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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    docetaxel
    Castration
    Prostatic Neoplasms
    Cytokines
    Growth Differentiation Factor 15
    Macrophages
    Interleukin-4
    Interleukin-6
    Interleukins
    Interleukin-12
    Prostate-Specific Antigen
    Coculture Techniques
    Interleukin-1

    Cite this

    McMahon, K., Lin, H., Castillo, L., Lee, B., Chatfield, M., Lee_Ng, M., ... 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
    McMahon, K ; Lin, H ; Castillo, Lesley ; Lee, B ; Chatfield, Mark ; Lee_Ng, M ; Chiam, K ; Breit, S ; Brown, David ; Molloy, M ; Marx, Gavin ; Pavlakis, Nick ; Boyer, Michael ; Stockler, Martin ; Daly, R ; Henshall, Susan ; Horvath, L. / Cytokine profiling of docetaxel-resistant castration-resistant prostate cancer. In: British Journal of Cancer. 2015 ; Vol. 112, No. 8. pp. 1340-1348.
    @article{c7132991715b480bb04b5a892edac1a7,
    title = "Cytokine profiling of docetaxel-resistant castration-resistant prostate cancer",
    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. ",
    keywords = "cytokine, docetaxel, eotaxin, gamma interferon, granulocyte colony stimulating factor, granulocyte macrophage colony stimulating factor, growth differentiation factor 15, interleukin 1 receptor blocking agent, interleukin 10, interleukin 12, interleukin 13, interleukin 15, interleukin 17, interleukin 1beta, interleukin 2, interleukin 23, interleukin 25, interleukin 4, interleukin 5, interleukin 6, interleukin 7, interleukin 8, interleukin 9, macrophage inflammatory protein 1alpha, macrophage inflammatory protein 1beta, platelet derived growth factor, prostate specific antigen, RANTES, tumor necrosis factor alpha, vasculotropin, adult, aged, Article, castration resistant prostate cancer, cell differentiation, coculture, cohort analysis, cytokine production, disease course, human, human cell, in vitro study, macrophage, major clinical study, male, monocyte, overall survival, priority journal, prostate cancer cell line",
    author = "K McMahon and H Lin and Lesley Castillo and B Lee and Mark Chatfield and M Lee_Ng and K Chiam and S Breit and David Brown and M Molloy and Gavin Marx and Nick Pavlakis and Michael Boyer and Martin Stockler and R Daly and Susan Henshall and L Horvath",
    year = "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, vol. 112, no. 8, pp. 1340-1348. https://doi.org/10.1038/bjc.2015.74

    Cytokine profiling of docetaxel-resistant castration-resistant prostate cancer. / McMahon, K; Lin, H; Castillo, Lesley; Lee, B; Chatfield, Mark; Lee_Ng, M; Chiam, K; Breit, S; Brown, David; Molloy, M; Marx, Gavin; Pavlakis, Nick; Boyer, Michael; Stockler, Martin; Daly, R; Henshall, Susan; Horvath, L.

    In: British Journal of Cancer, Vol. 112, No. 8, 31.03.2015, p. 1340-1348.

    Research output: Contribution to journalArticleResearchpeer-review

    TY - JOUR

    T1 - Cytokine profiling of docetaxel-resistant castration-resistant prostate cancer

    AU - McMahon, K

    AU - Lin, H

    AU - Castillo, Lesley

    AU - Lee, B

    AU - Chatfield, Mark

    AU - Lee_Ng, M

    AU - Chiam, K

    AU - Breit, S

    AU - Brown, David

    AU - Molloy, M

    AU - Marx, Gavin

    AU - Pavlakis, Nick

    AU - Boyer, Michael

    AU - Stockler, Martin

    AU - Daly, R

    AU - Henshall, Susan

    AU - Horvath, L

    PY - 2015/3/31

    Y1 - 2015/3/31

    N2 - 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. 

    AB - 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. 

    KW - cytokine

    KW - docetaxel

    KW - eotaxin

    KW - gamma interferon

    KW - granulocyte colony stimulating factor

    KW - granulocyte macrophage colony stimulating factor

    KW - growth differentiation factor 15

    KW - interleukin 1 receptor blocking agent

    KW - interleukin 10

    KW - interleukin 12

    KW - interleukin 13

    KW - interleukin 15

    KW - interleukin 17

    KW - interleukin 1beta

    KW - interleukin 2

    KW - interleukin 23

    KW - interleukin 25

    KW - interleukin 4

    KW - interleukin 5

    KW - interleukin 6

    KW - interleukin 7

    KW - interleukin 8

    KW - interleukin 9

    KW - macrophage inflammatory protein 1alpha

    KW - macrophage inflammatory protein 1beta

    KW - platelet derived growth factor

    KW - prostate specific antigen

    KW - RANTES

    KW - tumor necrosis factor alpha

    KW - vasculotropin

    KW - adult

    KW - aged

    KW - Article

    KW - castration resistant prostate cancer

    KW - cell differentiation

    KW - coculture

    KW - cohort analysis

    KW - cytokine production

    KW - disease course

    KW - human

    KW - human cell

    KW - in vitro study

    KW - macrophage

    KW - major clinical study

    KW - male

    KW - monocyte

    KW - overall survival

    KW - priority journal

    KW - prostate cancer cell line

    U2 - 10.1038/bjc.2015.74

    DO - 10.1038/bjc.2015.74

    M3 - Article

    VL - 112

    SP - 1340

    EP - 1348

    JO - British Journal of Cancer

    JF - British Journal of Cancer

    SN - 0007-0920

    IS - 8

    ER -

    McMahon K, Lin H, Castillo L, Lee B, Chatfield M, Lee_Ng M et al. Cytokine profiling of docetaxel-resistant castration-resistant prostate cancer. British Journal of Cancer. 2015 Mar 31;112(8):1340-1348. https://doi.org/10.1038/bjc.2015.74