Cytokine profiling of docetaxel-resistant castration-resistant prostate cancer

K McMahon; H Lin; Lesley Castillo; B Lee; Mark Chatfield; M Lee_Ng; K Chiam; S Breit; David Brown; M Molloy; Gavin Marx; Nick Pavlakis; Michael Boyer; Martin Stockler; R Daly; Susan Henshall; L Horvath

doi:10.1038/bjc.2015.74

Cytokine profiling of docetaxel-resistant castration-resistant prostate cancer

K McMahon, H Lin, Lesley Castillo, B Lee, Mark Chatfield, M Lee_Ng, K Chiam, S Breit, David Brown, M Molloy, Gavin Marx, Nick Pavlakis, Michael Boyer, Martin Stockler, R Daly, Susan Henshall, L Horvath

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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-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	https://doi.org/10.1038/bjc.2015.74
Publication status	Published - 31 Mar 2015

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McMahon, K., Lin, H., Castillo, L., Lee, B., Chatfield, M., Lee_Ng, M., Chiam, K., Breit, S., Brown, D., Molloy, M., Marx, G., Pavlakis, N., Boyer, M., Stockler, M., Daly, R., Henshall, S., & Horvath, L. (2015). Cytokine profiling of docetaxel-resistant castration-resistant prostate cancer. British Journal of Cancer, 112(8), 1340-1348. https://doi.org/10.1038/bjc.2015.74

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

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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-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. ",

keywords = "cytokine, docetaxel, eotaxin, gamma interferon, granulocyte colony stimulating factor, granulocyte macrophage colony stimulating factor, growth differentiation factor 15, interleukin 1 receptor blocking agent, interleukin 10, interleukin 12, interleukin 13, interleukin 15, interleukin 17, interleukin 1beta, interleukin 2, interleukin 23, interleukin 25, interleukin 4, interleukin 5, interleukin 6, interleukin 7, interleukin 8, interleukin 9, macrophage inflammatory protein 1alpha, macrophage inflammatory protein 1beta, platelet derived growth factor, prostate specific antigen, RANTES, tumor necrosis factor alpha, vasculotropin, adult, aged, Article, castration resistant prostate cancer, cell differentiation, coculture, cohort analysis, cytokine production, disease course, human, human cell, in vitro study, macrophage, major clinical study, male, monocyte, overall survival, priority journal, prostate cancer cell line",

author = "K McMahon and H Lin and Lesley Castillo and B Lee and Mark Chatfield and M Lee_Ng and K Chiam and S Breit and David Brown and M Molloy and Gavin Marx and Nick Pavlakis and Michael Boyer and Martin Stockler and R Daly and Susan Henshall and L Horvath",

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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

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

C2 - PubMed:25867259

VL - 112

SP - 1340

EP - 1348

JO - British Journal of Cancer

JF - British Journal of Cancer

SN - 0007-0920

IS - 8

ER -