Limits...
Cytokine profiling of docetaxel-resistant castration-resistant prostate cancer.

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 - Br. J. Cancer (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: 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.

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.

Show MeSH

Related in: MedlinePlus

The relationship between changes in cytokine levels after cycle 1 of chemotherapy and chemotherapy response. (A) Heat map of changes in seven cytokine levels after cycle 1 that are significantly different between clinical benefit (PR or SD) and PD groups. (B) P-values from Mann–Whitney U-test comparing cytokine fold changes (FC) between clinical benefit and PD groups. (C) ROC analysis assessing the efficacy of a change in IL4 after cycle 1 to predict PD. (D) ROC analysis assessing the efficacy of combined changes in IL4, MIC1 and IL6 levels after cycle 1 to predict PD.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4402456&req=5

fig2: The relationship between changes in cytokine levels after cycle 1 of chemotherapy and chemotherapy response. (A) Heat map of changes in seven cytokine levels after cycle 1 that are significantly different between clinical benefit (PR or SD) and PD groups. (B) P-values from Mann–Whitney U-test comparing cytokine fold changes (FC) between clinical benefit and PD groups. (C) ROC analysis assessing the efficacy of a change in IL4 after cycle 1 to predict PD. (D) ROC analysis assessing the efficacy of combined changes in IL4, MIC1 and IL6 levels after cycle 1 to predict PD.

Mentions: The levels of 28 cytokines were quantitated in the plasma and serum samples. Six cytokines (IL-2, IL-15, IL-17, βFGF, GMCSF and MIP1α) were below the limit of detection in >50% of samples and were excluded from statistical analysis. The range and median of the cytokine levels in the cohort are shown in Supplementary Table 2. Seven cytokines (IL-1ra, IL-1β, IL-4, IL-6, IL-12, IFNγ and MIC1) had significantly increased levels after cycle 1 of chemotherapy in patients with PD compared with those with clinical benefit (PR or SD; Figure 2A and B). Baseline cytokine levels were not associated with chemotherapy response, as the levels were not significantly different between the clinical benefit and PD groups of patients (P>0.05). Overall, both the in vitro and human data demonstrate an inflammatory response to docetaxel resistance involving pro-inflammatory mediators and cytokines involved in macrophage recruitment, activation and TAM phenotype such as IL-1ra and MIC1.


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

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 - Br. J. Cancer (2015)

The relationship between changes in cytokine levels after cycle 1 of chemotherapy and chemotherapy response. (A) Heat map of changes in seven cytokine levels after cycle 1 that are significantly different between clinical benefit (PR or SD) and PD groups. (B) P-values from Mann–Whitney U-test comparing cytokine fold changes (FC) between clinical benefit and PD groups. (C) ROC analysis assessing the efficacy of a change in IL4 after cycle 1 to predict PD. (D) ROC analysis assessing the efficacy of combined changes in IL4, MIC1 and IL6 levels after cycle 1 to predict PD.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4402456&req=5

fig2: The relationship between changes in cytokine levels after cycle 1 of chemotherapy and chemotherapy response. (A) Heat map of changes in seven cytokine levels after cycle 1 that are significantly different between clinical benefit (PR or SD) and PD groups. (B) P-values from Mann–Whitney U-test comparing cytokine fold changes (FC) between clinical benefit and PD groups. (C) ROC analysis assessing the efficacy of a change in IL4 after cycle 1 to predict PD. (D) ROC analysis assessing the efficacy of combined changes in IL4, MIC1 and IL6 levels after cycle 1 to predict PD.
Mentions: The levels of 28 cytokines were quantitated in the plasma and serum samples. Six cytokines (IL-2, IL-15, IL-17, βFGF, GMCSF and MIP1α) were below the limit of detection in >50% of samples and were excluded from statistical analysis. The range and median of the cytokine levels in the cohort are shown in Supplementary Table 2. Seven cytokines (IL-1ra, IL-1β, IL-4, IL-6, IL-12, IFNγ and MIC1) had significantly increased levels after cycle 1 of chemotherapy in patients with PD compared with those with clinical benefit (PR or SD; Figure 2A and B). Baseline cytokine levels were not associated with chemotherapy response, as the levels were not significantly different between the clinical benefit and PD groups of patients (P>0.05). Overall, both the in vitro and human data demonstrate an inflammatory response to docetaxel resistance involving pro-inflammatory mediators and cytokines involved in macrophage recruitment, activation and TAM phenotype such as IL-1ra and MIC1.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: 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.

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.

Show MeSH
Related in: MedlinePlus