Cytokine profiling of docetaxel-resistant castration-resistant prostate cancer

K. L. Mahon, H. M. Lin, L. Castillo, B. Y. Lee, M. Lee-Ng, M. D. Chatfield, K. Chiam, S. N. Breit, D. A. Brown, M. P. Molloy, G. M. Marx, N. Pavlakis, M. J. Boyer, M. R. Stockler, R. J. Daly, S. M. Henshall, L. G. Horvath*

*Corresponding author for this work

Research output: Contribution to journalArticle

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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-1β, 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 - 14 Apr 2015

Bibliographical note

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Keywords

  • castration-resistant prostate cancer
  • docetaxel chemotherapy
  • cytokines
  • therapeutic response
  • macrophage

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