanced survival of leukemic cells, while endothelial cells and chondrocytes did not. Gene expression profile analysis indicated two soluble factors, hepatocyte growth factor and CXCL12, as potentially involved. We demonstrated that hepatocyte growth factor and CXCL12 are produced only by mesenchymal lineages that sustain the survival of leukemic cells. Indeed chronic lymphocytic leukemic cells express a functional hepatocyte growth factor receptor (c-MET) and hepatocyte growth factor enhanced the viability of these cells through STAT3 phosphorylation, which was blocked by a c-MET tyrosine kinase inhibitor. The role of hepatocyte growth factor was confirmed by its short interfering RNA-mediated knock-down in mesenchymal cells.
  
  
  CONCLUSIONS
  The finding that hepatocyte growth factor prolongs the survival of chronic lymphocytic leukemic cells is novel and we suggest that the interaction between hepatocyte growth factor-producing mesenchymal and neoplastic cells contributes to maintenance of the leukemic clone.
authors.affiliation: Stem Cell Laboratory, Advanced Biotechnology Center, 16132 Genova, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Giannoni
authors.forename: Silvia
authors.initials: S
authors.lastname: Scaglione
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Quarto
authors.forename: Roberto
authors.initials: R
authors.lastname: Narcisi
authors.forename: Manuela
authors.initials: M
authors.lastname: Parodi
authors.forename: Enrico
authors.initials: E
authors.lastname: Balleari
authors.forename: Federica
authors.initials: F
authors.lastname: Barbieri
authors.forename: Alessandra
authors.initials: A
authors.lastname: Pattarozzi
authors.forename: Tullio
authors.initials: T
authors.lastname: Florio
authors.forename: Silvano
authors.initials: S
authors.lastname: Ferrini
authors.forename: Giorgio
authors.initials: G
authors.lastname: Corte
authors.forename: Daniela
authors.initials: D
authors.lastname: de Totero
mesh_terms: D017209:Apoptosis / Q000235:genetics; D002460:Cell Line; D002470:Cell Survival; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism; D019295:Computational Biology; D020869:Gene Expression Profiling; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D010766:Phosphorylation; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D019718:Receptors, CXCR4 / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000378:metabolism*
chemical_list: C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D012333:RNA, Messenger; D019718:Receptors, CXCR4; D050796:STAT3 Transcription Factor; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met