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

doi:10.1038/bjc.2015.74

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

Department of Molecular Sciences

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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 language	English
Pages (from-to)	1340-1348
Number of pages	9
Journal	British Journal of Cancer
Volume	112
Issue number	8
DOIs	https://doi.org/10.1038/bjc.2015.74
Publication status	Published - 14 Apr 2015

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Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Keywords

castration-resistant prostate cancer
docetaxel chemotherapy
cytokines
therapeutic response
macrophage

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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. / Cytokine profiling of docetaxel-resistant castration-resistant prostate cancer. In: British Journal of Cancer. 2015 ; Vol. 112, No. 8. pp. 1340-1348.

@article{36f09d32071d4932ac17efb337642880,

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.",

keywords = "castration-resistant prostate cancer, docetaxel chemotherapy, cytokines, therapeutic response, macrophage",

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

note = "Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.",

year = "2015",

month = "4",

day = "14",

doi = "10.1038/bjc.2015.74",

language = "English",

volume = "112",

pages = "1340--1348",

journal = "British Journal of Cancer",

issn = "0007-0920",

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Mahon, KL, Lin, HM, Castillo, L, Lee, BY, Lee-Ng, M, Chatfield, MD, Chiam, K, Breit, SN, Brown, DA, Molloy, MP, Marx, GM, Pavlakis, N, Boyer, MJ, Stockler, MR, Daly, RJ, Henshall, SM & Horvath, LG 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. / 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.

In: British Journal of Cancer, Vol. 112, No. 8, 14.04.2015, p. 1340-1348.

Research output: Contribution to journal › Article

TY - JOUR

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

AU - Mahon, K. L.

AU - Lin, H. M.

AU - Castillo, L.

AU - Lee, B. Y.

AU - Lee-Ng, M.

AU - Chatfield, M. D.

AU - Chiam, K.

AU - Breit, S. N.

AU - Brown, D. A.

AU - Molloy, M. P.

AU - Marx, G. M.

AU - Pavlakis, N.

AU - Boyer, M. J.

AU - Stockler, M. R.

AU - Daly, R. J.

AU - Henshall, S. M.

AU - Horvath, L. G.

N1 - Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

PY - 2015/4/14

Y1 - 2015/4/14

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-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.

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-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.

KW - castration-resistant prostate cancer

KW - docetaxel chemotherapy

KW - cytokines

KW - therapeutic response

KW - macrophage

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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

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