title: Involvement of CCR6/CCL20/IL-17 axis in NSCLC disease progression.
abstract: OBJECTIVE
  Autocrine and paracrine chemokine/chemokine receptor-based interactions promote non-small-cell-lung-cancer (NSCLC) carcinogenesis. CCL20/CCR6 interactions are involved in prostatic and colonic malignancy pathogenesis. The expression and function of CCL20/CCR6 and its related Th-17 type immune response in NSCLC is not yet defined. We sought to characterize the role of the CCL20/CCR6/IL-17 axis in NSCLC tumor growth.
  
  
  METHODS
  A specialized histopathologist blindly assessed CCL20/CCR6 expression levels in 49 tissue samples of NSCLC patients operated in our department. Results were correlated to disease progression. Colony assays, ERK signaling and chemokine production were measured to assess cancer cell responsiveness to CCL20 and IL-17 stimulation.
  
  
  RESULTS
  CCL20 was highly expressed in the majority (38/49, 77.5%) of tumor samples. Only a minority of samples (8/49, 16.5%) showed high CCR6 expression. High CCR6 expression was associated with a shorter disease-free survival (P = 0.008) and conferred a disease stage-independent 4.87-fold increased risk for disease recurrence (P = 0.0076, CI 95% 1.52-15.563). Cancerous cell colony-forming capacity was increased by CCL20 stimulation; this effect was dependent in part on ERK phosphorylation and signaling. IL-17 expression was detected in NSCLC; IL-17 potentiated the production of CCL20 by cancerous cells.
  
  
  CONCLUSIONS
  Our findings suggest that the CCL20/CCR6 axis promotes NSCLC disease progression. CCR6 is identified as a potential new prognostic marker and the CCL20/CCR6/IL-17 axis as a potential new therapeutic target. Larger scale studies are required to consolidate these observations.
authors.affiliation: Goldyne Savad Institute of Gene Therapy, Hadassah University Hospital, Jerusalem, Israel.
authors.forename: Sophie
authors.initials: S
authors.lastname: Kirshberg
authors.forename: Uzi
authors.initials: U
authors.lastname: Izhar
authors.forename: Gail
authors.initials: G
authors.lastname: Amir
authors.forename: Jonathan
authors.initials: J
authors.lastname: Demma
authors.forename: Fiona
authors.initials: F
authors.lastname: Vernea
authors.forename: Katia
authors.initials: K
authors.lastname: Beider
authors.forename: Zippora
authors.initials: Z
authors.lastname: Shlomai
authors.forename: Hanna
authors.initials: H
authors.lastname: Wald
authors.forename: Gideon
authors.initials: G
authors.lastname: Zamir
authors.forename: Oz M
authors.initials: OM
authors.lastname: Shapira
authors.forename: Amnon
authors.initials: A
authors.lastname: Peled
authors.forename: Ori
authors.initials: O
authors.lastname: Wald
mesh_terms: D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D054418:Chemokine CCL20 / Q000378:metabolism*; D018450:Disease Progression; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism*; D008175:Lung Neoplasms / Q000201:enzymology / Q000473:pathology*; D008297:Male; D010766:Phosphorylation; D054399:Receptors, CCR6 / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C108355:CCL20 protein, human; C106311:CCR6 protein, human; D054418:Chemokine CCL20; C508717:IL17A protein, human; D020381:Interleukin-17; D054399:Receptors, CCR6; D048049:Extracellular Signal-Regulated MAP Kinases