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

Abstract

Purpose Molecular characterization of renal cell carcinoma (RCC) may help in differentiating benign oncocytomas from malignant RCC subtypes and predict metastasis. Chemokines (e.g., interleukin-8 (IL-8)) and chemokine receptors (e.g., CXCR4, CXCR7) promote inflammation and metastasis. Stroma derived factor (SDF-1) is a ligand for CXCR4 and CXCR7, with six known isoforms. We evaluated the expression of these chemokines and chemokine receptors in kidney specimens. Materials and Methods Using quantitative PCR, mRNA levels of IL-8, CXCR4, CXCR7 and SDF1 isoforms α, β and γ were measured in 166 specimens from 86 patients (tumor: 86; matched normal kidney: 80); mean and median follow-up: 18.9 ± 12; Median: 19.5 months. RCC specimens included: clear cell RCC (ccRCC): 65; papillary: 10; chromophobe: 5; oncocytoma: 6; metastasis (+): 17. Results Median levels of CXCR4, CXCR7 and SFD1-γ were 2–10-fold elevated and SDF1-α and SDF1-β levels were either unchanged or lower in ccRCC and papillary tumors when compared to normal tissues. Median SDF1-γ, IL-8, CXCR4 and CXCR7 levels were 3–40-fold elevated in chromophobe tumors when compared to oncocytoma. Both CXCR4 and CXCR7 levels were elevated in tumors < 4-cm (3057±2230; 806±691) when compared to oncocytoma (336±325; 201±281; P≤0.016). In multivariate analyses, CXCR4 (P=0.01), CXCR7 (0.02) and SDF1-β (P=0.005) were independently associated with metastasis. Combined CXCR7+SDF1-α and CXCR7+IL-8 markers showed the highest sensitivity (71–81%) and specificity (75–80%) among all individual or combined markers. Conclusions Chemokines and chemokine receptors differentiate between RCC and oncocytoma. Combined SDF1-α+CXCR7 and IL-8+CXCR7 markers have ~ 80% accuracy in predicting RCC metastasis.

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Llama-derived Single Variable Domains (Nanobodies) Directed against Chemokine Receptor CXCR7 Reduce Head and Neck Cancer Cell Growth in Vivo

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Knockdown of CXCR7 inhibits proliferation and invasion of osteosarcoma cells through inhibition of the PI3K/Akt and β-arrestin pathways

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