Cytokine profiling of docetaxel-resistant castration-resistant prostate cancer

K McMahon, H Lin, Lesley Castillo, B Lee, Mark Chatfield, M Lee_Ng, K Chiam, S Breit, David Brown, M Molloy, Gavin Marx, Nick Pavlakis, Michael Boyer, Martin Stockler, R Daly, Susan Henshall, L Horvath

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    Abstract

    Background: Docetaxel improves symptoms and survival in metastatic castration-resistant prostate cancer (CRPC). However, ~50% of patients are chemoresistant. This study examined whether changes in cytokine levels predict for docetaxel resistance in vitro and in a clinical cohort.


    Methods: PC3 cells or their docetaxel-resistant subline (PC3Rx) were co-cultured with U937 monocytes, with and without docetaxel treatment, and cytokine levels were measured. The circulating levels of 28 cytokines were measured pre-/post cycle 1 of docetaxel from 55 men with CRPC, and compared with prostate-specific antigen (PSA) response.


    Results: PC3Rx-U937 co-culture expressed more cytokines, chiefly markers of alternative macrophage differentiation, compared with PC3-U937 co-culture. Docetaxel treatment enhanced cytokine production by PC3Rx-U937 co-culture, while reducing cytokine levels in PC3-U937. In patients, changes in the levels of seven circulating cytokines (macrophage inhibitory cytokine 1 (MIC1), interleukin (IL)-1ra, IL-1?, IL-4, IL-6, IL-12 and IFNγ) after cycle 1 of docetaxel were associated with progressive disease (all P<0.05). The combination of changes in MIC1, IL-4 and IL-6 most strongly predicted PSA response (P=0.002).


    Conclusions: In vitro studies suggest docetaxel resistance is mediated, at least in part, by cytokines induced by the interaction between the docetaxel-resistant tumour cells and macrophages. Early changes in circulating cytokine levels were associated with docetaxel resistance in CRPC patients. When considered together, these data suggest a significant role for the inflammatory response and macrophages in the development of docetaxel resistance in CRPC. 

    Original languageEnglish
    Pages (from-to)1340-1348
    Number of pages9
    JournalBritish Journal of Cancer
    Volume112
    Issue number8
    DOIs
    Publication statusPublished - 31 Mar 2015

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    McMahon, K., Lin, H., Castillo, L., Lee, B., Chatfield, M., Lee_Ng, M., Chiam, K., Breit, S., Brown, D., Molloy, M., Marx, G., Pavlakis, N., Boyer, M., Stockler, M., Daly, R., Henshall, S., & Horvath, L. (2015). Cytokine profiling of docetaxel-resistant castration-resistant prostate cancer. British Journal of Cancer, 112(8), 1340-1348. https://doi.org/10.1038/bjc.2015.74