Racial differences in the systemic inflammatory response to prostate cancer

Systemic inflammation may increase risk for prostate cancer progression, but the role it plays in prostate cancer susceptibility is unknown. From a cohort of over 10,000 men who had either a prostate biopsy or transurethral resection that yielded a benign finding, we analyzed 517 incident prostate cancer cases identified during follow-up and 373 controls with one or more white blood cell tests during a follow-up period between one and 18 years. Multilevel, multivariable longitudinal models were fit to two measures of systemic inflammation, neutrophil-to-lymphocyte ratio (NLR) and monocyte-to-lymphocyte ratio (MLR), to determine NLR and MLR trajectories associated with increased risk for prostate cancer. For both measures, we found no significant differences in the trajectories by case/control status, however in modeling NLR trajectories there was a significant interaction between race (white or Black and case-control status. In race specific models, NLR and MLR values were consistently higher over time among white controls than white cases while case-control differences in NLR and MLR trajectories were not apparent among Black men. When cases were classified as aggressive as compared to non-aggressive, the case-control differences in NLR and MLR values over time among white men were most apparent for non-aggressive cases. For NLR among white men, significant case-control differences were observed for the entire duration of observation for men who had inflammation in their initial prostate specimen. It is possible that, among white men, monitoring of NLR and MLR trajectories after an initial negative biopsy may be useful in monitoring prostate cancer risk

The interplay of growth differentiation factor 15 (GDF15) expression and M2 macrophages during prostate carcinogenesis

M2 (tumor-supportive) macrophages may upregulate growth differentiation factor 15 (GDF15), which is highly expressed in prostate tumors, but the combined utility of these markers as prognostic biomarkers are unclear. We retrospectively studied 90 prostate cancer cases that underwent radical prostatectomy as their primary treatment and were followed for biochemical recurrence (BCR). These cases also had a benign prostate biopsy at least 1 year or more before their prostate cancer surgery. Using computer algorithms to analyze digitalized immunohistochemically stained slides, GDF15 expression and the presence of M2 macrophages based on the relative density of CD204- and CD68-positive macrophages were measured in prostate: (i) benign biopsy, (ii) cancer and (iii) tumor-adjacent benign (TAB) tissue. Both M2 macrophages (P = 0.0004) and GDF15 (P \u3c 0.0001) showed significant inter-region expression differences. Based on a Cox proportional hazards model, GDF15 expression was not associated with BCR but, in men where GDF15 expression differences between cancer and TAB were highest, the risk of BCR was significantly reduced (hazard ratio = 0.26; 95% confidence interval = 0.09-0.94). In addition, cases with high levels of M2 macrophages in prostate cancer had almost a 5-fold increased risk of BCR (P = 0.01). Expression of GDF15 in prostate TAB was associated with M2 macrophage levels in both prostate cancer and TAB and appeared to moderate M2-macrophage-associated BCR risk. In summary, the relationship of GDF15 expression and CD204-positive M2 macrophage levels is different in a prostate tumor environment compared with an earlier benign biopsy and, collectively, these markers may predict aggressive disease

Growth and differentiation factor 15 and NF-κB expression in benign prostatic biopsies and risk of subsequent prostate cancer detection

Growth and differentiation factor 15 (GDF-15), also known as macrophage inhibitory cytokine 1 (MIC-1), may act as both a tumor suppressor and promotor and, by regulating NF-κB and macrophage signaling, promote early prostate carcinogenesis. To determine whether expression of these two inflammation-related proteins affect prostate cancer susceptibility, dual immunostaining of benign prostate biopsies for GDF-15 and NF-κB was done in a study of 503 case-control pairs matched on date, age, and race, nested within a historical cohort of 10,478 men. GDF-15 and NF-κB expression levels were positively correlated (r = 0.39; p \u3c 0.0001), and both were significantly lower in African American (AA) compared with White men. In adjusted models that included both markers, the odds ratio (OR) for NF-κB expression was statistically significant, OR =0.87; p = 0.03; 95% confidence interval (CI) =0.77-0.99, while GDF-15 expression was associated with a nominally increased risk, OR =1.06; p = 0.27; 95% CI =0.96-1.17. When modeling expression levels by quartiles, the highest quartile of NF-κB expression was associated with almost a fifty percent reduction in prostate cancer risk (OR =0.51; p = 0.03; 95% CI =0.29-0.92). In stratified models, NF-κB had the strongest negative association with prostate cancer in non-aggressive cases (p = 0.03), older men (p = 0.03), and in case-control pairs with longer follow-up (p = 0.02). Risk associated with GDF-15 expression was best fit using nonlinear regression modeling where both first (p = 0.02) and second (p = 0.03) order GDF-15 risk terms were associated with significantly increased risk. This modeling approach also revealed significantly increased risk associated with GDF-15 expression for subsamples defined by AA race, aggressive disease, younger age, and in case-control pairs with longer follow-up. Therefore, although positively correlated in benign prostatic biopsies, NF-κB and GDF-15 expression appear to exert opposite effects on risk of prostate tumor development

Racial Disparities in Expression of GDF15 and NFκB in Prostate Cancer and Benign Prostatic Epithelium

Prostate cancer (PC) outcomes are more adverse for African-American (AA) than white (W) men. Growth differentiation factor 15 (GDF15, PDF, NAG-1) is a stress-induced anti-inflammatory cytokine with immunosuppressive and tumor growth-promoting functions. GDF15 inversely regulates NFκB, a transcription factor enabling pro-inflammatory gene expression and becomes constitutively activated in androgen-independent PC. Tissue microarrays (TMAs), prepared from prostatectomy tissue at three institutions, comprised 688 cases (364 W and 324 AA). Each case included ≥3 tumor punches plus ≥3 non-neoplastic punches. TMAs were stained separately for GDF15 and NFκB and evaluated by two pathologists, using the 0-3+ scale. PC, compared to benign epithelium, had elevated mean GDF15 expression (1.93 vs. 0.99) and also, NFκB (1.18 vs. 0.96, both P<0.0001). Only in AA men did PC show gradewise or stagewise altered expression of these markers. In AA men, GDF15 expression fell as stage rose in PC (P=0.007) and also in benign epithelium (P =0.003). In W men, GDF15 expression in benign epithelium fell as stage (P=0.01) and grade (P=0.01) rose. NFκB expression was higher in AA than W men only in high-grade PC (P =0.01). NFκB expression rose with increasing tumor grade only in AA men (P =0.027) and in the benign prostate component only in W men (P=0.007). Benign and tumor NFκB expression did not vary with stage. PC showed significant alterations in GDF15 and NFκB expression in accord with cancer aggressiveness in AA men only: stagewise decrease in GDF15, and gradewide increase in NFκB.  Findings suggest a disparity for immune response by race in prostate carcinogenesis

Larger Men Have Larger Prostates: Detection Bias in Epidemiologic Studies of Obesity and Prostate Cancer Risk

BACKGROUND: Obesity is associated with risk of aggressive prostate cancer (PCa), but not with over-all PCa risk. However, obese men have larger prostates which may lower biopsy accuracy and cause a systematic bias toward the null in epidemiologic studies of over-all risk. METHODS: Within a cohort of 6692 men followed-up after a biopsy or transurethral resection of the prostate (TURP) with benign findings, a nested case-control study was conducted of 495 prostate cancer cases and controls matched on age, race, follow-up duration, biopsy versus TURP, and procedure date. Data on body mass index and prostate volume at the time of the initial procedure were abstracted from medical records. RESULTS: Prior to consideration of differences in prostate volume, overweight (OR = 1.41; 95%CI 1.01, 1.97), and obese status (OR = 1.59; 95%CI 1.09, 2.33) at the time of the original benign biopsy or TURP were associated with PCa incidence during follow-up. Prostate volume did not significantly moderate the association between body-size and PCa, however it did act as an inverse confounder; adjustment for prostate volume increased the effect size for overweight by 22% (adjusted OR = 1.52; 95%CI 1.08, 2.14) and for obese status by 23% (adjusted OR = 1.77; 95%CI 1.20, 2.62). Larger prostate volume at the time of the original benign biopsy or TURP was inversely associated with PCa incidence during follow-up (OR = 0.92 per 10 cc difference in volume; 95%CI 0.88, 0.97). In analyses that stratified case-control pairs by tumor aggressiveness of the case, prostate volume acted as an inverse confounder in analyses of non-aggressive PCa but not in analyses of aggressive PCa. CONCLUSIONS: In studies of obesity and PCa, differences in prostate volume cause a bias toward the null, particularly in analyses of non-aggressive PCa. A pervasive underestimation of the association between obesity and overall PCa risk may exist in the literature

Race Differences in Telomere length in benign prostate biopsies and subsequent risk of prostate cancer

BACKGROUND: Telomere shortening is linked to aging and may be associated with increased risk for cancer. Most cancer studies have used telomere length in leukocytes rather than in the target tissue of cancer origin. METHODS: A case-control study of 524 case-control pairs with a benign prostate biopsy nested within a historical cohort of 10,478 men was conducted to determine whether pre-malignant prostate telomere length (assessed using a modified quantitative real-time PCR) is associated with prostate cancer risk. RESULTS: Telomere lengths in benign prostate biopsies of cases vs. controls were similar (1.46 {plus minus} 0.38 vs. 1.45 {plus minus} 0.42; p=0.49). African American (AA) men had significantly shorter telomeres compared with white men (1.51 {plus minus} 0.38 vs. 1.63 {plus minus} 0.39; p\u3c0.0001). In race-stratified analyses, increasing telomere length was more strongly associated with prostate cancer risk in white men, wherein those with telomere length in the highest quartile had 1.9-fold greater adjusted risk of prostate cancer compared to men with prostate telomere lengths in the lowest quartile (OR=1.90; 95% CI = 1.08 - 3.36). Men in the highest telomere length quartile also had a greater risk of aggressive prostate cancer compared with men with telomere lengths in the lowest quartile (OR=2.78; 95% CI =1.25 - 6.19). CONCLUSION: White men have longer telomeres in benign prostate tissue compared with AA men, and those with the longest telomeres may be at increased risk for prostate cancer, particularly the more aggressive form of the disease. IMPACT: Race-specific telomere length measures may be an early biomarker of aggressive prostate cancer

Changes in GDF15 (Growth/Differentiation Factor 15) Expression and M2 Macrophages During Prostate Carcinogenesis

GDF15 (growth/differentiation factor 15), also known as MIC-1 (Macrophage inhibitory cytokine 1), is a divergent member of the TGFβ superfamily of cytokines and is highly expressed in prostate tumors, but its role in prostate carcinogenesis and utility as a prognostic biomarker is unclear. We studied 91 prostate cancer cases that underwent surgery as their primary treatment and were then subsequently followed for biochemical recurrence (BCR). These cases also had a benign prostate biopsy at least one year before their prostate cancer diagnosis. In both the benign biopsy and tumor specimens, we quantified the intensity of GDF15 expression and characterized the presence of tumor associated macrophages by measuring the density of CD68-positive stained cells, and the M2 macrophage marker CD204 by immunohistochemical analysis. Marker expression was measured in prostate a) benign biopsy (BS), b) tumor-adjacent benign (BGS) and c) tumor tissue (MGS) using an automated multi-image processing macro developed in the ImageJ software. A Cox proportional hazards model was used to test the association of time to BCR of the low expression group compared with medium or high biomarker expression. The risk of BCR differed with the extent of GDF15 expression in the prostatic epithelial tissue of benign and tumor regions of the prostate. For instance, in BGS, high expression of GDF15 was associated with increased risk of BCR (hazard ratio (HR)=2.58, p=0.07). After controlling for PSA at diagnosis, Gleason grade and pathologic stage, high expression of GDF15 in BGS had a stronger association with BCR (HR=3.30, p=0.04). The risk of BCR increased with increasing level of infiltration of CD204/CD68 positive macrophages in BGS (HR=4.19, p=0.02) and MGS (HR=4.16, p=0.01) even after controlling for PSA at diagnosis, Gleason grade and pathologic stage. The combined expression levels of GDF15 and CD204/CD68 showed that prostate cancer cases with small GDF15 expression changes between BGS and MGS and high CD204/CD68 expression in BGS were at 3-fold higher risk of BCR (HR=3.67, p=0.05). In summary, expression levels of GDF15 and CD204 M2 macrophages in different regions of the prostate can change as the disease progresses from benign to a tumorigenic state and serve as markers for aggressive disease. Further evaluation of these dynamic differences in the prostate immune cellular profile in the pre-malignant and malignant state may offer additional insight into inflammatory-mediated prostate carcinogenesis

Potential effect of anti-inflammatory drug use on PSA kinetics and subsequent prostate cancer diagnosis: Risk stratification in black and white men with benign prostate biopsy

BACKGROUND: Rising prostate-specific antigen (PSA) levels are associated with both increased risk of prostate cancer and prostatic inflammation. The confounding effects of inflammation on the utility of PSA kinetics to predict prostate cancer may be partially mitigated by anti-inflammatory drug use. We investigated the influence of anti-inflammatory drug use on the association of PSA kinetics with prostate cancer risk. METHODS: We studied 488 prostate cancer case-control pairs (290 white, 198 African American (AA)) nested in a retrospective cohort of men with a benign prostate biopsy. A series of multivariable models estimated prostate cancer risk associated with PSA velocity (PSAV) at different levels of anti-inflammatory drug use while adjusting for the presence of both clinical and histologic prostatitis. RESULTS: In men with one, two, or three or more courses of anti-inflammatory drug use, for each ng/mL/year increase in PSAV, prostate cancer risk increased 1.21-fold, 1.83-fold, and 1.97-fold, respectively ( P \u3c 0.0001). In controls with histologic prostatitis, anti-inflammatory drug use was associated with a significantly lower PSAV ( P \u3c 0.0001). This association was not observed in men with histologic prostatitis who were subsequently diagnosed with prostate cancer. A positive interaction between anti-inflammatory drug use and PSAV-associated prostate cancer risk was only observed in AA men, as well as a strong positive association between any anti-inflammatory drug use and clinical prostatitis ( P = 0.004). CONCLUSIONS: In men with benign prostate biopsy, accounting for the presence of histologic prostatitis and anti-inflammatory drug use, particularly in AA men, may help distinguish between men with rising PSA because of prostatitis vs undiagnosed cancer

The role of GDF15 (growth/differentiation factor 15) during prostate carcinogenesis

GDF15 (growth/differentiation factor 15), also known as MIC-1 (Macrophage inhibitory cytokine 1), is a divergent member of the TGFβ superfamily of cytokines and is highly expressed in prostate tumors, but its role in prostate carcinogenesis and utility as a prognostic biomarker is unclear. We studied 91 prostate cancer cases that underwent surgery as their primary treatment and were then subsequently followed for biochemical recurrence (BCR). These cases also had a benign prostate biopsy at least one year before their prostate cancer diagnosis. In both the benign biopsy and tumor specimens, we quantified the intensity of GDF15 expression and characterized the presence of tumor associated macrophages by measuring the density of CD68-positive stained cells and the M2 macrophage marker CD204 by immunohistochemical analysis. Marker expression was measured in a) benign biopsy, b) tumor-adjacent benign and c) tumor tissue using an automated multi-image processing macro developed in the ImageJ software. Expression measurements were log2 transformed and high-low cut-off points were selected that optimized the association of biomarker expression with BCR-free survival. A Cox proportional hazards model was used to test the association of time to BCR with low vs high biomarker expression. During follow-up, 23 cases (25.2%) experienced BCR (96% of men without BCR had at least one year of follow-up). An increased hazard ratio (HR) for BCR was found in men with a higher ratio of GDF15 expression in their tumor vs. tumor-adjacent benign tissue (HR: 3.74; 95% confidence interval (CI) = 1.27-10.99) Adjusting for tumor grade, pathological tumor stage and PSA at diagnosis did not alter risk estimates significantly. In these same prostate tumor specimens, increased hazard ratios for BCR were found among men who had elevated CD204 expression in tumor (HR = 5.24; 95% CI = 2.02-13.62) and in tumor-adjacent benign tissue (HR = 3.29; 95% CI = 1.32, 8.23). We found no association of BCR-free survival with either GDF15 or CD204 expression in pre-diagnostic benign biopsies. Our results suggest that men who have a larger difference in GDF15 expression levels between prostate tumor and tumor-adjacent benign tissue, and with increased levels of M2 macrophages in both tumor and tumor-adjacent benign tissue, are at greater risk of disease recurrence. Further evaluation of the differences in the prostate immune cellular profile in the pre-malignant and malignant state may offer additional insight into inflammatory mediated prostate carcinogenesis