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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.

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Related in: MedlinePlus

Baseline MIC1 levels and change in PSA after chemotherapy as predictors of overall survival. (A) Kaplan–Meier analysis demonstrating that a baseline MIC1 level greater than the median confers a poorer overall survival. (B) Kaplan–Meier analysis of the relationship between a ⩾30% decline in PSA at 3 months after commencing chemotherapy and overall survival. (C) ROC curve revealing baseline MIC1 level is superior to maximal change in PSA within 3 months in predicting death within 12 months of commencing chemotherapy.
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fig3: Baseline MIC1 levels and change in PSA after chemotherapy as predictors of overall survival. (A) Kaplan–Meier analysis demonstrating that a baseline MIC1 level greater than the median confers a poorer overall survival. (B) Kaplan–Meier analysis of the relationship between a ⩾30% decline in PSA at 3 months after commencing chemotherapy and overall survival. (C) ROC curve revealing baseline MIC1 level is superior to maximal change in PSA within 3 months in predicting death within 12 months of commencing chemotherapy.

Mentions: Circulating MIC1 levels have prognostic utility in all stages of prostate cancer (Brown et al, 2009). In our cohort, patients with baseline MIC1 levels greater than the median (5591 pg ml−1) had a significantly shorter overall survival (P<0.001, Figure 3A). Although previous studies have established a normal MIC1 level to be below 1070–1150 pg ml−1 (Koopmann et al, 2004; Selander et al, 2007), too few patients in our cohort of metastatic CRPC had normal values to use this as a discriminator. For illustrative purposes, we chose to use the median value as a cut-point for Kaplan–Meier analysis. This showed that baseline MIC1 was a superior prognostic marker to a ⩾30% fall in PSA within 3 months (Figure 3A and B). As a continuous variable on ROC curve analysis, baseline MIC1 was a better predictor of death within 12 months than maximal change in PSA over 3 months (Figure 3C).


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)

Baseline MIC1 levels and change in PSA after chemotherapy as predictors of overall survival. (A) Kaplan–Meier analysis demonstrating that a baseline MIC1 level greater than the median confers a poorer overall survival. (B) Kaplan–Meier analysis of the relationship between a ⩾30% decline in PSA at 3 months after commencing chemotherapy and overall survival. (C) ROC curve revealing baseline MIC1 level is superior to maximal change in PSA within 3 months in predicting death within 12 months of commencing chemotherapy.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig3: Baseline MIC1 levels and change in PSA after chemotherapy as predictors of overall survival. (A) Kaplan–Meier analysis demonstrating that a baseline MIC1 level greater than the median confers a poorer overall survival. (B) Kaplan–Meier analysis of the relationship between a ⩾30% decline in PSA at 3 months after commencing chemotherapy and overall survival. (C) ROC curve revealing baseline MIC1 level is superior to maximal change in PSA within 3 months in predicting death within 12 months of commencing chemotherapy.
Mentions: Circulating MIC1 levels have prognostic utility in all stages of prostate cancer (Brown et al, 2009). In our cohort, patients with baseline MIC1 levels greater than the median (5591 pg ml−1) had a significantly shorter overall survival (P<0.001, Figure 3A). Although previous studies have established a normal MIC1 level to be below 1070–1150 pg ml−1 (Koopmann et al, 2004; Selander et al, 2007), too few patients in our cohort of metastatic CRPC had normal values to use this as a discriminator. For illustrative purposes, we chose to use the median value as a cut-point for Kaplan–Meier analysis. This showed that baseline MIC1 was a superior prognostic marker to a ⩾30% fall in PSA within 3 months (Figure 3A and B). As a continuous variable on ROC curve analysis, baseline MIC1 was a better predictor of death within 12 months than maximal change in PSA over 3 months (Figure 3C).

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