Leukaemia inhibitory factor: a novel mediator of prostate cancer-induced bone disease?


Year:

Session type:

Theme:

Christina Turner1,Srinivasa Rao1,Jessica Whitburn1,Xiaotong Cheng1,Freddie Hamdy1,Claire Edwards1
1University of Oxford

Abstract

Background

Bone metastasis is a frequent complication of advanced prostate cancer (PCa). Following metastasis, survival rates plummet to 30% and treatment options become limited. There is therefore a need to elucidate the mechanisms that drive metastasis to identify novel therapeutics and biomarkers. Leukaemia inhibitory factor (LIF) is an IL-6 family cytokine known to be involved in a wide range of biological functions including haematopoiesis and bone formation. The aim of this project is to determine the role of LIF in PCa-induced bone disease.

Method

We have employed a powerful combination of in vitro, in vivo and ex vivo techniques including; cytokine array analysis of patient samples, co-culture systems to mimic the tumour-bone microenvironment, qPCR and ELISAs.

Results

Soluble LIF was elevated in patient serum before development of bone metastases vs non-metastatic patients (57.15% ± 17.06% increase, p<0.01). LIF mRNA and protein expression was increased in bone metastatic PCa cell lines (p<0.001) and in an in vivo murine model of PCa bone metastasis, LIF mRNA expression strongly correlated with tumour burden (Pearson r = 0.9941). LIF serum levels were also correlated with late stage weight loss in tumour-bearing mice (p<0.01) as well circulating leptin levels (p<0.05). Treatment of a panel of prostate cancer cells with LIF activated differential signalling cascades in bone-metastatic PCa cells as compared to non-bone metastatic, with increases in pSTAT3, P70 S6K and pMAPK. PCa/stromal cell co-cultures demonstrated that PCa cells upregulate LIF expression in stromal cells (p<0.001), accompanied by an upregulation in RANKL (p<0.001) and a downregulation of osteoprotegerin expression (p<0.0001) indicating a mechanism by which LIF may be involved in PCa-induced bone disease.

Conclusion

Our results indicate LIF is associated with bone metastases in vivo, with functional effects in cells of the tumour-bone niche that may promote disease progression in advanced PCa.