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 language | English |
|---|---|
| Pages (from-to) | 1340-1348 |
| Number of pages | 9 |
| Journal | British Journal of Cancer |
| Volume | 112 |
| Issue number | 8 |
| DOIs | |
| Publication status | Published - 31 Mar 2015 |
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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 journal › Article › Research › peer-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 -