Expression levels of the JAK/STAT pathway in the transition from hormone-sensitive to hormone-refractory prostate cancer

Abstract

The main cause of prostate cancer-related mortality is the development of hormone-refractory disease. Circulating serum levels of IL-6 are raised in hormone-refractory prostate cancer patients and evidence from cell line studies suggests that the IL-6R/JAK/STAT3 pathway may be involved in development of this disease. In the current study we investigate if expression levels of these family members are implicated in the development of hormone-refractory prostate cancer. Immunohistochemistry using IL-6R, JAK1, STAT3, pSTAT3(Tyr705) and pSTAT3(Ser727) antibodies was performed on 50 matched hormone-sensitive and hormone-refractory tumours pairs. An increase in expression of cytoplasmic IL-6 receptor, with the development of hormone-refractory prostate cancer was associated with reduced time to relapse (P=0.0074) while an increase in expression of cytoplasmic pSTAT3(Tyr705) was associated with reduced patient survival (P=0.0003). In addition, those patients with high expression of cytoplasmic pSTAT3(Tyr705) in their hormone-refractory tumours had significantly shorter time to death from biochemical relapse and overall survival in comparison to those patients with low expression of cytoplasmic pSTAT3(Tyr705) (P=0.002 and P=0.0027, respectively). Activation of STAT3, via phosphorylation is associated with reduced patient survival, suggesting that activation of the IL-6R/JAK/STAT3 pathway is involved with development of hormone-refractory prostate cancer.

Figure 1

Images of matched hormone-sensitive and hormone-refractory prostate tumours whose expression increased in the transition from hormone-sensitive to hormone-refractory disease (upper panel: IL-6 receptor and lower panel: pSTAT3^Tyr705). Positive staining is brown in colour and is indicated by arrows according to their location, M, membrane; C, cytoplasm; and N, nucleus. Counterstaining is blue and is represented in the stroma (S).

Figure 2

(A) Kaplan–Meier plot comparing time to death from biochemical relapse for those patients with hormone-refractory tumours with high cytoplasmic pSTAT3^Tyr705 expression (solid line) (27 patients) compared to those patients with hormone-refractory tumours with low cytoplasmic pSTAT3^Tyr705 expression (broken line) (23 patients) (P=0.002, hazard ratio 4.2 (95% CI 1.59–11.34)). (B) Kaplan–Meier plot comparing overall survival for those patients with hormone-refractory tumours with high-cytoplasmic pSTAT3^Tyr705 expression (solid line) (19 patients) compared to those patients with hormone-refractory tumours with low cytoplasmic pSTAT3^Tyr705 expression (broken line) (31 patients) (P=0.0027, hazard ratio 2.87 (95% CI 1.39–5.92)). (C) Kaplan–Meier plot for high-pSTAT3^Tyr705 protein expression in the nucleus vs low nuclear pSTAT3^Tyr705 protein expression in hormone-refractory prostate tumours. Those patients with high pSTAT3^Tyr705 (solid line) (22 patients) expression had shorter overall survival compared to those with low pSTAT3^Tyr705 (broken line) (28 patients); however this was not a significant change (P=0.25).

Figure 3

Kaplan–Meier plot for an increase in IL-6R protein expression vs no change or a decrease in IL-6R protein expression in the transition from hormone-sensitive to hormone-refractory disease. Those patients with an increase in IL-6R expression (solid line) (six patients) had significantly shorter time to biochemical relapse compared to those with no change or a decrease in IL-6R expression (broken line) (45 patients) (P=0.0076, hazard ratio 3.45 (95% CI 1.31–9.07)).

Figure 4

Kaplan–Meier plot for an increase in pSTAT3^Tyr705 protein expression in the cytoplasm vs no change or a decrease in pSTAT3^Tyr705 protein expression in the transition from hormone-sensitive to hormone-refractory disease. Those patients with an increase in pSTAT3^Tyr705 (solid line) (nine patients) expression had significantly shorter overall survival compared to those with no change or a decrease in pSTAT3^Tyr705 expression (broken line) (50 patients) (P=0.0003, hazard ratio 4.52 (95% CI 1.85–11.52)).