title: Chemokine and chemokine receptor expression in kidney tumors: molecular profiling of histological subtypes and association with metastasis.
abstract: OBJECTIVE
  Molecular characterization of renal cell carcinoma may help differentiate benign oncocytoma from malignant renal cell carcinoma subtypes and predict metastasis. Chemokines, eg IL-8 and chemokine receptors such as CXCR4 and 7, promote inflammation and metastasis. SDF-1 is a CXCR4 and 7 ligand with 6 known isoforms. We evaluated the expression of these chemokines and chemokine receptors in kidney specimens.
  
  
  METHODS
  Using quantitative polymerase chain reaction we measured mRNA levels of IL-8, CXCR4 and 7, and SDF1 isoforms α, β and γ in a total of 166 specimens from 86 patients, including 86 tumor samples and 80 matched normal kidney samples. Mean ± SD followup was 18.9 ± 12 months (median 19.5). Renal cell carcinoma specimens included the clear cell, papillary and chromophobe subtype in 65, 10 and 5 cases, respectively, and oncocytoma in 6. A total of 17 cases were positive for metastasis.
  
  
  RESULTS
  Median CXCR4 and 7, and SFD1-γ levels were increased twofold to tenfold. SDF1-α and β were unchanged or lower in clear cell renal cell carcinoma and papillary tumors than in normal tissue. Median SDF1-γ, IL-8, and CXCR4 and 7 were increased threefold to fortyfold in chromophobe tumors compared to oncocytoma. CXCR4 and 7 were increased in tumors less than 4 cm (mean 3,057 ± 2,230 and 806 ± 691) compared to oncocytoma (336 ± 325 and 201 ± 281, respectively, p ≤0.016). On multivariate analysis CXCR4 (p = 0.01), CXCR7 (p = 0.02) and SDF1-β (p = 0.005) were independently associated with metastasis. Combined CXCR7 plus SDF1-α and CXCR7 plus IL-8 markers showed the highest sensitivity (71% to 81%) and specificity (75% to 80%) of all individual or combined markers.
  
  
  CONCLUSIONS
  Chemokines and chemokine receptors differentiate renal cell carcinoma and oncocytoma. Combined SDF1-α plus CXCR7 and IL-8 plus CXCR7 markers have about 80% accuracy for predicting renal cell carcinoma metastasis.
authors.affiliation: Department of Urology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida 33101, USA.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Gahan
authors.forename: Miguel
authors.initials: M
authors.lastname: Gosalbez
authors.forename: Travis
authors.initials: T
authors.lastname: Yates
authors.forename: Ezekiel E
authors.initials: EE
authors.lastname: Young
authors.forename: Diogo O
authors.initials: DO
authors.lastname: Escudero
authors.forename: Andrew
authors.initials: A
authors.lastname: Chi
authors.forename: Michael
authors.initials: M
authors.lastname: Garcia-Roig
authors.forename: Ramgopal
authors.initials: R
authors.lastname: Satyanarayana
authors.forename: Mark S
authors.initials: MS
authors.lastname: Soloway
authors.forename: Vincent G
authors.initials: VG
authors.lastname: Bird
authors.forename: Vinata B
authors.initials: VB
authors.lastname: Lokeshwar
mesh_terms: D018249:Adenoma, Oxyphilic / Q000378:metabolism* / Q000473:pathology; D014408:Biomarkers, Tumor / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000378:metabolism* / Q000473:pathology; D054377:Chemokine CXCL12 / Q000378:metabolism*; D003627:Data Interpretation, Statistical; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D016133:Polymerase Chain Reaction; D011237:Predictive Value of Tests; D012333:RNA, Messenger / Q000378:metabolism; D054387:Receptors, CXCR / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis
chemical_list: C501896:ACKR3 protein, human; D014408:Biomarkers, Tumor; D054377:Chemokine CXCL12; D016209:Interleukin-8; D012333:RNA, Messenger; D054387:Receptors, CXCR; D019718:Receptors, CXCR4