Importance of the IL-6 / STAT3 signalling pathway in prostate cancer stem cells

Kroon, Paula (2012) Importance of the IL-6 / STAT3 signalling pathway in prostate cancer stem cells. PhD thesis, University of York.

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Abstract

Prostate cancer is the most diagnosed cancer in men in the Western world. Currently, most treatments are directed towards an androgen receptor-expressing cell, which encompasses the majority of prostate tumours. Unfortunately, the tumour recurs in the majority of patients. This recurrence is thought to arise due to the presence of a rare population of prostate cancer stem cells. These cells are also hypothesized to be responsible for tumour initiation, maintenance, recurrence and metastasis. It is therefore important to develop novel therapies to target these tumour-initiating cells. Interleukin-6 (IL-6) is a pro-inflammatory cytokine, which is involved in the regulation of a multitude of cellular functions, including proliferation, apoptosis, and differentiation. IL-6 and the associated JAK-STAT signalling pathway have been implicated in the development and progression of a variety of tumours, including prostate cancer. In this study we have demonstrated that these stem-like cells, selected from primary prostate cancer cultures have elevated IL-6 levels and express the IL-6 receptor, suggesting that these cells are constitutively active. Targeting IL-6, and downstream activation of STAT3, resulted in a significant decrease in colony forming ability of these stem-like cells. Moreover, treatment with a small molecule inhibitor of STAT3 resulted in a modest inhibition of tumour growth, with a significant increase in the proportion of CD24+ luminal cells. Whilst the impact on established tumours was modest, LLL12 abolished tumour initiation, suggesting that activation of STAT3, through IL-6, is important for the maintenance of the undifferentiated stem-like cells within prostate tumours. Targeting the JAK-STAT signalling pathway in this cell population might result in a more durable response to current standard of care therapies.