title: Interaction between neoplastic cells and cancer-associated fibroblasts through the CXCL12/CXCR4 axis: role in non-small cell lung cancer tumor proliferation.
abstract: OBJECTIVE
  Carcinoma-associated fibroblasts are reported to communicate microenvironment-derived signals through chemokine/chemokine receptor interaction, influencing carcinogenesis. We sought to characterize roles of CXCL12/CXCR4 in crosstalk between non-small cell lung cancer epithelial cell and carcinoma-associated fibroblasts and in tumor growth.
  
  
  METHODS
  Non-small cell lung cancer tumor samples obtained at surgery and from tumor arrays, as well as primary carcinoma-associated fibroblast and epithelial cell lines generated from fresh tumors, were assessed for CXCL12/CXCR4 expression, tissue localization, and production. Colony assays, extracellular signal-regulated kinase signaling, and chemokine production were measured to assess cancer cell responsiveness to CXCL12 stimulation with or without CXCR4 antagonists.
  
  
  RESULTS
  CXCL12 and CXCR4 were detected in all major subtypes of non-small cell lung cancer. CXCL12-expressing carcinoma-associated fibroblasts were mostly located near CXCL12-negative tumor cells, whereas CXCL12-positive tumor cells were mostly surrounded by CXCL12-negative stroma. Intratumoral CXCL12 levels were significantly higher than serum levels. CXCL12 expression correlated with advanced disease stage. In vitro, tumor cell lines produced variable amounts of CXCL12 and expressed high levels of CXCR4. Carcinoma-associated fibroblasts cell lines produced high amounts of CXCL12 and expressed variable levels of CXCR4. Stimulation of non-small cell lung cancer neoplastic cells with CXCL12 increased colony-forming capacity, induced extracellular signal-regulated kinase phosphorylation, and production of the proinflammatory chemokine CCL20. CXCR4 antagonists attenuated these effects.
  
  
  CONCLUSIONS
  Interaction between carcinoma-associated fibroblasts and tumor epithelial cells through the CXCL12/CXCR4 axis plays a role in non-small cell lung cancer tumor proliferation, marking this axis as a target for immune intervention.
authors.affiliation: Department of Cardiothoracic Surgery, Hadassah University Hospital, Jerusalem, Israel. ori.wald@mail.huji.ac.il
authors.forename: Ori
authors.initials: O
authors.lastname: Wald
authors.forename: Uzi
authors.initials: U
authors.lastname: Izhar
authors.forename: Gail
authors.initials: G
authors.lastname: Amir
authors.forename: Sophie
authors.initials: S
authors.lastname: Kirshberg
authors.forename: Zippora
authors.initials: Z
authors.lastname: Shlomai
authors.forename: Gideon
authors.initials: G
authors.lastname: Zamir
authors.forename: Amnon
authors.initials: A
authors.lastname: Peled
authors.forename: Oz M
authors.initials: OM
authors.lastname: Shapira
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000276:immunology* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D054418:Chemokine CCL20 / Q000378:metabolism; D054377:Chemokine CXCL12 / Q000097:blood / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000378:metabolism; D008175:Lung Neoplasms / Q000276:immunology* / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009367:Neoplasm Staging; D010766:Phosphorylation; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D046888:Tissue Array Analysis; D059016:Tumor Microenvironment
chemical_list: D000970:Antineoplastic Agents; C108355:CCL20 protein, human; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054418:Chemokine CCL20; D054377:Chemokine CXCL12; D018836:Inflammation Mediators; D019718:Receptors, CXCR4; D048049:Extracellular Signal-Regulated MAP Kinases