Risk of prostate cancer is not associated with levels of C-reactive protein and other commonly used markers of inflammation

Most population-based studies studied the association between inflammation and prostate cancer (PCa) by assessing C-reactive protein (CRP). As these findings have shown inconsistent results, we aimed to also study different markers that have been commonly taken as indications of inflammation. A cohort based on four groups of men (n = 34,891), according to age at cohort entry (45, 55, 65 and 75 years), with measurements of glucose, triglycerides, total cholesterol, haptoglobin, albumin, hemoglobin and leukocytes were selected from the Apolipoprotein Mortality Risk database. A total of 17,937 men had measurements of non-high-sensitive CRP. Multivariate Cox proportional hazard models were used to analyze associations between inflammatory markers and PCa. A total of 49 of 12,063 men developed PCa in the age 45 group, whereas 207 of 9,940, 472 of 8,266 and 276 of 3,618 were diagnosed in the age 55, 65 and 75 groups, respectively. Mean follow-up time was 7.5 years (SD: 3.9). No markers showed an association with PCa risk, nor was there a trend by quartiles or an indication for different PCa risks by strata of hypercholesterolemia, hyperglycemia and hypertriglyceridemia status. The studied markers were not found to be associated with PCa risk. These null findings might be due to methodological issues; however, it is unlikely that strong and long-lasting associations between inflammation and PCa risk were missed as this was a large database with long follow-up. This indicates need for international consensus on appropriate inflammatory markers in the context of cancer that may be practically applied in large studies.     

Inflammatory serum markers and risk and severity of prostate cancer: The PROCA-life study

Whether chronic inflammation mirrored by high levels of systemic inflammatory markers such as high sensitive-CRP (hs-CRP) and white blood cell count (WBC) are associated with prostate cancer development remains unclear. In the Prostate Cancer Study throughout Life (PROCA-life), a prospective population-based cohort study, 7,356 men were included. Prediagnostic WBC and hs-CRP were assessed from blood collected at study entry; 2,210 participants also had a second CRP measure during follow-up. During a mean 11.8 years follow-up, 509 men developed prostate cancer (mean age at diagnosis 71.7 years). Multivariable Cox proportional hazard regression models were used to study whether individual biomarkers (WBC, hs-CRP), a combined score based on analyte tertiles (score range 2–6), or change in CRP were associated with risk and severity of prostate cancer. We observed a positive dose–response relationship between hs-CRP and prostate cancer risk with a Hazard Ratio (HR) per mg/l of 1.3, 95% CI 1.00–1.07. Men with an increase in hs-CRP between two measurements (Δhs-CRP) of ≥1.00 mg/l had a 36% increased risk of prostate cancer (HR 1.36, 95% CI 1.02–1.82), compared to men with no change or decrease in hs-CRP. Men with a systemic inflammatory score of 5 or 6 had a 68% higher risk of being diagnosed with metastatic disease (HR 1.68, 95% CI, 1.04–2.73) compared to men with lower scores. Our study supports that hs-CRP including repeated measurements alone or in combination with WBC may be a useful inflammation-related biomarker for prostate cancer risk and prognosis.     

Prediagnostic circulating markers of inflammation and risk of prostate cancer

Accruing evidence suggests that inflammation plays a role in prostate carcinogenesis. However, studies evaluating this association using C‐reactive protein (CRP) and interleukin‐6 as markers of inflammation have reported conflicting results. We investigated the associations of three common markers of inflammation (CRP, fibrinogen and leukocyte count) with the risk of prostate cancer in a prospective cohort of 2,571 men from Finland. During an average follow‐up period of 24 years (21–26 years), 203 men from the cohort who developed prostate cancer were identified via linkage to the nationwide Finnish Cancer Registry. We investigated the associations between the markers and the risk of prostate cancer using Cox proportional hazards model, adjusting for potential confounders. Elevated prediagnostic leukocyte count was associated with an increased risk of prostate cancer. In multivariable adjusted model, the relative risk of prostate cancer among men in the highest tertile of leukocyte count compared to men in the lowest tertile was 1.60 (95% confidence interval [CI] = 1.10–2.29, p‐trend = 0.01). Circulating CRP and fibrinogen were not associated with increased risk. The corresponding relative risks for elevated CRP and fibrinogen concentrations were 1.08 (95% CI: 0.74–1.60, p‐trend = 0.56) and 1.25 (95% CI: 0.87–1.81, p‐trend = 0.14), respectively. Men with elevated leukocyte counts had a 2.57‐fold (95% CI: 0.99–6.79) increased risk of prostate cancer mortality. The increased risk associated with elevated leukocyte counts warrants confirmation in other studies. Larger studies should consider combining at least two markers or using an inflammation score derived from many inflammatory markers to evaluate prostate cancer risk.     

Comparison of the prognostic value of selected markers of the systemic inflammatory response in patients with colorectal cancer

There is increasing evidence that the presence of a systemic inflammatory response plays an important role in predicting survival in patients with colorectal cancer. However, it is not clear what components of the systemic inflammatory response best predict survival. The aim of the present study was to compare the prognostic value of an inflammation-based prognostic score (modified Glasgow Prognostic Score (Mgps) 0=C-reactive protein <10 mg l(-1), 1=C-reactive protein >10 mg l(-1), and 2=C-reactive protein >10 mg l(-1) and albumin<35 g l(-1)) with that of components of the white cell count (neutrophils, lymphocytes, monocytes and platelets using standard thresholds) in patients with colorectal cancer. Two patient groups were studied: 149 patients who underwent potentially curative resection for colorectal cancer and 84 patients who had synchronous unresectable liver metastases. In those patients who underwent potentially curative resection the minimum follow-up was 36 months and 20 patients died of their cancer. On multivariate survival analysis only TNM stage (HR 3.75, 95% CI 1.54-9.17, P=0.004), monocyte count (HR 3.79, 95% CI 1.29-11.12, P=0.015) and mGPS (HR 2.21, 95% CI 1.11-4.41, P=0.024) were independently associated with cancer-specific survival. In patients with synchronous unresectable liver metastases the minimum follow-up was 6 months and 71 patients died of their cancer. On multivariate survival analysis only single liver metastasis >5 cm (HR 1.78, 95% CI 0.99-3.21, P=0.054), extra-hepatic disease (HR 2.09, 95% CI 1.05-4.17, P=0.036), chemotherapy treatment (HR 2.40, 95% CI 1.82-3.17, P<0.001) and mGPS (HR 1.44, 95% CI 1.01-2.04, P=0.043) were independently associated with cancer-specific survival. In summary, markers of the systemic inflammatory response are associated with poor outcome in patients with either primary operable or synchronous unresectable colorectal cancer. An acute-phase protein-based prognostic score, the mGPS, appears to be a superior predictor of survival compared with the cellular components of the systemic inflammatory response.     

Circulating prediagnostic interleukin‐6 and C‐reactive protein and prostate cancer incidence and mortality

Interleukin‐6 (IL‐6) and C‐reactive protein (CRP) are elevated in prostate cancer patients, but the role of prediagnostic levels of these inflammatory mediators on prostate cancer outcomes is unclear. We undertook a large, prospective case‐control study to evaluate the relation between prediagnostic levels of IL‐6 and CRP and prostate cancer incidence and mortality. We also investigated the role of the IL‐6 (?174 G/C) polymorphism in relation to circulating levels of IL‐6 and CRP, as well as cancer risk and mortality. We used unconditional logistic regression that adjusted for matching factors to analyze prostate cancer risk. For analyses of prostate cancer mortality, we conducted survival analyses in cases. Because of the strong link between inflammatory markers and body mass index (BMI), we assessed interactions between BMI and plasma levels on prostate cancer outcomes. Neither IL‐6 nor CRP plasma levels varied significantly by IL‐6 genotype. Genotype was not associated with prostate cancer risk or survival. Though neither IL‐6 nor CRP was associated with prostate cancer incidence overall, we observed a statistically significant interaction between IL‐6 and BMI on prostate cancer incidence (p_interaction < 0.01). Increasing IL‐6 levels were positively associated with risk in healthy weight men, but inversely associated with risk in overweight men. Further, prediagnostic IL‐6 was associated with time to prostate cancer progression/death among healthy weight prostate cancer cases (p_trend = 0.02). Adjusted hazard ratios were 1.73 (95% CI: 0.86, 3.51) comparing the highest to lowest IL‐6 level. Our study suggests that IL‐6 may potentially be involved in the development or progression of prostate cancer. © 2008 Wiley‐Liss, Inc.     

C-reactive protein as a prognostic marker for men with androgen-independent prostate cancer: results from the ASCENT trial

BACKGROUND.

Studies of cancer risk and molecular carcinogenesis suggest a role for inflammation in cancer development and progression. The authors sought to determine whether specific blood proteins associated with inflammation predict for outcomes in men with metastatic androgen‐independent prostate cancer (AIPC) who are initiating docetaxel‐based chemotherapy.

METHODS.

Baseline plasma samples were stored (?80°C) from 160 of 250 patients enrolled in the AIPC Study of Calcitriol ENhancing Taxotere (ASCENT) trial, a randomized, placebo‐controlled trial comparing weekly docetaxel plus high‐dose calcitriol with weekly docetaxel. Multiplex immunoassays measured 16 cytokine, chemokine, cardiovascular, or inflammatory markers. The Cox proportional hazards model was used to assess associations between baseline biomarkers, clinical characteristics, and survival. Logistic regression was used for analyses of associations with prostate‐specific antigen (PSA) decline.

RESULTS.

C‐reactive protein (CRP) was found to be significantly predictive of a shorter overall survival (hazards ratio [HR] of 1.41 for each natural logarithm [ln] [CRP] increase; 95% confidence interval [95% CI], 1.20–1.65 [P < .0001]). When CRP (continuous) was entered into a multivariate model using 13 baseline clinical variables, only elevated CRP remained a significant predictor (P < .0001) of shorter overall survival. When categorized as normal (≤8 mg/L) or abnormal (>8 mg/L), elevated CRP was found to be a significant predictor of shorter overall survival (HR of 2.96; 95% CI, 1.52–5.77 [P = .001]), as was hemoglobin (P = .007). Elevated CRP was also associated with a lower probability of PSA decline (odds ratio of 0.74 for each ln(CRP) increase; 95% CI, 0.60–0.92 [P = .007]).

CONCLUSIONS.

Elevated plasma CRP concentrations appear to be a strong predictor of poor survival and lower probability of PSA response to treatment in patients with AIPC who are receiving docetaxel‐based therapy. Cancer 2008. © 2008 American Cancer Society.     

Vitamin antioxidants, lipid peroxidation and the systemic inflammatory response in patients with prostate cancer

The relationship between lipid soluble antioxidant vitamins, lipid peroxidation, disease stage and the systemic inflammatory response were examined in healthy subjects (n = 14), patients with benign prostate hyperplasia BPH (n = 20), localized (n = 40) and metastatic (n = 38) prostate cancer. Prostate cancer patients had higher concentrations of malondialdehyde (p < 0.05) and lower circulating concentrations of lutein (p < 0.05), lycopene (p < 0.001) and beta-carotene (p < 0.05). Patients with metastatic prostate cancer, when compared with patients having localized disease, had a higher Gleason score (p < 0.01) and had more hormonal treatment, but lower concentrations of PSA (p < 0.05), alpha-tocopherol (p < or = 0.05), retinol (p < 0.01), lutein (p < 0.05) and lycopene (p < 0.01). In the prostate cancer patients, PSA was correlated with the concentrations of the lipid peroxidation product, malondialdehyde (rs= 0.353, p = 0.002). C-reactive protein was not correlated with the vitamin antioxidants nor malondialdehyde. In contrast, there was a negative correlation between malondialdehyde concentrations and both lutein (rs= -0.263, p = 0.020) and lycopene (rs= -0.269, p = 0.017). These results indicate that lower concentrations of carotenoids, in particular, lycopene reflect disease progression rather than the systemic inflammatory response in patients with prostate cancer.     

Dairy intake in relation to prostate cancer survival

Dairy intake has been associated with increased risk of advanced prostate cancer. Two US cohort studies reported increased prostate cancer‐specific mortality with increased high‐fat milk intake. We examined whether dairy and related nutrient intake were associated with prostate cancer progression in a Swedish patient population with high dairy consumption. We prospectively followed 525 men with newly diagnosed prostate cancer (diagnosed 1989–1994). We identified and confirmed deaths through February 2011 (n = 222 prostate cancer‐specific, n = 268 from other causes). Cox proportional hazards regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI) for the associations between food or nutrient intake and prostate cancer‐specific death. On average, patients consumed 5.0 servings/day of total dairy products at diagnosis. In the whole population, high‐fat milk intake was not associated with prostate cancer‐specific death (95% CI: 0.78, 2.10; p‐trend = 0.32; multivariate‐adjusted model). However, among patients diagnosed with localized prostate cancer, compared to men who consumed <1 servings/day of high‐fat milk, those who drank ≥3 servings/day had an increased hazard of prostate cancer mortality (HR = 6.10; 95% CI: 2.14, 17.37; p‐trend = 0.004; multivariate‐adjusted model). Low‐fat milk intake was associated with a borderline reduction in prostate cancer death among patients with localized prostate cancer. These associations were not observed among patients diagnosed with advanced stage prostate cancer. Our data suggest a positive association between high‐fat milk intake and prostate cancer progression among patients diagnosed with localized prostate cancer. Further studies are warranted to investigate this association and elucidate the mechanisms by which high‐fat milk intake may promote prostate cancer progression.     

Prostate cancer risk in the Swedish AMORIS study: the interplay among triglycerides, total cholesterol, and glucose

BACKGROUND:

In a cohort including 5112 prostate cancer (pCa) patients, the authors investigated associations among triglycerides (TG), total cholesterol (TC), and pCa while taking into account glucose.

METHODS:

A cohort (n = 200,660) based on 4 groups of men, according to age at cohort entry, with TG, TC, and glucose measurements was selected from the Apolipoprotein MOrtality RISk (AMORIS) database. Of these, 5112 men developed pCa. Multivariate Cox proportional hazard models were used to analyze associations among TG, TC, and pCa. Competing risks were assessed graphically.

RESULTS:

Age‐stratified analyses for quartiles of TG, TC, and glucose showed a negative association between glucose and pCa risk (HR, 0.93; 95% CI, 0.86‐1.01), 0.93 (0.86‐1.01), 0.87 (0.81‐0.94) for the second, third, and fourth quartiles compared with the first (P_trend = .001). Stratified analysis by glucose levels (<6.11 or ≥6.11 mmol/L) showed a positive association between hypertriglyceridemia (TG≥1.71 mmol/L) and pCa risk, when there were high glucose levels (HR, 1.23; 95% CI, 1.01‐1.48). No association was found for hypercholesterolemia (TC≥6.50 mmol/L). Competing risk analysis showed that protective effects of glucose were overestimated in conventional Cox proportional hazard models and strengthened positive findings between TG and pCa risk.

CONCLUSIONS:

The authors'; findings supported the hypothesis that factors of the glucose and lipid metabolism influence pCa risk. Competing risk assessment showed that it is important to take into account the long natural history and age distribution of pCa when interpreting results. The authors'; findings indicate another reason to fight the increasing prevalence of obesity and dyslipidemia. Cancer 2011. © 2010 American Cancer Society.     

Serum steroids in relation to prostate cancer risk in a case-control study (Greece)

Blood samples were collected from 52 incident cases of histologicallyconfirmed prostate cancer and 52 age- and town of residence-matched healthycontrols in Athens, Greece. Samples were analyzed blindly in Boston,Massachusetts (USA) for testosterone (T), estradiol (E2), sex hormone-bindingglobulin (SHBG), and dihydrotestosterone (DHT). The data were modeled usingmultiple logistic regression with adjustment for age, height, body mass index(wt/ht2), years of schooling, and mutually among hormones. DHT was associatedinversely, significantly, and strongly with the risk of prostate cancer,whereas T was associated marginally positively, and E2 was associatednonsignificantly inversely with the disease. No association was observed inthis study with respect to SHBG.     

Serum interleukin-6 levels reflect the disease status of colorectal cancer

BACKGROUND AND OBJECTIVES: Interleukin-6 (IL-6) has been shown to be associated with cancer development. However, its role in the progression of colorectal cancer has never been elucidated. Our intention was to investigate this role and identify its prognostic significance. METHODS: One hundred and sixty-four consecutive colorectal cancer patients, whose local lesions were resected, were selected. The preoperative serum IL-6 levels were measured and the relationships between the elevation of IL-6 and both the clinicopathological factors and prognosis of patients were investigated. RESULTS: Median IL-6 level was significantly higher in patients with colorectal cancer than in normal controls. High levels of serum IL-6 (>12 pg/ml) were correlated with larger tumor size, elevated serum CRP levels, and liver metastases (P < 0.05). IL-6 levels also increased in a stage-related manner (P < 0.01). Although serum IL-6 correlated with survival, it is not an independent prognostic indicator. CONCLUSIONS: Serum IL-6 levels correlated with disease status of colorectal cancer but could not be regarded as an independent predictor for prognosis.     

Obesity is associated with increased risks of prostate cancer metastasis and death after initial cancer diagnosis in middle-aged men

BACKGROUND: Current research is inconclusive regarding the effect of obesity on outcomes after a prostate cancer diagnosis. The objective of this study was to examine associations between obesity and the risks of developing metastasis or prostate cancer-specific mortality in a population-based cohort of men with prostate cancer. METHODS: Seven hundred fifty-two middle-aged men with prostate cancer who were enrolled in a case-control study and remain under long-term follow-up for disease progression and mortality formed the study cohort. Body mass index (BMI) in the year before diagnosis was obtained at the time of initial interview. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs) of prostate cancer metastasis and mortality associated with obesity, controlling for age, race, smoking status, Gleason score, stage at diagnosis, diagnostic prostate-specific antigen level, and primary treatment. RESULTS: Obesity (BMI >or=30 kg/m(2)) was associated with a significant increase in prostate cancer mortality (HR, 2.64; 95% CI, 1.18-5.92). Among men who were diagnosed with local- or regional-stage disease, obesity also was associated with an increased risk of developing metastasis (HR, 3.61; 95% CI, 1.73-7.51). Associations generally were consistent across strata defined by Gleason score (2-6 or 7 [3 + 4] vs 7 [4 + 3] or 8-10), stage (local vs regional/distant for mortality), and primary treatment (androgen-deprivation therapy use: yes vs no). CONCLUSIONS: Obesity at the time of diagnosis was associated with increased risks of prostate cancer metastasis and death. The increased risk of prostate cancer death or metastasis associated with obesity largely was independent of key clinical prognostic factors at diagnosis.     

Low-temperature plasma treatment induces DNA damage leading to necrotic cell death in primary prostate epithelial cells

Background:

In recent years, the rapidly advancing field of low-temperature atmospheric pressure plasmas has shown considerable promise for future translational biomedical applications, including cancer therapy, through the generation of reactive oxygen and nitrogen species.

Method:

The cytopathic effect of low-temperature plasma was first verified in two commonly used prostate cell lines: BPH-1 and PC-3 cells. The study was then extended to analyse the effects in paired normal and tumour (Gleason grade 7) prostate epithelial cells cultured directly from patient tissue. Hydrogen peroxide (H₂O₂) and staurosporine were used as controls throughout.

Results:

Low-temperature plasma (LTP) exposure resulted in high levels of DNA damage, a reduction in cell viability, and colony-forming ability. H₂O₂ formed in the culture medium was a likely facilitator of these effects. Necrosis and autophagy were recorded in primary cells, whereas cell lines exhibited apoptosis and necrosis.

Conclusions:

This study demonstrates that LTP treatment causes cytotoxic insult in primary prostate cells, leading to rapid necrotic cell death. It also highlights the need to study primary cultures in order to gain more realistic insight into patient response.     

前列腺癌相关分子生物标记的研究进展

随着前列腺癌发病率在我国的逐年升高,泌尿外科医生对此疾病的早期诊断与治疗也越来越关注。科研人员期望从分子水平上找到对前列腺癌诊断具有特异性的标记物并对分子靶向治疗提供有效的信息和资源。目前,对一些指标的发现和研究取得了一定的进展,本文对近年所关注的一些与前列腺癌有关的重要生物标记进行了综述。     

ROS signaling by NADPH oxidase 5 modulates the proliferation and survival of prostate carcinoma cells

Prostate cancer (PCa) is the most commonly diagnosed cancer and second leading cause of male cancer death in Western nations. Thus, new treatment modalities are urgently needed. Elevated production of reactive oxygen species (ROS) by NADPH oxidase (Nox) enzymes is implicated in tumorigenesis of the prostate and other tissues. However, the identity of the Nox enzyme(s) involved in prostate carcinogenesis remains largely unknown. Analysis of radical prostatectomy tissue samples and benign and malignant prostate epithelial cell lines identified Nox5 as an abundantly expressed Nox isoform. Consistently, immunohistochemical staining of a human PCa tissue microarray revealed distinct Nox5 expression in epithelial cells of benign and malignant prostatic glands. shRNA‐mediated knockdown of Nox5 impaired proliferation of Nox5‐expressing (PC‐3, LNCaP) but not Nox5‐negative (DU145) PCa cell lines. Similar effects were observed upon ROS ablation via the antioxidant N‐acetylcysteine confirming ROS as the mediators. In addition, Nox5 silencing increased apoptosis of PC‐3 cells. Concomitantly, protein kinase C zeta (PKCζ) protein levels and c‐Jun N‐terminal kinase (JNK) phosphorylation were reduced. Moreover, the effect of Nox5 knockdown on PC‐3 cell proliferation could be mimicked by pharmacological inhibition of JNK. Collectively, these data indicate that Nox5 is expressed at functionally relevant levels in the human prostate and clinical PCa. Moreover, findings herein suggest that Nox5‐derived ROS and subsequent depletion of PKCζ and JNK inactivation play a critical role in modulating intracellular signaling cascades involved in the proliferation and survival of PCa cells. © 2014 The Authors. Molecular Carcinogenesis published by Wiley Periodicals, Inc.