Cytokine profiling of docetaxel-resistant castration-resistant prostate cancer
BACKGROUND: Docetaxel improves symptoms and survival in metastatic castration-resistant prostate cancer (CRPC). However, approximately 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-1beta, IL-4, IL-6, IL-12 and IFNgamma) 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.
|ISBN||1532-1827 (Electronic) 0007-0920 (Linking)|
|Authors||Mahon, K. L. ; Lin, H. M. ; Castillo, L. ; Lee, B. Y. ; Lee-Ng, M. ; Chatfield, M. D. ; Chiam, K. ; Breit, S. N. ; Brown, D. A. ; Molloy, M. P. ; Marx, G. M. ; Pavlakis, N. ; Boyer, M. J. ; Stockler, M. R. ; Daly, R. J. ; Henshall, S. M. ; Horvath, L. G.;|
|Publisher Name||British Journal of Cancer|
|URL link to publisher's version||http://www.ncbi.nlm.nih.gov/pubmed/25867259|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/12836|