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Decreased infiltration of macrophage scavenger receptor-positive cells in initial negative biopsy specimens is correlated with positive repeat biopsies of the prostate
Cancer Science
Abstract
Macrophage scavenger receptor (MSR)-positive inflammatory cells and tumor-associated macrophages (TAMs) have been reported to regulate the growth of various cancers. In this study, the infiltration of MSR-positive cells and TAMs was analyzed to predict the outcome of repeat biopsy in men diagnosed as having no malignancy at the first prostate biopsy. Repeat biopsy of the prostate was carried out in 92 patients who were diagnosed as having no malignancy at the first biopsy. Of these, 30 patients (32.6%) were positive for prostate cancer at the repeat biopsy. Tumor-associated macrophages and MSR-positive cells were immunohistochemically stained with mAbs CD68 and CD204, respectively. Six ocular measuring fields were chosen randomly under a microscope at x400 power in the initial negative biopsy specimens, and the mean TAM and MSR counts for each case were determined. No difference in TAM count was found between the cases with or without prostate cancer. By contrast, the MSR count in patients with cancer was significantly lower than that in patients without cancer at the repeat biopsy (P < 0.001). Logistic regression analysis indicated that the MSR count at first biopsy is a significantly better predictive factor for positive repeat biopsy than PSA velocity, interval between first and repeat biopsies, or TAM count. Decreased infiltration of MSR-positive cells in negative first biopsy specimens was correlated with positive findings in the repeat biopsy. The MSR count might be a good indicator for avoiding unnecessary repeat biopsies.
... 5,6 Other studies have reported on immune response as a prognostic factor in PCa patients. 7,8 There is strong evidence that tumor-associated macrophages (TAMs) are involved in an inflammatory sequence that promotes tumor development. 9e11 TAMs play an important role in tumor progression and response to ADT. 7,12 However, the clinical significance of TAMs in various cancers is not fully understood. ...
... 7,8 There is strong evidence that tumor-associated macrophages (TAMs) are involved in an inflammatory sequence that promotes tumor development. 9e11 TAMs play an important role in tumor progression and response to ADT. 7,12 However, the clinical significance of TAMs in various cancers is not fully understood. The role of TAMs in PCa progression is multifactorial. ...
... 8,12,14,15 The clinical significance of TAM infiltration for PCa progression and patient survival is gradually becoming clearer. Two studies reported that increased TAM infiltration was associated with poor cancer-specific survival and recurrence-free survival, 7,16 whereas others found that increased TAM infiltration in prostate tumors was predictive of improved disease-free survival. 17 In PCa, vascular invasion should be also evaluated in addition to tumor assessment because the presence of malignant cells in blood vessels increases the risk of pelvic metastasis. ...
Background
Tumor-associated macrophages (TAMs) and microvessel density (MVD) play an essential role for tumor progression in prostate cancer (PCa). In this study, we evaluated the association between TAMs, the infiltration with tumor angiogenesis and the response to androgen deprivation therapies (ADTs) in PCa to evaluate TAM infiltration as a predictive factor for PCa survival.
Materials and methods
Fifty-four specimens were collected and stained with CD 68 antibody to investigated TAM infiltration in tumor. Von Willebrand factor was stained to evaluate MVD around the cancer foci. We assessed the association between patient's age, preoperative serum prostate-specific antigen, pathologic Gleason sum (GS), TAM infiltration, MVD, and the response to ADT for 5 years after PCa diagnosis.
Results
The median TAM was observed in 28 (6-76)/high power field (x400). Increasing TAM correlated with increasing tumor angiogenesis (P < 0.001, r = 0.61), and the response to ADT was significantly better in patients with fewer TAMs (<28) than in patients with higher TAMs (>28) (P = 0.003). TAM infiltration was significantly higher in those with higher serum prostate-specific antigen, higher GS, and metastasis. Multivariate analysis showed that GS, ADT type, and MVD number were significant prognostic factors for response to ADT in PCa (P < 0.0001). An increased infiltration of TAM [hazards ratio (HR) = 4.47; 95% confidence interval (CI): 1.97–10.15], MVD (HR = 2.66; 95% CI: 1.27–5.61), metastatic status (HR = 2.29; 95% CI: 0.14-0.60), and prostate volume (HR = 2.19; 95% CI: 1.27–3.12) significantly correlated with shorter survival in PCa patients by univariate analysis (P < 0.05). Multivariate analyses revealed that TAM and metastatic status significantly correlated with poor overall survival.
Conclusions
TAM infiltration is associated with response to ADT and increased tumor angiogenesis in PCa. GS, ADT type, and MVD in PCa specimens are useful predictive factors for poor response to ADT. Increasing TAM and positive metastatic status were prognostic factors for a poorer survival in PCa patients.
... Those biomarkers including inflammatory and immune cell infiltration-[CD3 + T cells, macrophage scavenger receptor 1 (MSR1)+ cells and CD 68 + macrophages cells], angiogenesis-[CD31 + vascular endothelial cells and vascular endothelial growth factor (VEGF)], proliferation and apoptotic markers-[Ki-67, minichromosome maintenance complex protein 2 (Mcm2) and active-casp3 (a-casp3)] and some protein expression markers-[p-AKT and p-STAT3]. 11,[14][15][16][17][18][19] However, no studies have evaluated the joint performance of the above 10 biomarkers in a repeat biopsy cohort. Therefore, we designed the present study to investigate if above biomarkers are associated with repeat biopsy outcomes and if the combined biomarkers of various implications could enhance the capacity of decision-making for repeat prostate biopsy. ...
... The slides were evaluated by observers who were blinded to the origin of the samples using an inverted Olympus microscope with the assistance of image processing software: Image Pro Plus 6.0 software (Media Cybernetics Inc). According to the staining proteins and previous studies, 11,[14][15][16][17][18][19] three methods were used to evaluate the immunostaining: (a) When scoring the immunoreactivity of VEGF, p-STAT3, p-AKT, and a-casp3, we employed H-score a semi-continuous variable scoring system which has been used in large number of previous studies. [25][26][27] In detail, the percentage of immunostaining and the staining intensity were recorded. ...
To evaluate whether the addition of biomarkers to traditional clinicopathological parameters may help to increase the accurate prediction of prostate re‐biopsy outcome. A training cohort with 98 patients and a validation cohort with 72 patients were retrospectively recruited into our study. Immunohistochemical analysis was used to evaluate the immunoreactivity of a group of biomarkers in the initial negative biopsy normal‐looking tissues of the training and validation cohorts. p‐STAT3, Mcm2, and/or MSR1 were selected out of 10 biomarkers to construct a biomarker index for predicting cancer and high‐grade prostate cancer (HGPCa) in the training cohort based on the stepwise logistic regression analysis; these biomarkers were then validated in the validation cohort. In the training cohort study, we found that the biomarker index was independently associated with the re‐biopsy outcomes of cancer and HGPCa. Moreover supplementing the biomarker index with traditional clinical‐pathological parameters can improve the area under the receiver operating characteristic curve of the model from 0.722 to 0.842 and from 0.735 to 0.842, respectively, for predicting cancer and HGPCa at re‐biopsy. In the decision‐making analysis, we found the model supplemented with the biomarker index can improve patients’ net benefit. The application of the model to clinical practice, at a 10% risk threshold, would reduce the number of biopsies by 34.7% while delaying the diagnosis of 7.8% cancers and would reduce the number of biopsies by 73.5% while delaying the diagnosis of 17.8% HGPCas. Taken together, supplementing the biomarker index with clinicopathological parameters may help urologists in re‐biopsy decision‐making processes. p‐STAT3, Mcm2, and/or MSR1 were selected out of 10 biomarkers to construct biomarker index. Biomarker index are associated with positive repeat prostate biopsy results. Supplementing biomarker index help urologists in re‐biopsy decision‐making processes.
... CD204-positive macrophages have been reported to correlate with tumor progression and poor patient outcome in glioma, ovarian epithelial tumors, lung, pancreatic, gastric, renal, oral and esophageal cancers (15)(16)(17)(18)(19)(20). In prostate cancer, two studies have shown that decreased numbers of CD204-positive cells are associated with a higher likelihood of cancer and cancer progression (21,22), but a third study found that, in men with prostate cancer, CD204 expression is higher in cancer than in adjacent normal cells (8). ...
... M2 phenotype macrophages appear to increase in a stepwise fashion from normal (i.e., no inflammation) prostate tissue, to primary untreated carcinomas, to hormone-naïve regional lymph Downloaded from https://academic.oup.com/carcin/article/41/8/1074/5866515 by Withers user on 23 August 2023 node metastases, to metastatic castrate-resistant prostate cancer (46). Interestingly, Nonomura et al. (21) found that the count of M2 positive macrophages in benign biopsy was predictive of a later positive prostate cancer biopsy. In our study, M2 macrophage density in benign prostate biopsy was not predictive of prostate cancer BCR, but M2 macrophage density in benign prostate was predictive of prostate cancer outcome when taking into account the M2 macrophage density in prostate tumor. ...
M2 (tumor-supportive) macrophages may upregulate GDF15 (growth/differentiation factor 15), 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 one 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: a) benign biopsy, b) cancer and c) tumor-adjacent benign (TAB) tissue. Both M2 macrophages (p=0.0004) and GDF15 (p<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, risk of BCR was significantly reduced (hazards ratio (HR) = 0.26; 95% confidence interval = 0.09 - 0.94). In addition, cases with high levels of M2 macrophages in prostate cancer had almost a five-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.
... Shirotake et al. showed that both high monocyte chemoattractant protein-1 (MCP-1) expression and high macrophage infiltration in prostate cancer specimens correlate with a high prostate-specific antigen (PSA) recurrence rate and that AT1R blockade (ARB) inhibits MCP-1 expression through the PI3K/Akt pathway and blocks macrophage infiltration in castration-resistant prostate cancer [96]. Nonomura et al. [97] found that TAM infiltration was significantly correlated with serum PSA level, Gleason score, and clinical stage. Shimura et al. [98] demonstrated the association between TAM infiltration and disease-free survival after radical prostatectomy. ...
... Decreased infiltration of MSR-positive inflammatory cells in negative first biopsy specimens was correlated with positive findings in the repeat biopsy. MSR count has been, therefore, proposed as a valid index to avoid unnecessary repeat biopsies [97]. Gollapudi et al. [99] have recently shown that mean TAM number was higher in cancer cores versus prostatic intraepithelial neoplasia (PIN) and benign tissue and higher in high-grade prostate cancer supporting the potential role of TAMs in prostate cancer development. ...
Despite years of intensive investigation that has been made in understanding prostate cancer, it remains a major cause of death in men worldwide. Prostate cancer emerges from multiple alterations that induce changes in expression patterns of genes and proteins that function in networks controlling critical cellular events. Based on the exponential aging of the population and the increasing life expectancy in industrialized Western countries, prostate cancer in the elderly men is becoming a disease of increasing significance. Aging is a progressive degenerative process strictly integrated with inflammation. Several theories have been proposed that attempt to define the role of chronic inflammation in aging including redox stress, mitochondrial damage, immunosenescence, and epigenetic modifications. Here, we review the innate and adaptive immune systems and their senescent remodeling in elderly men with prostate cancer.
... Despite increasing incidence, prostate cancer-related mortality rate has been decreasing. This may be explained by the widely-used prostate-specific antigen (PSA) screening as well as novel management approaches (Nonomura et al., 2010). ...
... Yasemin Benderli Cihan¹*, Alaettin Arslan¹, Mehmet Ali Ergul² the incidence of prostate cancer, similar to certain types of cancer (Cheng et al., 2005;Nonomura et al., 2010;Fujita et al., 2012;Sfanos and De Marzo 2012). Nelson and Harris (2000) also reported that the prevalence of symptomatic prostatitis was 9% in men above the age of 40 years, although the prevalence of asymptomatic prostatitis was unknown. ...
Background:
This study aimed to evaluate the baseline white blood cell (WBC), neutrophil, lymphocyte, monocyte, basophil, eosinophil count, total prostate-specific antigen (TPSA), free PSA (FPSA) level, neutrophil- to-lymphocyte and neutrophil-to-monocyte ratios among patients with prostate cancer and benign prostatic hyperplasia (BPH), as well as healthy individuals.
Materials and methods:
2005-2012 laboratory files of 160 patients with prostate cancer at Kayseri Training and Research Hospital, Oncology Outpatient Clinic, 285 patients who were pathologically diagnosed with BPH in Urology Outpatient Clinic and 200 healthy individuals who were admitted to Internal Medicine Outpatient Clinic were retrospectively analyzed. Baseline WBC, neutrophil, lymphocyte, monocyte, basophil, eosinophil count, TPSA, FPSA level, neutrophil-to-lymphocyte ratio and neutrophil-to-monocyte ratio were recorded and compared across groups.
Results:
Patients with prostate cancer had a lower lymphocyte level compared to the patients with BPH and healthy controls (p<0.001). The mean monocyte count, leukocyte-to-monocyte ratio, and leukocyte-to-lymphocyte ratio were higher in patients with prostate cancer, but without significance. The mean WBC and leukocyte count were lower in patients with prostate cancer, but again without statistical significance (p=0.130). The mean TPSA and FPSA were 39.4 and 5.67, respectively in patients with prostate cancer, while they were 5.78 and 1.28 in patients with BPH. There was a significant difference in the mean TPSA and FPSA levels between the patient groups (p<0.001).
Conclusions:
Our study results showed that patients with prostate cancer had a lower level of lymphocytes, neutrophils and WBCs and a higher level of monocytes with a significant difference in lymphocyte count, compared to healthy controls. We suggest that lymphocyte count may be used in combination with other parameters in the diagnosis of prostate cancer, thanks to its ease of assessment.
... Initially, TAMs were shown to participate in the early eradication of tumor cells in vitro (Romieu-Mourez et al., 2006). However, other studies have suggested that TAMs may contribute to carcinogenesis, as there is a positive correlation between increased numbers of TAMs and poor prognosis in some human cancers (Bingle et al., 2002; El-Rouby, 2010; Leek et al., 1996; Lin and Pollard, 2007; Nonomura et al., 2010; Shabo et al., 2008; Sica et al., 2006; Steidl et al., 2010). TAMs can fail to recognize tumor antigens (Fadok et al., 1998) and may release factors that directly stimulate tumor growth and angiogenesis (Lin et al., 2006; Lin and Pollard, 2007). ...
... Also, it is possible that tumors may produce factors that act on TAMs in a paracrine fashion (Balkwill and Mantovani, 2001). A positive correlation between increased numbers of macrophages and poor prognosis in various human cancers has been demonstrated (Bingle et al., 2002; El-Rouby, 2010; Lin and Pollard, 2007; Nonomura et al., 2010; Shabo et al., 2008; Sica et al., 2006; Steidl et al., 2010 ). It is possible that the weaker classical activation state favors production of procarcinogenic growth factors by TAMs. ...
Tumor-associated macrophages (TAMs) may have an important role in tumor immunity. We studied the activation state of TAMs in cutaneous SCC, the second most common human cancer. CD163 was identified as a more abundant, sensitive, and accurate marker of TAMs when compared with CD68. CD163(+) TAMs produced protumoral factors, matrix metalloproteinases 9 and 11 (MMP9 and MMP11), at the gene and protein levels. Gene set enrichment analysis (GSEA) was used to evaluate M1 and M2 macrophage gene sets in the SCC genes and to identify candidate genes in order to phenotypically characterize TAMs. There was coexpression of CD163 and alternatively activated "M2" markers, CD209 and CCL18 (chemokine (C-C motif) ligand 18). There was enrichment for classically activated "M1" genes in SCC, which was confirmed in situ by colocalization of CD163 and phosphorylated STAT1 (signal transducer and activator of transcription 1), IL-23p19, IL-12/IL-23p40, and CD127. Also, a subset of TAMs in SCC was bi-activated as CD163(+) cells expressed markers for both M1 and M2, shown by triple-label immunofluorescence. These data support heterogeneous activation states of TAMs in SCC, and suggest that a dynamic model of macrophage activation would be more useful to characterize TAMs.
... On the other hand, tumor-associated macrophage (TAM) in ltration in the tumor microenvironment is directly associated with tumor invasion, nodal status, and clinical stage in some cancers, and TAMs also have been reported to regulate the growth of prostate cancer [17][18] [19]. A previous study reported that M2 TAMs inhibit cytotoxic CD8 + cell, resulting in weakened anti-tumor immunity and the CD204 silencingenhanced tumor cell death was associated with elevated IFN-γ levels in tumor tissue and increased tumor-in ltrating CD8 + cells [20]. ...
To stratify the heterogeneity of prostate cancer (PCa) with seminal vesicle invasion (SVI) immunologically after radical prostatectomy (RP) focusing on the tumor microenvironment. We retrospectively reviewed the clinicopathological data of 71 PCa patients with SVI, which is known as a factor of very high risk PCa. Preoperative clinical variables and postoperative pathological variables were evaluated as predictors of BCR with a multivariate logistic regression. Immune cell infiltration including the CD8-positive cell (CD8 ⁺ cell) and CD204-positive M2 macrophage (CD204 ⁺ cell) was investigated by immunohistochemistry. The cumulative incidence and risk of BCR were assessed with a Kaplan–Meier analysis and competing risks regression. A higher CD8 ⁺ cell count in the SVI area significantly indicated a favorable prognosis for cancers with SVI (p = 0.004). A lower CD204 ⁺ cell count in the SVI area also significantly indicated a favorable prognosis for cancers with SVI (p = 0.004). Furthermore, the combination of the CD8 ⁺ and CD204 ⁺ cell infiltration ratio of the SVI area to the main tumor area was a significant factor for BCR in the patients with the PCa with SVI (p = 0.001). In PCa patients with SVI, the combination of CD8 ⁺ and CD204 ⁺ cell infiltration is useful to predict the prognosis.
... However, macrophage scavenger receptor (MSR) is only expressed in macrophages, and MSR-positive inflammatory cells are broadly considered as M2-subtype in several types of malignancies, like glioma and ovarian epithelial tumors. In contrast, a sequence deficiency of MSR was initially found in one metastatic PCa sample, and the decreased expression of MSR was a predictor of poor prognosis [72,73]. Immunohistochemistry analysis suggests that MSR labels most M2-macrophages in the PCa biopsy. ...
The morbidity of prostate cancer (PCa) is rising year by year, and it has become the primary cause of tumor-related mortality in males. It is widely accepted that macrophages account for 50% of the tumor mass in solid tumors and have emerged as a crucial participator in multiple stages of PCa, with the huge potential for further treatment. Oftentimes, tumor-associated macrophages (TAMs) in the tumor microenvironment (TME) behave like M2-like phenotypes that modulate malignant hallmarks of tumor lesions, ranging from tumorigenesis to metastasis. Several clinical studies indicated that mean TAM density was higher in human PCa cores versus benign prostatic hyperplasia (BPH), and increased biopsy TAM density potentially predicts worse clinicopathological characteristics as well. Therefore, TAM represents a promising target for therapeutic intervention either alone or in combination with other strategies to halt the “vicious cycle,” thus improving oncological outcomes. Herein, we mainly focus on the fundamental aspects of TAMs in prostate adenocarcinoma, while reviewing the mechanisms responsible for macrophage recruitment and polarization, which has clinical translational implications for the exploitation of potentially effective therapies against TAMs.
... This showed a correlation between increase in tumor volume with decrease in MTMs [28,29]. Further studies could prove that there is a correlation between the aggressiveness of the prostate tumor and an increased occurrence of TAMs [11,30]. The exact role of TAMs in different types of cancers has not been fully clarified. ...
Simple Summary
Magnetic resonance imaging (MRI) is a non-invasive method and can be used to diagnose prostate cancer (PCa). Due to their high biological safety, iron oxide nanoparticles are becoming increasingly important as contrast agents for MRI. Macrophages are able to take up these iron particles, which leads to a loss of signal in T2- and T2*-weighted images during MRI. Macrophages play an important role in the development and progression of prostate cancer. In this article, ferumoxytol is visualized at two different PCa volumes on MRI in a xenograft mouse model. Ferumoxytol is a superparamagnetic iron oxide probe and was used here as a contrast agent. The in vivo data were correlated with histological data. When using ferumoxytol, we found that small tumors took up more ferumoxytol than larger tumor volumes. These results were obtained in vivo as well as ex vivo.
Abstract
Prostate cancer (PCa) is one of the most common cancers in men. For detection and diagnosis of PCa, non-invasive methods, including magnetic resonance imaging (MRI), can reduce the risk potential of surgical intervention. To explore the molecular characteristics of the tumor, we investigated the applicability of ferumoxytol in PCa in a xenograft mouse model in two different tumor volumes, 500 mm³ and 1000 mm³. Macrophages play a key role in tumor progression, and they are able to internalize iron-oxide particles, such as ferumoxytol. When evaluating T2*-weighted sequences on MRI, a significant decrease of signal intensity between pre- and post-contrast images for each tumor volume (n = 14; p < 0.001) was measured. We, furthermore, observed a higher signal loss for a tumor volume of 500 mm³ than for 1000 mm³. These findings were confirmed by histological examinations and laser ablation inductively coupled plasma-mass spectrometry. The 500 mm³ tumors had 1.5% iron content (n = 14; σ = 1.1), while the 1000 mm³ tumors contained only 0.4% iron (n = 14; σ = 0.2). In vivo MRI data demonstrated a correlation with the ex vivo data (R² = 0.75). The results of elemental analysis by inductively coupled plasma-mass spectrometry correlated strongly with the MRI data (R² = 0.83) (n = 4). Due to its long retention time in the blood, biodegradability, and low toxicity to patients, ferumoxytol has great potential as a contrast agent for visualization PCa.
... On the other hand, tumor-associated macrophage (TAM) infiltration in the tumor microenvironment is directly associated with tumor invasion, nodal status, and clinical stage in some cancers, and TAMs also have been reported to regulate the growth of prostate cancer [18][19][20] . A previous study reported that M2 TAMs inhibit cytotoxic CD8 + cell, resulting in weakened anti-tumor immunity and increased tumor-infiltrating CD8 + cells 21 . ...
To stratify the heterogeneity of prostate cancer (PCa) with seminal vesicle invasion (SVI) immunologically after radical prostatectomy focusing on the tumor microenvironment. We retrospectively reviewed the clinicopathological data of 71 PCa patients with SVI, which is known as a factor of very high-risk PCa. Preoperative clinical variables and postoperative pathological variables were evaluated as predictors of biochemical recurrence (BCR) with a multivariate logistic regression. Immune cell infiltration including the CD8-positive cell (CD8+ cell) and CD204-positive M2-like macrophage (CD204+ cell) was investigated by immunohistochemistry. The cumulative incidence and risk of BCR were assessed with a Kaplan–Meier analysis and competing risks regression. A higher CD8+ cell count in the SVI area significantly indicated a favorable prognosis for cancers with SVI (p = 0.004). A lower CD204+ cell count in the SVI area also significantly indicated a favorable prognosis for cancers with SVI (p = 0.004). Furthermore, the combination of the CD8+ and CD204+ cell infiltration ratio of the SVI area to the main tumor area was a significant factor for BCR in the patients with the PCa with SVI (p = 0.001). In PCa patients with SVI, the combination of CD8+ and CD204+ cell infiltration is useful to predict the prognosis.
... It has been recognized that inflammation increases the risk of PCa, similar to some other cancers. [10,11] A lot of oxidative materials are released by inflammatory cells that may cause cellular and gene damage, ultimately leading to gene mutations and PCa. These findings have been confirmed by epidemiologic and molecular biology studies. ...
It has been reported that inflammation and immune system are related to prostate cancer. The neutrophil-to-lymphocyte ratio (NLR), as well as the platelet-to-lymphocyte ratio (PLR), have already been proposed as new indices to help diagnose prostate cancer (PCa). However, the monocyte-to-lymphocyte ratio (MLR) with regard to PCa has rarely been mentioned.
To investigate the capability of the MLR to predict PCa.
Patients who were pathologically diagnosed with PCa in our hospital and healthy control subjects who conformed to the inclusion criteria were enrolled. Patient data were recorded, including age, complete blood counts, blood biochemistry, and serum prostate-specific antigen (PSA) levels. The differences in these data between the groups were analyzed and the diagnostic value of the MLR was compared with PSA.
Our study included a total of 100 patients with PCa and 103 healthy control subjects. Patients with PCa presented with a significantly higher NLR, MLR, and PLR compared to control subjects. However, the hemoglobin and lymphocyte levels were lower (P < .05) in PCa patients. The area under the curve (AUC) of PSA and ratio of free/total serum prostate-specific antigen were 0.899 (95% confidence interval [CI]: 0.857–0.942) and 0.872 (95% CI: 0.818–0.926), respectively, while the AUC of the MLR was 0.852 (95% CI: 0.798–0.906), which was higher than that of the NLR, PLR, and any other blood parameters. Additionally, the optimal cut-off value of the MLR for PCa was 0.264, with a specificity of 87.4% and a sensitivity of 72.0%. An evaluation of the diagnostic value of MLR + PSA gave an AUC of 0.936 (95% CI: 0.902–0.970). However, the AUC of MLR + PSA + f/tPSA was 0.996 (95% CI: 0.991–1.000). The diagnostic value of MLR + NLR + PSA gave an AUC of 0.945 (95% CI: 0.913–0.977), and the specificity is 0.971.
PSA remains the most important diagnostic indicator. MLR combined with PSA and f/tPSA has the higher predictive value than PSA. It suggests that MLR may be another good predictive indicator of PCa. It can help reduce the clinical false positive rate.
... TMA of 192 prostate cancer samples from the USA cohort revealed greater amount of CD206+ TAMs in primary adenocarcinoma and lymphatic metastases in comparison to benign prostate tissues (269). IHC analysis of 373 prostate biopsy samples (Japanese cohort) demonstrated significantly lower numbers CD204+ TAMs in cases with prostate cancer in comparison to benign specimens (270). Negative correlation between the density of CD204+ TAMs and the clinical T stage was confirmed in the retrospective study of 135 PC patients from the Japanese cohort (259). ...
Tumor-associated macrophages (TAMs) are major innate immune cells that constitute up to 50% of the cell mass of human tumors. TAMs are highly heterogeneous cells that originate from resident tissue-specific macrophages and from newly recruited monocytes. TAMs’ variability strongly depends on cancer type, stage, and intratumor heterogeneity. Majority of TAMs are programmed by tumor microenvironment to support primary tumor growth and metastatic spread. However, TAMs can also restrict tumor growth and metastasis. In this review, we summarized the knowledge about the role of TAMs in tumor growth, metastasis and in the response to cancer therapy in patients with five aggressive types of cancer: breast, colorectal, lung, ovarian, and prostate cancers that are frequently metastasize into distant organs resulting in high mortality of the patients. Two major TAM parameters are applied for the evaluation of TAM correlation with the cancer progression: total amount of TAMs and specific phenotype of TAMs identified by functional biomarkers. We summarized the data generated in the wide range of international patient cohorts on the correlation of TAMs with clinical and pathological parameters of tumor progression including lymphatic and hematogenous metastasis, recurrence, survival, therapy efficiency. We described currently available biomarkers for TAMs that can be measured in patients’ samples (tumor tissue and blood). CD68 is the major biomarker for the quantification of total TAM amounts, while transmembrane receptors (stabilin-1, CD163, CD206, CD204, MARCO) and secreted chitinase-like proteins (YKL-39, YKL-40) are used as biomarkers for the functional TAM polarization. We also considered that specific role of TAMs in tumor progression can depend on the localization in the intratumoral compartments. We have made the conclusion for the role of TAMs in primary tumor growth, metastasis, and therapy sensitivity for breast, colorectal, lung, ovarian, and prostate cancers. In contrast to other cancer types, majority of clinical studies indicate that TAMs in colorectal cancer have protective role for the patient and interfere with primary tumor growth and metastasis. The accumulated data are essential for using TAMs as biomarkers and therapeutic targets to develop cancer-specific immunotherapy and to design efficient combinations of traditional therapy and new immunomodulatory approaches.
... In this regard, re-education of TAMs toward a pro-inflammatory, anti-tumorigenic functional status has been recently proposed as a potential therapeutic approach to treat different types of cancer, including prostate cancer (Guerriero et al., 2017;Hagemann et al., 2009;Pyonteck et al., 2013;Salvagno et al., 2019). In prostate cancer the frequency and activation state of infiltrating macrophages have been associated with disease progression and therapy resistance (Escamilla et al., 2015;Lanciotti et al., 2014;Nonomura et al., 2010). Nevertheless, current knowledge on the interplay between macrophages and prostate cancer is still limited, and further investigation is required. ...
Tumor-associated macrophages (TAMs) represent a major component of the tumor microenvironment supporting tumorigenesis. TAMs re-education has been proposed as a strategy to promote tumor inhibition. However, whether this approach may work in prostate cancer is unknown. Here we find that Pten-null prostate tumors are strongly infiltrated by TAMs expressing C-X-C chemokine receptor type 2 (CXCR2), and activation of this receptor through CXCL2 polarizes macrophages toward an anti-inflammatory phenotype. Notably, pharmacological blockade of CXCR2 receptor by a selective antagonist promoted the re-education of TAMs toward a pro-inflammatory phenotype. Strikingly, CXCR2 knockout monocytes infused in Ptenpc−/−; Trp53pc−/− mice differentiated in tumor necrosis factor alpha (TNF-α)-releasing pro-inflammatory macrophages, leading to senescence and tumor inhibition. Mechanistically, PTEN-deficient tumor cells are vulnerable to TNF-α-induced senescence, because of an increase of TNFR1. Our results identify TAMs as targets in prostate cancer and describe a therapeutic strategy based on CXCR2 blockade to harness anti-tumorigenic potential of macrophages against this disease. : Di Mitri et al. show that CXCR2 blockade in prostate cancer triggers TAMs re-education, leading to tumor inhibition. CXCR2-KO monocytes infused in Ptenpc−/−; Trp53pc−/− tumor-bearing mice differentiate into TNFα-releasing pro-inflammatory macrophages that induce senescence in tumor cells. PTEN-null tumors display higher sensitivity to TNF-α-induced senescence because of TNFR1 upregulation. Keywords: prostate cancer, tumor immunology, immunomodulation, immune response to cancer, tumor associated macrophages
... 3,4 Increasing evidence suggests that macrophages function as specific effector cells in cancer immunotherapy, and their degree of tumour infiltration is correlated with prognostic outcomes in many different types of cancer. 5,6 The primary aim of this present study was to investigate the extent of macrophage infiltration in benign and malignant ureteral polyps. The secondary aim was to observe the relationship between macrophages and T-lymphocyte subtypes in the pathological process of ureteral diseases. ...
Objective
To evaluate the role of macrophage infiltration in the differentiation process of ureteral polyps and cancers.
Methods
This retrospective immunohistochemical study analysed archival samples of pathologically-confirmed specimens of low- and high-grade ureteral cancer, ureteral papilloma and ureteral polyps. The samples were immunohistochemically stained for cluster of differentiation (CD)4, CD8, CD16, CD25, CD56 and CD68 using immunofluorescence in order to identify different T-lymphocyte populations and macrophages.
Results
A total of 70 specimens were included in the analysis: 21 specimens of ureteral cancer, 17 specimens of ureteral papilloma, and 32 specimens of ureteral polyps. The largest proportion of CD4+CD25+ regulatory T cells was observed in the low-grade ureteral cancer group and almost none were observed in ureteral papillomas. The largest proportion of CD8+ cytotoxic T-lymphocytes was observed in the ureteral polyps. The largest proportion of CD56+ natural killer cells was detected in the ureteral polyps, with very low levels observed in the other three groups. The largest proportion of CD16+CD68+ macrophages was observed in the high-grade ureteral cancer group, which was significantly higher than that observed in the ureteral papillomas.
Conclusions
This study revealed that CD16+CD68+ macrophages appear to participate in ureteral neoplastic transformation.
... Nonsense and missense mutations of MSR1 were identified to be associated with increased Pca risk [25]. Intriguingly, recent clinical studies indicate that increased MSR1 expression is correlated with good prognosis in Pca [26,27]. In current study, we systematically reviewed the relevant literature and performed a meta-analysis to determine the prognostic value of the level of TAMs and MSR1 in Pca. ...
Recent studies suggested that the tumour associated macrophages may be associated with prostate cancer outcome. A meta-analysis was performed to evaluate the prognostic value of tumor associated macrophages and macrophage scavenger receptor 1, marker for a subset of macrophages, by pooled hazard ratio and 95% confidence intervals from qualified studies following a systemic search. The results indicate that higher infiltration of tumor associated macrophages predicts poor overall survival (HR=1.57, 95%CI: 1.15-1.98), but not biochemical recurrence (HR=1.01, 95%CI: 0.98-1.04) or recurrence-free survival (HR=1.03, 95%CI: 0.05-2.01). In contrast, elevated level of macrophage scavenger receptor 1 was significantly associated with better recurrence-free survival (HR=3.26, 95%CI: 1.22-5.29). Thus, our analysis confirmed the prognostic value of these markers in prostate cancer outcome. We also discussed potential causes of the controversies in the literature and future research directions.
... Bu bulgumuz Afrika kökenli Amerikalılarla yapılan ve nötropenik (<1500 10 3 /mkrL) hastalarda daha az diferansiye PCa olma riski olduğunu gösteren çalışma ile de uyumlu görünmektedir 14,15 . İmmünhistokimyasal sonuçların değerlendirildiği bir çalışmada ise, ilk TRUS biyopside azalmış makrofaj infiltrasyonunun tekrarlanan pozitif biyopsi ile ilişkili olduğunu göstermiştir 16 . Prostat kanser hücrelerinden salgılanan IL-8 ve epitelyal nötrofil aktive edici faktör-78'in nötrofil düzeyini etkilediği düşünülmektedir 17 . ...
We aimed to evaluate, if complete blood counts (CBC) evaluated before prostate biopsy could predict the result of the prostate biopsy performed due to the increased PSA levels. We retrospectively reviewed the data of 281 patients who had undergone prostate biopsy because of the increased levels of PSA in three university hospital. Patient’s age, pre-biopsy CBC, total PSA, free PSA, prostate volume and biopsy results were recorded. Patients were grouped according to the prostate biopsy results as; I: prostate cancer, II: Benign prostate hiperplasia, III: chronic prostatitis. We invastigated whether CBC counts and their ratios of this counts have any statistically significant predictive value in the three groups. A statistically significant difference was detected among the three groups regarding platelet count, neutrophil/monocyte (NMR) and platelet/lymphocyte ratios (PLR). The patelet count and PLRs were significantly higher in Group III rather than Groups I and II. Also the NMR was significantly higher in Group III than Group II. We have shown that pre-biopsy platelet count, NMR and PLR could predict thethe outcome of chronic prostatitis who had undergone prostate biopsy because of the increased levels of PSA. Furthermore, prospective case-controlled, large studies would be helpful to explore the predictive value of CBC on the prostate biopsy results.
... However, the clinical significance of TAM infiltrates in prostate cancer remains controversial. Kiran el al reported that the mean number of TAMs was higher in prostate cancer than in benign tissue [31], whereas Norio et al reported the opposite result [32]. In the present study, we observed increased macrophage infiltration in prostate cancer and BPH with chronic inflammation compared with benign tissue. ...
Tumor development and progression are influenced by macrophages of the surrounding microenvironment. To investigate the influences of an inflammatory tumor microenvironment on the growth and metastasis of prostate cancer, the present study used a co-culture model of prostate cancer (PCa) cells with tumor-associated macrophage (TAM)-conditioned medium (MCM). MCM promoted PCa cell (LNCaP, DU145 and PC-3) growth, and a xenograft model in nude mice consistently demonstrated that MCM could promote tumor growth. MCM also stimulated migration and invasion in vitro. Somatostatin derivate (smsDX) significantly attenuated the TAM-stimulated proliferation, migration and invasion of prostate cancer. Immunohistochemistry revealed that NF-κB was over-expressed in PCa and BPH with chronic inflammatory tissue specimens and was positively correlated with macrophage infiltration. Further investigation into the underlying mechanism revealed that NF-κB played an important role in macrophage infiltration. SmsDX inhibited the paracrine loop between TAM and PCa cells and may represent a potential therapeutic agent for PCa.
Objectives:
In this study we compared neutrophil-to-lymphocyte ratio (NLR) and neutrophilto- monocyte ratio(NMR) between patients with prostate cancer after first transrectal ultrasound (TRUS)- guided biopsy and patients with benign prostate hyperplasia(BPH) after second TRUS-guided biyopsy.
Methods:
A total of 224 patients who underwent multi (≥12)-core TRUS -guided biopsy at our clinic for elevated PSA or abnormal digital rectal examination in between January 2008 and March 2015 were retrospectively analyzed. There were 2 groups. Group 1 consisted of 146 patients with a diagnosis of prostate cancer after the first TRUSguided biyopsy and group 2 consisted of 78 patients with a diagnosis of benign prostate hyperplasia after second TRUS-guided biyopsy. Age, PSA, NLR and NMR values were compared between the two groups.
Results:
There were no statistically significant correlation between PSA and NLR(p=0.46). The mean of age, PSA, NLR, NMR values in the group 1 and 2 were respectively 64.6±7.7 and 61.6±6.9, 6.5±1.9 and 5.3±1.2, 2.8±1.5 and 2.3±1.1, 9.2±3.9, 8.1±2.9 (p=0.03, p=0.001, p=0.012 and p=0.30). The mean PSA, NLR ,NMR values of the group 1 were significantly higher than those in group 2 (p=0.002). Gleason grade and pathological stage were significantly increases as NLR increases.
Conclusion:
NLR and NMR in patients with BPH after second TRUS-guided biopsy were lower than that of those with a diagnosis of prostate cancer after the first TRUS-guided biopsy.White blood test subtypes can be considered for the decision to perform a second TRUSguided biopsy in patients with previous negative biopsy with persistently elevated PSA.
Scavenger receptor A (SRA), also called CD204, is a phagocytic pattern recognition receptor primarily expressed on myeloid cells, such as macrophages and dendritic cells. Over the past 20 years, tremendous advances have been made in elucidating the diverse functions of SRA/CD204 in different cellular processes, including lipid metabolism, recognition and clearance of pathogens or modified self molecules, as well as immune homeostasis. In this chapter, we examine the current understanding of the important roles of SRA/CD204 in inflammatory responses, cytokine production, host defense and pathogenesis of diseases. We highlight a previously unrecognized feature of SRA/CD204 action in the attenuation of adaptive immune responses and tumor immunity. The molecular details of functional interference of toll-like receptor-elicited inflammatory signaling cascades by SRA/CD204 are also discussed. It is believed that a better understanding of the physiological functions of SRA/CD204 will lead to new opportunities for therapeutic intervention in cancer, cardiovascular disease and other diseases characterized by chronic inflammation.
Background:
The aims of this study were to investigate the utility of red blood cell distribution width (RDW) as a simple and readily available marker in prostate cancer, as well as to evaluate RDW as a predictor of progression in prostate cancer patients.
Materials and methods:
We evaluated 62 newly diagnosed prostate cancer patients who underwent transrectal ultrasound (TRUS)-guided biopsy and 62 healthy controls of mean age 64 (range, 45-75) years at the Urology Clinic of Bozok University Hospital. Data collection was performed using our laboratory information system database to retrieve findings regarding RDW, hemoglobin, prostate- specific antigen (PSA), and age. The RDW values were compared between the healthy control group and prostate cancer patients. A high risk of progression as defined as a Gleason score (GS) >6, total number of cores positive for cancer >33%, each core containing >50% cancer cells, and a prostate-specific antigen (PSA) level >10 ng/ mL. Patients were classified according to risk of progression, as well as divided into subgroups according to the RDW quartile.
Results:
The mean RDW value of prostate cancer patients was 14.6, compared with 13.7 in the healthy control group (p=0.001). A higher RDW was associated with an increased risk of progression, whereas a lower RDW value was correlated with a low risk of progression.
Conclusions:
RDW is an easily derived measure that might, in combination with other markers, help predict prostate cancer risk and progression. We suggest that RDW may be used in combination with other parameters in the assessment of prostate cancer.
Evidence suggests that CD204-positive (CD204(+)) tumor-infiltrating macrophages are associated with aggressive behavior of various cancers; however, the clinical, pathological, and prognostic associations of tumor-infiltrating CD204(+) macrophages in urothelial cancer have not been reported.
A tissue microarray was constructed from the centers and peripheries of 171 upper urinary tract cancers treated with nephroureterectomy. CD204 immunohistochemistry was performed. The density of CD204(+) cells was calculated using image analysis software, and survival analyses were performed using the Kaplan-Meier method and multivariate Cox proportional hazards regression models.
High CD204(+) cell density at the centers and peripheries of tumors was significantly associated with several adverse prognostic factors, including sessile architecture, histological high-grade, presence of lymphovascular invasion, concomitant carcinoma in situ, higher tumor stage, and lymph node metastasis. High CD204(+) cell density was significantly associated with shorter metastasis-free and cancer-specific survival (log-rank p < 0.001) and shorter metastasis-free survival in multivariate analysis.
A high density of tumor-infiltrating CD204(+) macrophages was associated with aggressive behavior of upper urinary tract cancer. Our results suggest that a specific immune microenvironment may be associated with the biological behavior of urothelial cancer and that CD204 may serve as a novel prognostic biomarker for these tumors.
Importance of the field:
Prostate cancer is a common and multifocal disease but the diagnostic methods available are unsatisfactory. Most tumors present are of low malignant potential, whereas others are highly aggressive. At present, imaging cannot be used to guide tissue biopsies safely towards the most aggressive tumor present. To handle this problem multiple needle biopsies are taken. The biopsies often contain only normal prostate tissue, and even if the tumor is sampled it is not known whether a more aggressive cancer is present elsewhere in the organ. If changes in the normal tissue indicate the presence and nature of tumors, this information could be used to improve diagnostics and prognostics of prostate cancer.
Areas covered in this review:
Current evidence that the tumor-adjacent morphologically normal prostate tissue is not completely normal is reviewed, and that this tissue, named tumor indicating normal tissue (TINT) by the authors, can be used to diagnose prostate cancer.
What the reader will gain:
The reader will understand that tumors need to affect their surroundings in order to grow and metastasize and that the normal prostate tissue is therefore tinted by the presence and nature of cancer and that this knowledge can be used to develop new diagnostic and prognostic markers.
Take home message:
TINT changes could probably, when more rigorously defined and validated, be used to diagnose and prognosticate prostate cancer.
Background:
Asymptomatic prostatic inflammation may cause increased PSA in some men, leading to unnecessary prostate biopsy. We investigated whether the differential white cell count could predict the result of prostate biopsy.
Methods:
Prostate needle biopsy was carried out in 323 Japanese men with elevated PSA levels or abnormal digital rectal findings. White blood cell count (WBC), differential white cell count (neutrophils, lymphocytes, basophils, eosinophils, and monocytes), and serum C-reactive protein level were assessed for associations with biopsy findings.
Results:
In all, 203 (62.1%) were positive for prostate cancer. WBC, neutrophil count, age, PSA, prostate volume, and PSA density (PSAD) were associated with the results of biopsy (P<0.05). Multivariate analysis showed that neutrophil count, age, PSA, prostate volume and PSAD were independent predictors. When the cut-off neutrophil count was set at 2900 μl(-1), 78 of 104 men (75.0%) with a count below this value had a positive biopsy, while 125 of 219 (57.0%) men with a count above this value were positive. The area under the receiver-operator characteristics curve (AUC) for the predicted probability of a positive biopsy for prostate cancer according to the optimum logistic model was 0.83 (95% confidence interval (CI) 0.78-0.87), while the AUC for PSA was 0.70 (95% CI 0.64-0.76) and that for PSAD was 0.79 (95% CI 0.74-0.84).
Conclusions:
An elevated neutrophil count may be a good indicator of a benign prostate biopsy. Men with a low neutrophil count and an increase of serum PSA should strongly be considered for biopsy.
Field cancerization denotes the occurrence of genetic, epigenetic, and biochemical aberrations in structurally intact cells in histologically normal tissues adjacent to cancerous lesions. This paper tabulates markers of prostate field cancerization known to date and discusses their potential clinical value in the analysis of prostate biopsies, including diagnosis, monitoring progression during active surveillance, and assessing efficacy of presurgical neoadjuvant and focal therapeutic interventions.
Macrophage cells derived from the human monocytic leukemia cell line, THP-1, accumulate esterified cholesterol when cultivated in the presence of acetylated low density lipoprotein (Ac-LDL) through scavenger receptors (ScR). In the present study, we isolated a subtype of THP-1 cells that failed to accumulate esterified cholesterol when cultivated in the presence of Ac-LDL. The cells had negligible amounts of cell association and degradation of Ac-LDL compared with the parent THP-1 cells. The subtype THP-1 cells did not express ScR mRNA as well as that of lipoprotein lipase. In contrast, the expression of apolipoprotein E mRNA was greater than that found in parent THP-1 cells. The culture medium of subtype THP-1 cells treated with 12-O-tetradecanoylphorbol-13-acetate inhibited the uptake of Ac-LDL and the expression of ScR in parent THP-1 cells. After a 48-h incubation in the culture medium containing 12-O-tetradecanoylphorbol-13-acetate, the culture medium of differentiated subtype THP-1 cells contained 6.9 ng/ml transforming growth factor (TGF)-beta 1, while that of parent THP-1 cells secreted below detection level, which was less than 3 ng/ml. This inhibitory effect of the conditioned medium on the expression of ScR in parent THP-1 cells was abolished by pretreatment of the culture medium with anti-TGF-beta 1 antibodies. Parent THP-1 cells expressed as much TGF-beta 1 mRNA as sTHP-1 cells after stimulation of differentiation. Although the precursor forms of TGF-beta 1 that were synthesized in both parent and subtype THP-1 cells were of similar size and were expressed at similar levels, latent TGF-beta 1-binding protein, which is necessary for the secretion of TGF-beta 1, could only be co-immunoprecipitated with anti-TGF-beta 1 antibody from subtype THP-1 cells. This suggests that subtype THP-1 cells secrete TGF-beta 1 into the medium by forming a functional complex with the latent TGF-beta 1-binding protein. We conclude that subtype THP-1 cells could not take up Ac-LDL because ScR was inhibited (leading to a loss of function) caused by the secreted TGF-beta 1.
Tumor-associated macrophages (TAMs) are highly active immune effector cells that may either positively or negatively regulate the growth of various malignant cells, depending on the biological context. However, the role of TAMs in human prostate cancer progression is unclear. TAMs were immunohistochemically labeled using a monoclonal (CD68) antibody in radical prostatectomy specimens derived from 81 prostate cancer patients. CD68-positive cells were counted with the aid of a microscope and expressed as macrophage index (MphiI), including TAMs/mm2 total tumor tissue (MphiItotal), TAMs/mm2 tumor stroma (MphiIstroma), and TAMs/mm2 cancer cell area (MphiIcancer). MphiIs were analyzed in association with patients' clinical and pathological stage, recurrence status, and histological grade of the cancer. There were significant inverse relationships between MphiItotal and MphiIstroma and clinical stage (P = 0.016 and P = 0.006, respectively). Reduced MphiItotal was also associated with the presence of positive lymph nodes (P = 0.010). Interestingly, although all of the MphiIs differed between Gleason score groups, only MphiIcancer was positively associated with Gleason score. Univariate analysis of MphiItotal and multivariate analysis of MphiItotal with specific pathological markers revealed that MphiItotal was an independent predictor for disease-free survival after surgery (Cox proportional hazard model, P = 0.044 and P = 0.007, respectively). For patients with high MphiItotal (> or = 185.8, the mean MphiItotal value), the disease-free probability 5 years after surgery was 0.75, which was significantly higher than for those with low MphiItotal (0.31, P = 0.0008). Additional immunohistochemical studies that evaluated cytotoxicity-related biomarkers in stroma-associated mononuclear cells suggested reduced functional activities in highly aggressive prostate cancer compared with less aggressive disease. Our results indicate that reduced MphiItotal is a novel prognostic marker for prostate cancer.
Deletions on human chromosome 8p22-23 in prostate cancer cells and linkage studies in families affected with hereditary prostate cancer (HPC) have implicated this region in the development of prostate cancer. The macrophage scavenger receptor 1 gene (MSR1, also known as SR-A) is located at 8p22 and functions in several processes proposed to be relevant to prostate carcinogenesis. Here we report the results of genetic analyses that indicate that mutations in MSR1 may be associated with risk of prostate cancer. Among families affected with HPC, we identified six rare missense mutations and one nonsense mutation in MSR1. A family-based linkage and association test indicated that these mutations co-segregate with prostate cancer (P = 0.0007). In addition, among men of European descent, MSR1 mutations were detected in 4.4% of individuals affected with non-HPC as compared with 0.8% of unaffected men (P = 0.009). Among African American men, these values were 12.5% and 1.8%, respectively (P = 0.01). These results show that MSR1 may be important in susceptibility to prostate cancer in men of both African American and European descent.
Rare germline mutations of macrophage scavenger receptor 1 (MSR1) gene were reported to be associated with prostate cancer risk in families with hereditary prostate cancer (HPC) and in patients with non-HPC (Xu et al. 2002). To further evaluate the role of MSR1 in prostate cancer susceptibility, at Johns Hopkins Hospital, we studied five common variants of MSR1 in 301 patients with non-HPC who underwent prostate cancer treatment and in 250 control subjects who participated in prostate cancer-screening programs and had normal digital rectal examination and PSA levels (<4 ng/ml). Significantly different allele frequencies between case subjects and control subjects were observed for each of the five variants (P value range.01-.04). Haplotype analyses provided consistent findings, with a significant difference in the haplotype frequencies from a global score test (P=.01). Because the haplotype that is associated with the increased risk for prostate cancer did not harbor any of the known rare mutations, it appears that the observed association of common variants and prostate cancer risk are independent of the effect of the known rare mutations. These results consistently suggest that MSR1 may play an important role in prostate carcinogenesis.
Recent data have expanded the concept that inflammation is a critical component of tumour progression. Many cancers arise from sites of infection, chronic irritation and inflammation. It is now becoming clear that the tumour microenvironment, which is largely orchestrated by inflammatory cells, is an indispensable participant in the neoplastic process, fostering proliferation, survival and migration. In addition, tumour cells have co-opted some of the signalling molecules of the innate immune system, such as selectins, chemokines and their receptors for invasion, migration and metastasis. These insights are fostering new anti-inflammatory therapeutic approaches to cancer development.
The class A macrophage scavenger receptor (SR-A) is expressed in antigen presenting cells and is involved in host immune responses. Germ-line mutation of this gene has been associated with increased risk of human prostate cancer. However, there is little known about its expression in normal or neoplastic human prostate tissues. Double immunofluorescent labeling with monoclonal antibodies to SR-A and specific macrophage and dendritic cell markers was used to identify cells expressing SR-A in human prostate tissues. SR-A immunohistochemical staining was performed on paraffin sections of normal prostate, prostatic intraepithelial neoplasia (PIN) lesions, and prostate cancers from radical prostatectomy specimens. SR-A was expressed in a subset of macrophages and dendritic cells that infiltrated prostatic tissues. The majority of SR-A-positive cells coexpressed CD68, and a relatively low percentage expressed S100 protein. The number of SR-A-positive cells was significantly increased in PIN as compared with normal prostatic tissue (P = 0.0176). In contrast, the number of SR-A-positive cells decreased with tumor progression. A lower SR-A-positive cell density was associated with higher clinical stage (rho = -0.26; P = 0.0234). Inverse associations were also found between SR-A density and positive lymph nodes (rho = -0.23; P = 0.0437), tumor size (rho = -0.31; P = 0.0100) and preoperative PSA levels (rho = -0.32; P = 0.0057). SR-A density is a significant predictor of disease-free survival after surgery univariately (P = 0.0003), as well as multivariately, adjusted for known clinical and pathological markers including preoperative prostate-specific antigen, clinical stage, Gleason score, surgical margin, extraprostatic extension, and seminal vesicle invasion, as well as lymph node metastasis (P = 0.0021). The preferential accumulation of SR-A-positive cells in PIN suggests a role for SR-A in the APC response to early malignancy. A reduction in the number of SR-A-positive cells demarcates tumor progression as indicated by clinical and pathological correlations. Our results additionally indicate that systematic measurement of SR-A density is a strong prognostic marker for clinical outcome after surgery.
Prostate cancer remains a significant health concern for men throughout the world. Recently, there has developed an expanding multidisciplinary body of literature suggesting a link between chronic inflammation and prostate cancer. In support of this hypothesis, population studies have found an increased relative risk of prostate cancer in men with a prior history of certain sexually transmitted infections or prostatitis. Furthermore, genetic epidemiological data have implicated germline variants of several genes associated with the immunological aspects of inflammation in modulating prostate cancer risk. The molecular pathogenesis of prostate cancer has been characterized by somatic alterations of genes involved in defenses against inflammatory damage and in tissue recovery. A novel putative prostate cancer precursor lesion, proliferative inflammatory atrophy, which shares some molecular traits with prostate intraepithelial neoplasia and prostate cancer, has been characterized. Here, we review the evidence associating chronic inflammation and prostate cancer and consider a number of animal models of prostate inflammation that should allow the elucidation of the mechanisms by which prostatic inflammation could lead to the initiation and progression of prostate cancer. These emerging insights into chronic inflammation in the etiology of prostate carcinogenesis hold the promise of spawning new diagnostic and therapeutic modalities for men with prostate cancer.
About 20% of all human cancers are caused by chronic infection or chronic inflammatory states. Recently, a new hypothesis has been proposed for prostate carcinogenesis. It proposes that exposure to environmental factors such as infectious agents and dietary carcinogens, and hormonal imbalances lead to injury of the prostate and to the development of chronic inflammation and regenerative 'risk factor' lesions, referred to as proliferative inflammatory atrophy (PIA). By developing new experimental animal models coupled with classical epidemiological studies, genetic epidemiological studies and molecular pathological approaches, we should be able to determine whether prostate cancer is driven by inflammation, and if so, to develop new strategies to prevent the disease.
BACKGROUND
Prostate tumors express high levels of transforming growth factor‐β1 (TGF‐β1) and seem to acquire resistance to its antiproliferative effects with tumor progression. Moreover, TGF‐β1 could be involved in tumor‐promoting processes such as angiogenesis, cell migration, and immunosuppression.
METHODS
Immunoreactivity for TGF‐β1 and its receptors type I and type II (TGFβ‐RI and TGFβ‐RII), tumor vascular count, and cell proliferation were studied in 73 cases of prostate cancer, diagnosed between 1975–1983 and followed with surveillance.
RESULTS
Patients with tumor overproduction of TGF‐β1 had shorter median cancer‐specific survival than patients with normal TGF‐β1 immunoreactivity (5.0 vs. 10 years, P = 0.006). Furthermore, increased TGF‐β1 staining was associated with tumor grade, high vascular counts, and metastasis (P = 0.02, 0.02, and 0.01, respectively). Patients with loss of tumor TGFβ‐RII expression in combination with TGF‐β1 overproduction showed particularly short survival (2.6 vs. 10 years, P = 0.0000), when compared to patients with normal immunoreactivity.
CONCLUSIONS
Overproduction of TGF‐β1 and loss of TGFβ‐RII expression are associated with poor clinical outcome in prostate cancer, and TGF‐β1 may promote tumor progression by stimulating angiogenesis and metastasis. Prostate 37:19–29, 1998. © 1998 Wiley‐Liss, Inc.
Prostate tumors express high levels of transforming growth factor-β1 (TGF-β1) and seem to acquire resistance to its antiproliferative effects with tumor progression. Moreover, TGF-β1 could be involved in tumor-promoting processes such as angiogenesis, cell migration, and immunosuppression.
Immunoreactivity for TGF-β1 and its receptors type I and type II (TGFβ-RI and TGFβ-RII), tumor vascular count, and cell proliferation were studied in 73 cases of prostate cancer, diagnosed between 1975–1983 and followed with surveillance.
Patients with tumor overproduction of TGF-β1 had shorter median cancer-specific survival than patients with normal TGF-β1 immunoreactivity (5.0 vs. 10 years, P = 0.006). Furthermore, increased TGF-β1 staining was associated with tumor grade, high vascular counts, and metastasis (P = 0.02, 0.02, and 0.01, respectively). Patients with loss of tumor TGFβ-RII expression in combination with TGF-β1 overproduction showed particularly short survival (2.6 vs. 10 years, P = 0.0000), when compared to patients with normal immunoreactivity.
Overproduction of TGF-β1 and loss of TGFβ-RII expression are associated with poor clinical outcome in prostate cancer, and TGF-β1 may promote tumor progression by stimulating angiogenesis and metastasis. Prostate 37:19–29, 1998.
The class A macrophage scavenger receptor (SR-A) is expressed in antigen presenting cells and is involved in host immune responses. Germ-line mutation of this gene has been associated with increased risk of human prostate cancer. However, there is little known about its expression in normal or neoplastic human prostate tissues. Double immunofluorescent labeling with monoclonal antibodies to SR-A and specific macrophage and dendritic cell markers was used to identify cells expressing SR-A in human prostate tissues. SR-A immunohistochemical staining was performed on paraffin sections of normal prostate, prostatic intraepithelial neoplasia (PIN) lesions, and prostate cancers from radical prostatectomy specimens. SR-A was expressed in a subset of macrophages and dendritic cells that infiltrated prostatic tissues. The majority of SR-A-positive cells coexpressed CD68, and a relatively low percentage expressed S100 protein. The number of SR-A-positive cells was significantly increased in PIN as compared with normal prostatic tissue ( P = 0.0176). In contrast, the number of SR-A-positive cells decreased with tumor progression. A lower SR-A-positive cell density was associated with higher clinical stage (ρ = −0.26; P = 0.0234). Inverse associations were also found between SR-A density and positive lymph nodes (ρ = −0.23; P = 0.0437), tumor size (ρ = −0.31; P = 0.0100) and preoperative PSA levels (ρ = −0.32; P = 0.0057). SR-A density is a significant predictor of disease-free survival after surgery univariately ( P = 0.0003), as well as multivariately, adjusted for known clinical and pathological markers including preoperative prostate-specific antigen, clinical stage, Gleason score, surgical margin, extraprostatic extension, and seminal vesicle invasion, as well as lymph node metastasis ( P = 0.0021). The preferential accumulation of SR-A-positive cells in PIN suggests a role for SR-A in the APC response to early malignancy. A reduction in the number of SR-A-positive cells demarcates tumor progression as indicated by clinical and pathological correlations. Our results additionally indicate that systematic measurement of SR-A density is a strong prognostic marker for clinical outcome after surgery.
Background. Tumor-associated macrophages (TAMs) can either promote angiogenesis (i.e., the formation of new blood vessels) in tumors
by secreting tumor necrosis factor-α (TNF-α) or inhibit angiogenesis by producing granulocyte-macrophage colony-stimulating
factor (GM-CSF), which in turn stimulates production of the antiangiogenic protein plasminogen activator inhibitor type 2
(PAI-2). We tested, alone or in combination, the anti-prostate cancer activity of agents that perturb macrophage function.
Methods: By use of enzyme- linked immunosorbent assays, we measured the effects of Linomide® (roquinimex), thalidomide, pentoxifylline,
and genistein on TNF-α and GM-CSF production in vitro by virally transformed RAW 264.7 mouse macrophages and on PAI-2 production
in vitro by human macrophages. The antitumor effects of these agents were tested in vivo on transplanted Dunning R-3327 MAT-Lu rat prostate cancers; TAM numbers and blood vessel densities in these cancers were
determined by use of immunocytochemistry. Results: Linomide selectively inhibited mouse macrophage secretion of TNF-α but not of GM-CSF; however, thalidomide, pentoxifylline,
and genistein inhibited the production of both cytokines. Linomide, but not thalidomide or pentoxifylline, increased production
of PAI-2 by human macrophages. When administered to rats bearing MAT-Lu tumors, each of the tested agents reduced TAM numbers
(Linomide, by 46%; thalidomide, by 94%; pentoxifylline, by 71%; and genistein, by 96%). However, all of the agents reduced
tumor blood vessel density and tumor growth, with Linomide being the most effective (44% reduction in blood vessel density
and 69% inhibition of tumor growth). None of the other agents potentiated Linomide's antitumor effect. Conclusions: Linomide is unique among the antiangiogenic agents tested, in that it inhibits the stimulatory effects of TAMs on tumor angiogenesis
without eliminating their antiangiogenic effects, and may thus prove to be more effective against prostate cancer.
Tumor-associated macrophages (TAM) are known to possess the immunosuppressive M2 macrophage phenotype. They contribute to tumor growth, invasion, and metastasis by producing various mediators. Macrophages, especially M2 polarized macrophages, preferentially express CD163 and CD204, but few studies have investigated macrophage phenotypes in human ovarian tumors. The purpose of the present study was therefore to present results on macrophage differentiation in human ovarian serous and mucinous epithelial tumors. The method focused on immunostaining of paraffin-embedded tumor samples. Almost all macrophages infiltrating tumor tissues expressed CD163 and CD204, indicating the phenotypic shift toward M2 macrophage. The numbers of CD68-positive macrophages as well as of CD163- and CD204-positive macrophages in borderline and malignant tumors were significantly higher than in benign tumors. They correlated well with histological gradient of malignancy. Macrophage colony-stimulating factor (also known as colony-stimulating factor; CSF-1), which is one of the cytokines considered to induce TAM to polarize toward an M2 phenotype, was then evaluated. CSF-1 expression in malignant tumor cells was significantly higher than that in benign tumor cells and correlated with histological malignancy. These results suggest that CSF-1 derived from tumor tissues induces macrophages to shift toward the M2 phenotype, which is considered to promote tumor growth.
Accurate estimates of risk are essential for physicians if they are to recommend a specific management to patients with prostate cancer. Accurate risk estimates also are required for clinical trial design to ensure that homogeneous, high-risk patient groups are used to investigate new cancer therapeutics. Using the MEDLINE database, a literature search was performed on prostate cancer predictive tools from January 1966 to July 2007. The authors recorded input variables, the prediction form, the number of patients used to develop prediction tools, the outcome being predicted, prediction tool-specific features, predictive accuracy, and whether validation was performed. Each prediction tool was classified into patient clinical disease state and the outcome being predicted. First, the authors described the criteria for evaluation (predictive accuracy, calibration, generalizability, head-to-head comparison, and level of complexity) and the limitations of current predictive tools. The literature search generated 109 published prediction tools, including only 68 that had undergone validation. An increasing number of predictive tools addressed important endpoints, such as disease recurrence, metastasis, and survival. Despite their limitations and the limitations of data, predictive tools are essential for individualized, evidence-based medical decision making. Moreover, the authors recommend wider adoption of risk-prediction models in the design and implementation of clinical trials. Among prediction tools, nomograms provide superior, individualized, disease-related risk estimations that facilitate management-related decisions. Nevertheless, many more predictive tools, comparisons between them, and improvements to existing tools are needed.
The aim of this study is to evaluate the expression of the macrophage scavenger receptor (MSR) in prostate needle biopsy specimens as a possible prognostic factor for prostate cancer. As MSR reportedly has a role in recognizing foreign pathogenic substances, MSR-positive inflammatory cells are often detected in solid tumours, and there is a correlation between the relative risk of prostate cancer and polymorphism of the MSR gene.
MSR was evaluated by immunostaining in needle biopsies of the prostate from 135 patients who were confirmed to have prostate cancer. Among these men, 70 were treated by radical prostatectomy or by radiotherapy as definitive therapy; the other 65 were treated by hormonal therapy because of advanced disease or age. Needle-biopsy specimens were sectioned at 5 microm and immunostained with a monoclonal antibody against MSR. Six microscopic (x400) fields around the cancer foci were selected in each case for analysis.
The median number of MSR-positive cells (MSR count) in each case was 24. There was an inverse correlation between the MSR count and Gleason score and clinical stage. The MSR count was lower in patients with biochemical (prostate-specific antigen, PSA) failure than that in those with no PSA failure (P < 0.001). In all patients, the recurrence-free survival (RFS) rate was significantly higher in those with a high MSR count (> or =24) than that in those with low MSR count (<24, P < 0.001). Moreover, for patients treated by definitive or hormonal therapy, the RFS rates in those with a higher MSR count were higher than in those with a lower MSR count (P < 0.001 and 0.014, respectively). Cox multivariate analysis showed that the MSR count was a prognostic factor for prostate cancer in addition to extraprostatic extension and Gleason score (P = 0.002, 0.038 and 0.011, respectively).
The results of immunostaining of MSR in needle-biopsy specimens is a prognostic factor for prostate cancer.
The biological heterogeneity of tumor cells requires a therapeutic modality that recognizes and kills resistant as well as susceptible tumor cells but does not harm normal cells. Tumoricidal macrophages appear to be able to fulfill these criteria. The mechanisms by which macrophages recognize tumor cells are not known, but they recognize carbohydrates and proteins that may be relevant for binding to tumor cells. In addition, phospholipids appear to be involved in the macrophage-tumor cell interaction. The abnormal presence of phosphatidylserine (PS) on the outer leaflet of tumor cells correlates with enhanced binding and cytotoxicity by macrophages.
In conclusion, PSA is the first prostate specific serum marker of clinical usefulness in urology. It represents a valuable clinical tool that has improved our ability to detect early prostate cancer and to monitor response to therapy. While large PSA screening studies have demonstrated an appreciable increase in the detection of organ confined, potentially curable prostate cancers, no study to date has yet demonstrated that the increased detection rate will decrease the prostate cancer-specific mortality rate. Yet more importantly, no study to date has demonstrated that early diagnosis using PSA will not decrease the prostate cancer specific mortality rate and until such data exist, PSA should be used to aid in early diagnosis and treatment planning for men with prostate cancer. PSA, when combined with other variables such as Gleason score and clinical stage, improves the prediction of pathological stage for prostate cancer. The introduction of PSA velocity and age specific reference ranges should further enhance the clinical usefulness of PSA. New advances in PSA research hold great promise for further improvements in PSA, and truly make it the most important and useful tumor marker for adenocarcinoma of the prostate.
Tumor-associated macrophages (TAMs) can either promote angiogenesis (i.e., the formation of new blood vessels) in tumors by secreting tumor necrosis factor-alpha (TNF-alpha) or inhibit angiogenesis by producing granulocyte-macrophage colony-stimulating factor (GM-CSF), which in turn stimulates production of the antiangiogenic protein plasminogen activator inhibitor type 2 (PAI-2). We tested, alone or in combination, the anti-prostate cancer activity of agents that perturb macrophage function.
By use of enzyme-linked immunosorbent assays, we measured the effects of Linomide (roquinimex), thalidomide, pentoxifylline, and genistein on TNF-alpha and GM-CSF production in vitro by virally transformed RAW 264.7 mouse macrophages and on PAI-2 production in vitro by human macrophages. The antitumor effects of these agents were tested in vivo on transplanted Dunning R-3327 MAT-Lu rat prostate cancers; TAM numbers and blood vessel densities in these cancers were determined by use of immunocytochemistry.
Linomide selectively inhibited mouse macrophage secretion of TNF-alpha but not of GM-CSF; however, thalidomide, pentoxifylline, and genistein inhibited the production of both cytokines. Linomide, but not thalidomide or pentoxifylline, increased production of PAI-2 by human macrophages. When administered to rats bearing MAT-Lu tumors, each of the tested agents reduced TAM numbers (Linomide, by 46%; thalidomide, by 94%; pentoxifylline, by 71%; and genistein, by 96%). However, all of the agents reduced tumor blood vessel density and tumor growth, with Linomide being the most effective (44% reduction in blood vessel density and 69% inhibition of tumor growth). None of the other agents potentiated Linomide's antitumor effect.
Linomide is unique among the antiangiogenic agents tested, in that it inhibits the stimulatory effects of TAMs on tumor angiogenesis without eliminating their antiangiogenic effects, and may thus prove to be more effective against prostate cancer.
We determine demographic and tumor related predictors of repeat biopsy cancer detection in men with suspected stage T1c-2 prostate cancer.
The study population included 298 consecutive men with suspected stage T1c-2 prostate cancer who had a benign prostate biopsy at 1 institution between January 1, 1992 and April 1, 1999 and underwent 1 repeat biopsy. Mean age plus or minus standard deviation was 66.8+/-6.7 years for 133 black (55%) and 165 white (45%) patients. Clinical measures included determination of high grade prostatic intraepithelial neoplasia in benign biopsy specimens, Gleason score of malignant biopsy specimens, prostate specific antigen (PSA), PSA density, annualized interbiopsy PSA change, percent free PSA (201 cases) and PSA velocity (171).
Cancer was detected on repeat biopsy in 80 cases (27%). Significant differences between patients with benign and malignant repeat biopsies included age (p = 0.001), PSA density (p = 0.0001), percent free PSA (p = 0.0001) and PSA velocity (p = 0.009). High grade prostatic intraepithelial neoplasia in an initial benign biopsy was not predictive of cancer in repeat biopsy (p = 0.12). Multiple logistic regression analysis of all cases showed that age (p = 0.002) and PSA density (p = 0.0002) were independent predictors of cancer. Subset multiple logistic regression analysis modeled with age, PSA density and percent free PSA demonstrated that age (p = 0.002) and percent free PSA (p = 0.0001) were significant independent predictors of malignancy. Subset multiple logistic regression analysis modeled with age, PSA density, percent free PSA and PSA velocity revealed that age (p = 0.02) and percent free PSA (p = 0.0003) were significant independent predictors of cancer. There were no significant differences between the Gleason scores of cancers detected on repeat biopsy compared to 587 stage T1c-2 cancers detected on initial biopsy during the study period (p = 0.09). PSA, PSA density, percent free PSA and PSA velocity were not significantly different among men without a cancer diagnosis who had high grade neoplasia in 1 or 2 benign biopsies.
Greater than 25% of this population of select patients with suspected stage T1c-2 prostate cancer had malignancy detected on repeat biopsy. Percent free PSA was the most powerful predictor of cancer. High grade prostatic intraepithelial neoplasia was not a predictor of repeat biopsy cancer detection and PSA functions were similar among men without cancer who did and did not have high grade neoplasia in 1 or more benign biopsies. This finding suggests that high grade prostatic intraepithelial neoplasia may not be a reliable indicator of clinically significant existing prostate cancer.
A prostate biopsy data base derived from patients referred to private practice urologists was analyzed for the cancer diagnosis rates of the "initial" biopsy and the repeated biopsy performed within 1 year for those patients with a noncancer diagnosis.
A retrospective analysis assessed 132,426 prostate biopsies received and processed by a single pathology laboratory between March 1994 and September 1998; none had had a previous biopsy processed at this laboratory. Prostate cancer was diagnosed in 50,521 of the patients (38.2%). The remaining 81,905 patients (61.8%) had a noncancer diagnosis of either no evidence of malignancy (NEM), high-grade prostatic intraepithelial neoplasia (HGPIN), small acinar glands suspicious for cancer (suspicious), or suspicious with HGPIN (Susp-HGPIN). We identified 6380 (7.8%) of these "noncancer" patients who underwent a repeated biopsy within 1 year.
The incidence of NEM, HGPIN, suspicious, and Susp-HGPIN biopsy diagnoses in the "noncancer" patients (81,905) was 55.3%, 3.7%, 2.5%, and 0.3%, respectively. The rate at which these "noncancer" patients (81,905) underwent a repeated biopsy was 4.8% for patients with a diagnosis of NEM, 26.6% for HGPIN, 40.4% for suspicious, and 47.5% for Susp-HGPIN. The overall cancer diagnosis rate in the repeated biopsy patient sample (6380) was 25.7%. When stratified by the initial biopsy diagnosis, the cancer diagnosis rate for the repeated biopsies was 19.8%, 22.6%, 40.0%, and 53.1%, for the patients with NEM, HGPIN, suspicious, and Susp-HGPIN, respectively. The repeated biopsy diagnosis rates did not vary dramatically when analyzed at 3-month intervals during the 1-year period. Also, a strong correlation (79%) was observed between the number of tissue samples obtained at the initial and repeated biopsy procedures. In a subset of patients with free and total prostate-specific antigen (PSA) results obtained before the repeated biopsy (n = 813), we were able to construct a multivariate logistic regression algorithm using the patients' age, initial biopsy diagnosis, total PSA, and free/total PSA ratio that could predict the likelihood of cancer on the repeated biopsy with an accuracy of 70%.
Men who have an initial noncancerous biopsy diagnosis remain at risk of prostate cancer, especially if the initial diagnosis was suspicious or Susp-HGPIN. These data suggest that the initial biopsy strategy needs to be improved and/or expanded to increase the overall cancer detection rate in the primary biopsy. In addition, combining factors such as the initial biopsy diagnosis, family history, digital rectal examination results, prostate gland volume, age, total PSA, and free/total PSA ratio could provide valuable information for predicting the likelihood of cancer.
We compare the ability of total prostate specific antigen (PSA), percent free PSA, PSA density and transition zone PSA density to predict the outcome of repeat prostatic biopsy in men with serum total PSA 4 to 10 ng./ml. who were diagnosed with benign prostatic hyperplasia after initial biopsy.
In this prospective study 1,051 men with total PSA 4 to 10 ng./ml. underwent transrectal ultrasound guided sextant biopsy with 2 additional transition zone biopsies. In 254 subjects biopsy specimens were also obtained from suspicious areas identified during transrectal ultrasound and digital rectal examination. All subjects with biopsy specimens negative for prostate cancer underwent repeat biopsy 6 weeks after initial biopsy. The ability of total PSA, percent free PSA, PSA density and transition zone PSA density to improve the diagnostic power of PSA testing was assessed with univariate and multivariate analyses as well as receiver operating characteristics (ROC) curves.
Initial biopsy was positive (prostate cancer) in 231 and negative (benign prostatic hyperplasia) in 820 of the 1,051 subjects. Prostate cancer was detected on repeat biopsy in 10% of subjects (83 of 820) with negative initial biopsy. Percent free PSA and transition zone PSA density were the most accurate predictors of prostate cancer in these subjects. At a cutoff of 30% percent free PSA would have detected 90% of cancers (sensitivity) and eliminated 50% of unnecessary repeat biopsies (specificity). Sensitivity and specificity of transition zone PSA density at a cutoff of 0.26 ng./ml./cc was 78% and 52%, respectively. ROC curve analysis also showed that percent free PSA was a significantly better predictor of repeat biopsy results than total PSA, PSA density and transition zone PSA density. The area under the ROC curve was 74.5% for percent free PSA, 69.1% for transition zone PSA density, 61.8% for PSA density and 60.3% for total PSA.
At least 10% of patients with negative initial prostatic biopsy results will be diagnosed with prostate cancer on repeat biopsy. Percent free PSA and transition zone PSA density enhance the specificity of PSA testing compared to total PSA or PSA density when determining which patients should undergo repeat biopsy. Repeat biopsy should be performed in patients with percent free PSA less than 30% or transition zone PSA density 0.26 ng./ml./cc or greater. In our study percent free PSA was the most accurate predictor of prostate cancer in repeat biopsy specimens.
To evaluate the factors influencing the cancer detection rate in men whose initial and repeat biopsies were both performed using an extended multisite biopsy scheme. Sextant biopsy of the prostate is associated with a significant false-negative rate, as evident from the high cancer detection rate after repeat prostate biopsy. Extended multisite biopsy schemes have therefore been recommended to maximize cancer detection.
Between June 1997 and August 2001, 939 men underwent prostate biopsy for early detection of prostate cancer using the extended multisite scheme (10 or 11 cores incorporating the anterior horn of the peripheral zone with or without midline peripheral zone and/or the transition zone). Of these 939 men, 89 (9.5%) underwent a repeat extended multisite prostate biopsy. The median prostate-specific antigen level was 6.9 ng/mL (range 0.7-36.1). Twenty-four men (27%) had an abnormal digital rectal examination at presentation. Most men (86%) in the group undergoing repeat biopsy had two or more risk factors for a positive biopsy. The median interval between biopsies was 4 months.
Of the 89 men, 15 (17%) had prostate cancer in the repeat biopsy specimen. Seven cancers (47%) were found only in the alternate biopsy sites, 5 (33%) cancers were found only in the sextant sites, and 3 in both sextant and alternate sites. Cancer was present in only one biopsy core in 11 (73%) of the 15 men, and the median Gleason score was 6 (range 6-8). On multivariate analysis, the presence of atypical glands suspicious for carcinoma (AGSC) was the only independent predictor of cancer in repeat biopsy (P <0.004). Of the 79 men without AGSC in the initial biopsy, 8 (10%) had a positive repeat biopsy. The total and percent free prostate-specific antigen level, digital rectal examination, ultrasound findings, and presence of high-grade prostatic intraepithelial neoplasia were not predictive of cancer detection.
The probability of a positive result for a repeat prostate biopsy is lower after an initial extended multisite biopsy compared with an initial sextant biopsy. The presence of AGSC was the only significant predictor of cancer in the repeat biopsy. Because nearly 50% of cancers detected in the repeat biopsy were in alternate sites only, using a sextant biopsy scheme for repeat biopsy would have missed these cancers.
We assess the feasibility of a urinary test for prostate cancer detection in a high-risk patient cohort based on methylation-specific PCR analysis of the pi class glutathione S-transferase (GSTP1) gene promoter.
A total of 45 men underwent transrectal ultrasound-guided biopsy of the prostate for suspected malignancy. Clean-catch voided urine specimens were prospectively collected from each patient immediately after biopsy. Genomic DNA was isolated from urine specimens and subjected to sodium bisulfite modification. Methylation of the GSTP1 promoter was examined in a blinded manner by methylation-specific PCR analysis and correlated with pathology results, and clinical information was obtained from the patient record.
Methylation of GSTP1 in the urine was detected in a total of 18 of 36 (50%) informative cases. A total of 7 of 18 (39%) patients with prostate adenocarcinoma identified on their initial biopsy had detectable urinary GSTP1 methylation (58% sensitivity among informative cases). Abnormal urinary GSTP1 methylation was also detected in 7 of 21 (33%) patients without evidence of cancer on biopsy and in 4 of 6 (67%) patients diagnosed with atypia or high-grade prostatic intraepithelial neoplasia.
We have demonstrated the feasibility of a novel, noninvasive molecular approach for the detection of epigenetic changes associated with prostate cancer. A screening test based on GSTP1 methylation in the urine specimens of patients with suspected prostate malignancy may be a useful adjunct to serum screening tests and digital rectal examination findings for identification of men at increased risk of harboring cancer despite a negative biopsy. This molecular assay has potential application for stratification of patients into low- and high-risk groups for surveillance versus repeat biopsy.
Although prostate cancer is found in about 30% of patients at the initial biopsy session, there is a need to identify those with a negative result but who are at high risk. Although individual risk factors have been found to be associated with cancer, patient counseling requires the integration of multiple risk factors to obtain a prediction for the individual.
We studied 343 patients with at least 1 initial negative biopsy who were tested from August 1999 to September 2001. At each biopsy session we recorded patient age, family history of prostate cancer, serum prostate specific antigen (PSA), PSA slope, digital rectal examination findings, months from the initial biopsy session, cumulative number of negative cores previously obtained, and history of high grade prostatic intraepithelial neoplasia or atypical small acinar proliferation. Through Cox regression analysis we determined the association of each variable with time to a positive biopsy. A nomogram was constructed using all variables and discrimination was calculated as the concordance index.
There were 661 biopsy sessions. A mean of 2.9 biopsy sessions were performed per patient and a mean of 9.15 cores were obtained per biopsy session for a mean of 25.2 per patient. Overall 20% of patients had cancer at the second biopsy session. The cumulative number of negative cores obtained, PSA slope, history of high grade prostatic intraepithelial neoplasia and history of atypical small acinar proliferation were associated with repeat biopsy findings (all p <0.05). A nomogram was constructed that had a concordance index of 0.70, which was greater than that of any single risk factor.
We created a nomogram that predicts a positive biopsy after a previous negative biopsy session. It provides a wide range of probabilities for cancer and may improve clinical judgment before the decision to repeat biopsy.
We performed a case-control study in which we tested the ability of a non-invasive assay to detect telomerase activity and to distinguish between prostatic cancer (Pca) and benign prostatic hyperplasia (BPH) on samples of epithelial cells obtained after prostatic massage.
Telomerase activity was determined by a telomeric repeat amplification protocol (TRAP) assay. We selected 60 patients with histologically proven Pca (30 cases) or BPH (30 cases). Specimens included in this study were from patients who had no suspicious findings on digital rectal examination for cancer, had clinical evidence of lower urinary tract symptoms, had no sonographic signs of Pca at the transrectal ultrasound evaluation, had total PSA values moderately elevated (2.6-15 ng/ml), and had no evidence of other urological cancers. The whole procedure was conducted in double blind between pathologists and molecular biology operators.
Telomerase activity was detected in 90% of Pca cases and in 13% of BPH cases. The sensitivity (90%) and specificity (76%) of this method were calculated. The positive predictive value, negative predictive value, and diagnostic efficiency were 87%, 90%, and 88% respectively.
Our data indicate that telomerase activity detected by TRAP assay on prostate epithelial cells collected by prostate massage can substantially improve the distinction between Pca and BPH conditions. One of the clinical benefits resulting from the use of this new assay would be to refine the biopsy indication and to avoid for several patients without Pca the unnecessary cost and the complications of prostate biopsy.
Existing clinical data have shown that high-grade prostatic intraepithelial neoplasia (HGPIN) is the most likely precursor to prostate cancer (CaP). Criteria to distinguish HGPIN that progress to CaP from those that do not remain poorly defined. Our objective was to evaluate microvessel density as a molecular marker for distinguishing HGPINs that have the potential of progressing to cancer.
Human prostatic tissue samples were collected randomly from 50 prostatectomy and cystoprostatectomy patients. Formalin-fixed and paraffin-embedded sections were used for immunohistochemical localization of rabbit anti-human von Willebrand factor VIII (vWF) IgG, mouse anti-high molecular weight cytokeratin 34BE-12 in basal cells, and mouse anti-heparan sulphate proteoglycan (HSPG) IgGs in basement membranes associated with benign prostatic hyperplasia (BPH), PIN associated with some BPH (isolated PIN), and PIN associated with CaP.
Analysis of immunostaining data showed that PINs could be categorized according to their distributions within and outside 2 standard deviations (SD) of the mean for microvessel density. The average number of microvessels was significantly higher (P < 0.0001) in PINs associated with Gleason score 7 tumors than those associated with Gleason scores 4-6 (P < 0.1328) or 8 and 9 tumors (P < 0.1708). Morphologically, PINs within 2 SD were composed of low- and high-grade type, whereas those outside 2 SD of microvessel density were predominantly of high-grade type. Cytokeratin and HSPG localization patterns also showed differences in PINs found within and outside 2 SD of microvessel density. We found localization of cytokeratin 34BE-12 in basal cells of specimens with BPH alone, isolated PIN, and PIN associated with CaP within 2 SD, whereas many PINs outside 2 SD showed disruptions in cytokeratin localization. The basement membranes of PINs within 2 SD of microvessel density were relatively intact, whereas those outside 2 SD were fragmented.
Our immunostaining data indicates that once HGPIN is found in the initial prostatic biopsy, it should be evaluated for microvessel density by localization of vWF. Our data indicate that characteristics of HGPIN can be augmented by evaluations of cytokeratin and HSPG molecular markers to assess the potential of HGPIN progression to malignancy. When biopsy samples show HGPIN with increased microvessel density and disrupted cytokeratin and HSPG markers, the patient may be a candidate for repeat biopsy. Since our study is limited to 50 prostate tissue samples, we emphasize that our conclusion is tentative and ought to be confirmed in a study with a larger sample size. This is the first report to show that microvessel density may distinguish HGPIN that is a precursor to prostate cancer.
In contemporary practice, most prostate cancers are either invisible on ultrasound or indistinguishable from concurrent benign prostatic hyperplasia. Diagnosis therefore rests on prostate biopsy. Biopsies are not simply directed at ultrasonically visible lesions, as these would miss many cancers; rather the whole gland is sampled. The sampling itself is systematic, using patterns based on prostate zonal anatomy and the geographical distribution and frequency of cancer. This review explains the evolution of the prostate biopsy technique, from the classical sextant biopsy method to the more recent extended biopsy protocols (8, 10, 12, >12 and saturation biopsy protocols). Extended protocols are increasingly being used to improve diagnostic accuracy, especially in those patients who require repeat biopsy. This trend has been facilitated by the ongoing improvement in safety and acceptability of the procedure, particularly with the use of antibiotic prophylaxis and local anaesthesia. The technical details of these extended protocols are discussed, as are the current data regarding procedure-related morbidity and how this may be minimized.
Tumour-associated macrophages (TAM) represent the major inflammatory component of the stroma of many tumours, and can affect different aspects of the neoplastic tissue. Many observations indicate that TAM express several M2-associated pro-tumoural functions, including promotion of angiogenesis, matrix remodelling and suppression of adaptive immunity. The pro-tumoural role of TAM in cancer is further supported by clinical studies that found a correlation between the high macrophage content of tumours and poor patient prognosis. Evidence is presented here supporting the view that TAM represent a unique and distinct M2-skewed myeloid population and are a potential target for anti-cancer therapy.
Men with elevated serum prostate-specific antigen (PSA) levels and negative prostate biopsy findings present a dilemma because of the lack of an accurate diagnostic test. We evaluated the potential utility of the investigational prostate cancer gene 3 (PCA3) urine assay to predict the repeat biopsy outcome.
Urine was collected after digital rectal examination (three strokes per lobe) from 233 men with serum PSA levels persistently 2.5 ng/mL or greater and at least one previous negative biopsy. The specimens were collected from April 2004 to January 2006. The PCA3 scores were determined using a highly sensitive quantitative assay with transcription-mediated amplification. The ability of the PCA3 score to predict the biopsy outcome was assessed and compared with the serum PSA levels.
The RNA yield was adequate for analysis in the urine samples from 226 of 233 men (ie, the informative specimen rate was 97%). Repeat biopsy revealed prostate cancer in 60 (27%) of the of 226 remaining subjects. Receiver operating characteristic curve analysis yielded an area under the curve of 0.68 for the PCA3 score. In contrast, the area under the curve for serum PSA was 0.52. Using a PCA3 score cutoff of 35, the assay sensitivity was 58% and specificity 72%, with an odds ratio of 3.6. At PCA3 scores of less than 5, only 12% of men had prostate cancer on repeat biopsy; at PCA3 scores greater than 100, the risk of positive biopsy was 50%.
In men undergoing repeat prostate biopsy to rule out cancer, the urinary PCA3 score was superior to serum PSA determination for predicting the biopsy outcome. The high specificity and informative rate suggest that the PCA3 assay could have an important role in prostate cancer diagnosis.
Genetic susceptibility to prostate cancer has been consistently observed by a large number of studies. Recently, several pieces of evidence obtained from epidemiological and pathological studies support that chronic inflammation in prostate tissues may play a role in prostate cancer development. Multiple genes that play critical roles in inflammatory pathways have been associated with prostate cancer risk. In this article we review the key genetic findings of the associated genes. This includes 2 genes identified through family studies, ribonuclease L (RNASEL) and macrophage scavenger receptor 1 (MSR1), as well as a number of genes suggested by case-control studies, such as macrophage inhibitory cytokine-1 (MIC-1), interleukins (IL-8, IL-10), vascular endothelial growth factor (VEGF), intercellular adhesion molecule (ICAM), and Toll-like receptors (TLR-4, TLR-1-6-10 gene cluster). Overall, recent studies seem to suggest multiple genes work together to increase prostate risk, and this is consistent with the reality that inflammation is a very complex process. Thus, future studies are expected to place an emphasis on the study of gene-gene interactions. Advances in high throughput genotyping, data mining, and algorithm development are needed in order to produce interpretable results.
Prostatitis and prostate carcinoma are both frequent entities of prostatic diseases. Epidemiological studies show significant associations between infection and inflammation and prostatic carcinoma. However, because of various confounding factors the results of these studies are inconclusive. Further findings are therefore needed to confirm the hypothesis that prostatic infection and inflammation might be a cause of prostatic carcinoma. We reviewed selected reports on the role of inflammation and infection in the pathogenesis of prostate carcinoma. Extensive genetic analyses show that several gene products, e.g. 2'-5'-oligoadenylate (2-5 A)-dependent Rnase, macrophage scavenger receptor 1 and Toll-like receptor-4, influence the susceptibility of prostate cells to infectious agents. Proliferative inflammatory atrophy (PIA) could be a connection between prostatitis and prostatic carcinoma. In the transition from PIA to prostatic intraepithelial neoplasia, the function of cellular detoxification is gradually lost by silencing of glutathione-S transferase, a detoxifying enzyme. This cellular feature leads to an increased susceptibility of the prostatic epithelial cells to genomic damage by inflammatory oxidants or nutritional carcinogens. Consecutive somatic genome damage might then arise which modulates the further pathogenesis of prostate carcinoma. Summarising these epidemiological, genetic and cell biological aspects, infectious prostatitis might have a causative role in the complex and multifactorial process of prostate carcinogenesis.
Each year, the American Cancer Society estimates the number of new cancer cases and deaths expected in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival based on incidence data from the National Cancer Institute, Centers for Disease Control and Prevention, and the North American Association of Central Cancer Registries and mortality data from the National Center for Health Statistics. Incidence and death rates are age-standardized to the 2000 US standard million population. A total of 1,437,180 new cancer cases and 565,650 deaths from cancer are projected to occur in the United States in 2008. Notable trends in cancer incidence and mortality include stabilization of incidence rates for all cancer sites combined in men from 1995 through 2004 and in women from 1999 through 2004 and a continued decrease in the cancer death rate since 1990 in men and since 1991 in women. Overall cancer death rates in 2004 compared with 1990 in men and 1991 in women decreased by 18.4% and 10.5%, respectively, resulting in the avoidance of over a half million deaths from cancer during this time interval. This report also examines cancer incidence, mortality, and survival by site, sex, race/ethnicity, education, geographic area, and calendar year, as well as the proportionate contribution of selected sites to the overall trends. Although much progress has been made in reducing mortality rates, stabilizing incidence rates, and improving survival, cancer still accounts for more deaths than heart disease in persons under age 85 years. Further progress can be accelerated by supporting new discoveries and by applying existing cancer control knowledge across all segments of the population.
We developed a predictive model that incorporates clinical data and prostate specific antigen kinetic from general practice to detect prostate cancer in patients with a previously negative prostate biopsy.
From January 2001 to January 2007 data on 419 men who underwent repeat prostate biopsy with 12 or more cores were used to develop the nomogram. From February 2007 to June 2007 data on 63 men with the same criteria were used to validate the nomogram. The factors that we evaluated for the risk of a positive repeat prostate biopsy were patient age, digital rectal examination findings, total prostate specific antigen, the free-to-total prostate specific antigen ratio, prostate specific antigen density and slope, and previous high grade prostatic intraepithelial neoplasia.
On multivariate logistic regression all factors except age and prostate specific antigen showed significant ability to predict the outcome of 12-core repeat prostate biopsy. In the validation group the AUC of the predicted results from the model was 0.856 (95% CI 0.744-0.931), better than that of prostate specific antigen, the free-to-total prostate specific antigen ratio, and prostate specific antigen density and slope (p <0.05).
We successfully developed an accurate model to predict the outcome of repeat prostate biopsy. Adding the free-to-total prostate specific antigen ratio, digital rectal examination, prostate specific antigen and slope, and history of high grade prostatic intraepithelial neoplasia sharply improves the accuracy of our model.
Within tumours, many non-neoplastic cells such as fibroblasts, endothelial cells, and macrophages assist tumour growth by producing various growth factors and pro-angiogenic cytokines. Various tumour-derived molecules drive tumour-associated macrophages towards an anti-inflammatory phenotype (M2) and thus promoting tumour growth. Here we investigated microglia/macrophage differentiation in glioma tissues by means of immunostaining of paraffin-embedded glioma samples. The number of microglia/macrophages with positive staining for CD163 and CD204, which are believed to be markers for M2 macrophages, was correlated with the histological grade of the gliomas. The ratio of M2 macrophages in the tumour-associated microglia/macrophages was also associated with the histological grade. Culture supernatant from the glioma cell line can stimulate macrophages to develop into the M2 phenotype in vitro. Macrophage colony-stimulating factor (M-CSF), which strongly induces M2 polarization of macrophages, was significantly correlated with histological malignancy and with the proportion of M2 microglia/macrophages in vivo. In addition, the proportion of M2 microglia/macrophages and M-CSF expression in tumour cells correlated well with proliferation of glioblastoma cells. These results suggest that tumour-derived M-CSF induces a shift of microglia/macrophages towards the M2 phenotype, which influences tumour growth. Evaluation of the proportion of M2 microglia/macrophages and M-CSF expression in tumour tissue would be useful for assessment of microglia/macrophage proliferative activity and the prognosis of patients with gliomas.
The Prostate CAncer gene 3 (PCA3) assay has shown promise as an aid in prostate cancer (pCA) diagnosis in identifying men with a high probability of a positive (repeat) biopsy.
This study evaluated the clinical utility of the PROGENSA PCA3 assay.
This European prospective, multicentre study enrolled men with one or two negative biopsies scheduled for repeat biopsy.
After digital rectal examination (DRE), first-catch urine was collected to measure PCA3 mRNA concentration and to calculate the PCA3 score. The PCA3 score was compared to biopsy outcome. The diagnostic accuracy of the PCA3 assay was compared to percent of free prostate-specific antigen (%fPSA).
In 463 men, the positive repeat biopsy rate was 28%. The higher the PCA3 score, the greater the probability of a positive repeat biopsy. The PCA3 score (cut-off of 35) had a greater diagnostic accuracy than %fPSA (cut-off of 25%). The PCA3 score was independent of the number of previous biopsies, age, prostate volume, and total prostate-specific antigen (PSA) level. Moreover, the PCA3 score was significantly higher in men with high-grade prostate intraepithelial neoplasia (HGPIN) versus those without HGPIN, clinical stage T2 versus T1, Gleason score >or=7 versus <7, and "significant" versus "indolent" (clinical stage T1c, PSA density [PSAD] <0.15ng/ml, Gleason score in biopsy <or=6, and percent positive cores <or=33%) pCA.
The probability of a positive repeat biopsy increases with rising PCA3 scores. The PCA3 score was superior to %fPSA for predicting repeat prostate biopsy outcome and may be indicative of clinical stage and significance of pCa.
- A Jemal
- R Siegel
- E Ward
Jemal A, Siegel R, Ward E et al. Cancer statistics, 2008. CA Cancer J Clin
2008; 58: 71-96.
Prostate cancer detection by GSTP1 methylation analysis of postbiopsy urine specimens
- Ml Gonzalgo
- Cp Pavlovich
- Sm Lee
11 Gonzalgo ML, Pavlovich CP, Lee SM et al. Prostate cancer detection by
GSTP1 methylation analysis of postbiopsy urine specimens. Clin Cancer Res
2003; 9: 2673–7.
- Sr Kirby
- Tj Christmas
- Mk Brawer
Kirby SR, Christmas TJ, Brawer MK. Prostate Cancer. London: Mosby,
2001.
The role of inflammation and infection in the pathogenesis of prostate carcinoma
- Fm Wagenlehner
- Je Elkahwaji
- F Algaba
- Etal
Optimal predictors of prostate cancer on repeat prostate biopsy: a prospective study of 1,051 men
- B Djavan
- A Zlotta
- M Remzi
- Etal
Detection of telomerase activity in prostate massage samples improves differentiating prostate cancer from benign prostatic hyperplasia
- C Vicentini
- Gl Gravina
- A Angelucci
- Etal
Acquisition of secretion of transforming growth factor-beta 1 leads to autonomous suppression of scavenger receptor activity in a monocyte-macrophage cell line, THP-1
- N Nishimura
- M Harada-Shiba
- S Tajima
- Etal
Common sequence variants of the macrophage scavenger receptor 1 gene are associated with prostate cancer risk
- J Xu
- Sl Zheng
- A Komiya
- Etal
Decreased immunostaining for macrophage scavenger receptor is associated with poor prognosis of prostate cancer
- H Takayama
- N Nonomura
- K Nishimura
- Etal
Microvessel density as a molecular marker for identifying high-grade prostatic intraepithelial neoplasia precursors to prostate cancer
- Aa Sinha
- Bj Quast
- Pk Reddy
- Etal
Prostate cancer detection by GSTP1 methylation analysis of postbiopsy urine specimens
- Gonzalgo ML