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-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.
authors: 1] Chris O'Brien Lifehouse, Missenden Road, Camperdown, NSW 2050, Australia [2] Cancer Research Division, Garvan Institute of Medical Research/The Kinghorn Cancer Centre, Darlinghurst, NSW 2010, Australia [3] University of Sydney, Sydney, New South Wales 2050, Australia.
authors: K L
authors: KL
authors: Mahon
authors: Cancer Research Division, Garvan Institute of Medical Research/The Kinghorn Cancer Centre, Darlinghurst, NSW 2010, Australia.
authors: H-M
authors: HM
authors: Lin
authors: Cancer Research Division, Garvan Institute of Medical Research/The Kinghorn Cancer Centre, Darlinghurst, NSW 2010, Australia.
authors: L
authors: L
authors: Castillo
authors: Cancer Research Division, Garvan Institute of Medical Research/The Kinghorn Cancer Centre, Darlinghurst, NSW 2010, Australia.
authors: B Y
authors: BY
authors: Lee
authors: St Vincent's Centre for Applied Medical Research, Liverpool Street, Darlinghurst, NSW 2010, Australia.
authors: M
authors: M
authors: Lee-Ng
authors: Menzies School of Health Research, Darwin, NT, Australia.
authors: M D
authors: MD
authors: Chatfield
authors: Cancer Research Division, Garvan Institute of Medical Research/The Kinghorn Cancer Centre, Darlinghurst, NSW 2010, Australia.
authors: K
authors: K
authors: Chiam
authors: St Vincent's Centre for Applied Medical Research, Liverpool Street, Darlinghurst, NSW 2010, Australia.
authors: S N
authors: SN
authors: Breit
authors: St Vincent's Centre for Applied Medical Research, Liverpool Street, Darlinghurst, NSW 2010, Australia.
authors: D A
authors: DA
authors: Brown
authors: Australian Proteome Analysis Facility, Macquarie University, NSW 2105, Australia.
authors: M P
authors: MP
authors: Molloy
authors: Northern Haematology and Oncology Group, SAN Clinic, Wahroonga, NSW 2076, Australia.
authors: G M
authors: GM
authors: Marx
authors: Royal North Shore Hospital, Pacific Highway, Sydney, NSW 2065, Australia.
authors: N
authors: N
authors: Pavlakis
authors: 1] Chris O'Brien Lifehouse, Missenden Road, Camperdown, NSW 2050, Australia [2] University of Sydney, Sydney, New South Wales 2050, Australia.
authors: M J
authors: MJ
authors: Boyer
authors: 1] Chris O'Brien Lifehouse, Missenden Road, Camperdown, NSW 2050, Australia [2] University of Sydney, Sydney, New South Wales 2050, Australia.
authors: M R
authors: MR
authors: Stockler
authors: Signalling Network Laboratory, Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, VIC 3800, Australia.
authors: R J
authors: RJ
authors: Daly
authors: Cancer Research Division, Garvan Institute of Medical Research/The Kinghorn Cancer Centre, Darlinghurst, NSW 2010, Australia.
authors: S M
authors: SM
authors: Henshall
authors: 1] Chris O'Brien Lifehouse, Missenden Road, Camperdown, NSW 2050, Australia [2] Cancer Research Division, Garvan Institute of Medical Research/The Kinghorn Cancer Centre, Darlinghurst, NSW 2010, Australia [3] University of Sydney, Sydney, New South Wales 2050, Australia.
authors: L G
authors: LG
authors: Horvath
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D016207:Cytokines / Q000097:blood*; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007610:Kallikreins / Q000097:blood*; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D017430:Prostate-Specific Antigen / Q000097:blood*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy / Q000378:metabolism*; D043823:Taxoids / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D043823:Taxoids; D000077143:Docetaxel; C549870:KLK3 protein, human; D007610:Kallikreins; D017430:Prostate-Specific Antigen