Chemokine and Chemokine Receptor Expression in Kidney Tumors: Molecular Profiling of Histological Subtypes and Association With Metastasis

Purpose: 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. Materials and Methods: Using quantitative polymerase chain reaction we measured mRNA levels of IL-8, CXCR4 and 7, and SDF1 isoforms alpha, beta and gamma 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-gamma levels were increased twofold to tenfold. SDF1-alpha and beta were unchanged or lower in clear cell renal cell carcinoma and papillary tumors than in normal tissue. Median SDF1-gamma, 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-beta (p = 0.005) were independently associated with metastasis. Combined CXCR7 plus SDF1-alpha 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-alpha plus CXCR7 and IL-8 plus CXCR7 markers have about 80% accuracy for predicting renal cell carcinoma metastasis.