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.

Purpose Stroma-Derived Factor (SDF)-1 is a ligand for chemokine receptors CXCR4 and CXCR7. The six known SDF-1 isoforms are generated by alternative mRNA splicing. While SDF-1 expression has been detected in various malignancies, only a few studies have reported differential expression of SDF-1 isoforms and its clinical significance. In this study we evaluated the expression three SDF-1 isoforms (α,β,γ) in bladder cancer (BCa). Methods Using quantitative PCR, mRNA levels of SDF-1α, SDF-1β and SDF-1γ were measured in bladder tissues (normal: 25; BCa: 44) and urine specimens (n=210; normal: 28; benign conditions: 74; BCa: 57, history of BCa (HxBCa): 35, Hx other Ca: 8; other Ca: 8) from consecutive patients. These levels were correlated with clinical outcome. Results Among SDF-1 isoforms, only SDF-1β mRNA was significantly overexpressed by 2.5-6-fold in BCa tissues when compared to normal bladder tissues. While SDF-1α was expressed in bladder tissues, SDF-1γ expression was undetectable. In multivariate analysis, SDF-1β (P=0.017) was an independent predictor of metastasis and disease specific mortality (P=0.043). In exfoliated urothelial cells, only SDF-1β mRNA levels were differentially expressed and having a 91.2% sensitivity and 73.8% specificity for detecting BCa. In patients with HxBCa, elevated SDF-1β levels indicated 4.3-fold increased risk (P=0.0001) for developing recurrence within 6-months. Conclusion SDF-1 isoforms are differentially expressed in bladder tissues and exfoliated urothelial cells. SDF-1β mRNA levels in BCa tissues predict poor prognosis. Further, SDF-1β mRNA levels in exfoliated cells detect BCa with high sensitivity and are potential predictors of future recurrence.

Background CXCR4 and CXCR7 are seven transmembrane chemokine receptors of the stroma-derived factor (SDF-1). CXCR4, but not CXCR7, has been examined in bladder cancer (BCa). We examined the functional and clinical significance of CXCR7 in BCa. Methods CXCR4 and CXCR7 levels were measured in BCa cell lines, tissues (normal = 25; BCa = 44) and urine specimens (n=186) by quantitative PCR and/or immunohistochemistry. CXCR7 function in BCa cells were examined by transient transfections using a CXCR7 expression vector or siRNA. Results In BCa cell lines CXCR7 mRNA levels were 5–37-fold higher than CXCR4 levels. Transient overexpression of CXCR7 in BCa cell lines promoted growth and chemotactic motility. CXCR7 co-localized and formed a functional complex with EGF-receptor, PI3-kinase/Akt, Erk and src and induced their phosphorylation. CXCR7 also induced upregulation of cyclin-D1 and bcl-2. Suppression of CXCR7 expression reversed these effects and induced apoptosis. CXCR7 mRNA levels and CXCR7 staining scores were significantly (5–10-fold) higher in BCa tissues than in normal tissues (P<0.001). CXCR7 expression independently associated with metastasis (P=0.019) and disease specific mortality (P=0.03). CXCR7 was highly expressed in endothelial cells in high-grade BCa tissues when compare to low-grade BCa and normal bladder. CXCR7 levels were elevated in exfoliated urothelial cells from high-grade BCa patients (P=0.0001; 90% sensitivity; 75% specificity); CXCR4 levels were unaltered. Conclusion CXCR7 promotes BCa cell proliferation and motility plausibly through EGF-receptor and Akt-signaling. CXCR7 expression is elevated in BCa tissues and exfoliated cells and is associated with high-grade and metastasis.

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