Circulating microRNAs are associated with docetaxel chemotherapy outcome in castration-resistant prostate cancer

Background:

Docetaxel is the first-line chemotherapy for castration-resistant prostate cancer (CRPC). However, response rates are ∼50% and determined quite late in the treatment schedule, thus non-responders are subjected to unnecessary toxicity. The potential of circulating microRNAs as early biomarkers of docetaxel response in CRPC patients was investigated in this study.

Methods:

Global microRNA profiling was performed on docetaxel-resistant and sensitive cell lines to identify candidate circulating microRNA biomarkers. Custom Taqman Array MicroRNA cards were used to measure the levels of 46 candidate microRNAs in plasma/serum samples, collected before and after docetaxel treatment, from 97 CRPC patients.

Results:

Fourteen microRNAs were associated with serum prostate-specific antigen (PSA) response or overall survival, according to Mann–Whitney U or log-rank tests. Non-responders to docetaxel and patients with shorter survival generally had high pre-docetaxel levels of miR-200 family members or decreased/unchanged post-docetaxel levels of miR-17 family members. Multivariate Cox regression with bootstrapping validation showed that pre-docetaxel miR-200b levels, post-docetaxel change in miR-20a levels, pre-docetaxel haemoglobin levels and visceral metastasis were independent predictors of overall survival when modelled together.

Conclusions:

Our study suggests that circulating microRNAs are potential early predictors of docetaxel chemotherapy outcome, and warrant further investigation in clinical trials.     

Biomarkers for prostate cancer detection

Since its approval by the US FDA in 1986, prostate-specific antigen (PSA) has been employed to monitor men with a diagnosis of prostate cancer. In 1994, PSA was approved for use in prostate cancer screening and has been employed worldwide. However, due to the limited specificity of PSA for the disease, novel biomarkers are needed for detecting prostate cancer and for determining which cancers need to be treated. This review will discuss the development of new biomarkers for prostate cancer detection and disease prognostication, focusing on recent progress and particular topical issues related to the development and validation of these new markers.     

Lead time associated with screening for prostate cancer

Screening serum levels of prostate-specific antigen (PSA) is now a major strategy for early detection of prostate cancer (PC). Quantification of the lead time thus obtained is important both for understanding the development of PC and for evaluating the advantages and disadvantages of widespread screening. In our study, 1,233 randomly selected men living in Stockholm in 1988 were invited to participate in an early detection (ED) program, in which suspicious findings provided by digital rectal examination (DRE), transrectal ultrasonography (TRUS) and/or a PSA value >/=10.0 ng/mL were followed up by biopsy. The cumulative incidence (Kaplan-Meier) of PC in the 946 participants (ED) during 12 years of follow-up was compared to that of an age-matched, randomly selected reference population (RP) of 657 men for whom PSA values (from frozen serum samples) could also be obtained. The PC incidence in men in the RP with PSA values >/=3.0 ng/mL reached the corresponding level for the ED group after 10.6 years (the "catch-up" point). After 12 years of follow-up, the estimated median lead time for men with PSA values in this interval was 4.5 years in the ED population, compared to 7.8 years in the RP. With 20 years of follow-up, the estimated median lead time of the RP was enhanced to 10.7 years. The lead time in connection with PC was influenced by the initial PSA level (although with large variations), length of follow-up and sensitivity of the ED procedure employed. The ED program described here was not associated with major overdetection.     

前列腺癌早期诊断的研究进展

前列腺癌(prostate cancer,Pca)是中老年男性常见恶性肿瘤之一,目前尚缺乏有效的晚期癌症治疗方法,因此早期诊断对于降低Pca死亡率至关重要.近年来,较多研究开发出多种新型诊断方法以改善对Pca诊断的准确性,同时避免过度诊疗,但其有效性及实用性尚需进一步验证.本文对目前新型生物标志物、联合成像技术及风险预...     

Biopsy sampling and histopathological markers for diagnosis of prostate cancer

Prostate cancer is one of the most common malignant tumors and a leading cause of cancer-related morbidity and mortality. Irrespective of the method that allows for risk stratification of prostate cancer suspects, diagnosis relies on tissue sampling through prostate biopsy and subsequent histopathological evaluation. This provides critical information about disease aggressiveness, which is required for adequate patient management. Prostate biopsy methods have significantly evolved over the years, including the definition of indications, sampling schemes and use of imaging techniques (ultrasound and MRI) that allow for more accurate tissue sampling. In response to the challenges emerging from more precise collection of minute prostate tissue samples for analysis, histopathological assessment should include not only the observation of routinely stained sections, but also, and increasingly so, a series of ancillary techniques, especially immunohistochemistry, which increment the accuracy of prostate cancer diagnosis and may provide relevant information to guide patient management.     

Dysbiotic gut microbiota in pancreatic cancer patients form correlation networks with the oral microbiota and prognostic factors

Microbiota in the gut and oral cavities of pancreatic cancer (PC) patients differ from those of healthy persons, and bacteria in PC tissues are associated with patients’ prognoses. However, the species-level relationship between a dysbiotic gut, oral and cancerous microbiota, and prognostic factors remains unknown. Whole-genome sequencing was performed with fecal DNA from 24 PC patients and 18 healthy persons (HD). Microbial taxonomies, metabolic pathways, and viral presence were determined. DNA was sequenced from saliva and PC tissues, and the association between the gut, oral, and cancer microbiota and prognostic factors in PC patients was analyzed. The PC microbiota were altered from those of the healthy microbiota in terms of microbial taxonomy, pathways and viral presence. Twenty-six species differed significantly between the PC and HD microbiota. Six fecal microbes, including Klebsiella pneumoniae, were associated with an increased hazard of death. In the co-occurrence network, microbes that were abundant in PC patients were plotted close together and formed clusters with prognosis-associated microbes, including K. pneumoniae. Multiple salivary microbes were present in the co-occurrence network. Microbacterium and Stenotrophomonas were detected in the PC tissues and formed a network with the fecal and salivary microbes. The dysbiotic gut microbiota in the PC patients formed a complex network with the oral and cancerous microbiota, and gut microbes abundant in the PC patients were closely linked with poor prognostic factors in the network.     

Polymorphism of the insulin gene is associated with increased prostate cancer risk

High insulin levels are linked with increased cancer risk, including prostate cancer. We examined the associations between prostate cancer with polymorphisms of the insulin gene (INS) and its neighbouring genes, tyrosine-hydroxylase and IGF-II (TH and IGF2). In this study, 126 case-control pairs matched on age, race, and countries of origin were genotyped for +1127 INS-PstI in INS, -4217 TH-PstI in TH, and +3580 IGF2-MspI in IGF2. The homozygous CC genotype of +1127 INS-PstI occurred in over 60% of the population. It was associated with an increased risk of prostate cancer in nondiabetic Blacks and Caucasians (OR=3.14, P=0.008). The CC genotype was also associated with a low Gleason score <7 (OR=2.60, P=0.022) and a late age of diagnosis (OR=2.10, P=0.046). Markers in the neighbouring genes of INS showed only null to modest associations with prostate cancer. The polymorphism of INS may play a role in the aetiology of prostate cancer. Given the high prevalence of the CC genotype and its association with late age of onset of low-grade tumours, this polymorphism may contribute to the unique characteristics of prostate cancer, namely a high prevalence of indolent cancers and the dramatic increase in incidence with age.     

Expression of CD147 is associated with prostate cancer progression

Novel molecular markers that are associated with prostate cancer (PCa) progression will provide valuable information in the diagnosis and treatment of the disease. Extracellular matrix metalloproteinase inducer (CD147) has been demonstrated to be involved in tumor invasion, metastasis, growth and survival. In our study, we examined whether the expression of CD147 can be used as a prognostic marker for predicting PCa progression. Tissue samples from 240 patients who received radical prostatectomy for PCa were obtained. CD147 expression in these samples was evaluated using immunohistochemical staining with a monoclonal antibody specifically against CD147. Increased expression of CD147 was correlated with higher Gleason scores (GS), positive surgical margin, prostate-specific antigen (PSA) failure, metastasis and reduced overall survival. Both univariate Cox regression analysis and multivariate analysis including competing biological variables demonstrated that increased CD147 expression was associated with increased risk for reduced PSA failure-free, metastasis-free and overall survival. Kaplan-Meier survival curves showed that the CD147 overexpression was a significant predictor for the PSA failure-free, metastasis-free and the overall survival in both pT2 and pT3 PCa patients. More significantly, higher expression of CD147 can serve as an independent prognostic predictor for PSA failure-free survival in PCa patients when they are stratified by GS. Our study results demonstrate the involvement of CD147 in PCa progression and suggest its potential role as an independent predictor of biochemical recurrence, development of metastasis and reduced overall survival in PCa.     

Changes in circulating microRNA levels associated with prostate cancer

Background:

The aim of this study was to investigate the hypothesis that changes in circulating microRNAs (miRs) represent potentially useful biomarkers for the diagnosis, staging and prediction of outcome in prostate cancer.

Methods:

Real-time polymerase chain reaction analysis of 742 miRs was performed using plasma-derived circulating microvesicles of 78 prostate cancer patients and 28 normal control individuals to identify differentially quantified miRs.

Results:

A total of 12 miRs were differentially quantified in prostate cancer patients compared with controls, including 9 in patients without metastases. In all, 11 miRs were present in significantly greater amounts in prostate cancer patients with metastases compared with those without metastases. The association of miR-141 and miR-375 with metastatic prostate cancer was confirmed using serum-derived exosomes and microvesicles in a separate cohort of patients with recurrent or non-recurrent disease following radical prostatectomy. An analysis of five selected miRs in urine samples found that miR-107 and miR-574-3p were quantified at significantly higher concentrations in the urine of men with prostate cancer compared with controls.

Conclusion:

These observations suggest that changes in miR concentration in prostate cancer patients may be identified by analysing various body fluids. Moreover, circulating miRs may be used to diagnose and stage prostate cancer.     

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

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

EphA6 promotes angiogenesis and prostate cancer metastasis and is associated with human prostate cancer progression

Metastasis is the primary cause of prostate cancer (CaP)-related death. We investigate the molecular, pathologic and clinical outcome associations of EphA6 expression and CaP metastasis. The expression profiling of Eph receptors (Ephs) and their ephrin ligands was performed in parental and metastatic CaP cell lines. Among Ephs and ephrins, only EphA6 is consistently overexpressed in metastatic CaP cells. Metastatic potential of EphA6 is assessed by RNAi in a CaP spontaneous metastasis mouse model. EphA6 knock-down in human PC-3M cells causes decreased invasion in vitro and reduced lung and lymph node metastasis in vivo. In addition, knock-down of EphA6 decreases tube formation in vitro and angiogenesis in vivo. EphA6 mRNA expression is higher in 112 CaP tumor samples compared with benign tissues from 58 benign prostate hyperplasia patients. Positive correlation was identified between EphA6 expression and vascular invasion, neural invasion, PSA level, and TNM staging in CaP cases. Further, genome-wide gene expression analysis in EphA6 knock-down cells identified a panel of differentially regulated genes including PIK3IPA, AKT1, and EIF5A2, which could contribute to EphA6-regulated cancer progression. These findings identify EphA6 as a potentially novel metastasis gene which positively correlates with CaP progression. EphA6 may be a therapeutic target in metastatic CaP.     

Identification of prostate cancer biomarkers in urinary exosomes

Exosomes have recently appeared as a novel source of non-invasive cancer biomarkers since tumour-specific molecules can be found in exosomes isolated from biological fluids. We have here investigated the proteome of urinary exosomes by using mass spectrometry to identify proteins differentially expressed in prostate cancer patients compared to healthy male controls. In total, 15 control and 16 prostate cancer samples of urinary exosomes were analyzed. Importantly, 246 proteins were differentially expressed in the two groups. The majority of these proteins (221) were up-regulated in exosomes from prostate cancer patients. These proteins were analyzed according to specific criteria to create a focus list that contained 37 proteins. At 100% specificity, 17 of these proteins displayed individual sensitivities above 60%. Even though several of these proteins showed high sensitivity and specificity for prostate cancer as individual biomarkers, combining them in a multi-panel test has the potential for full differentiation of prostate cancer from non-disease controls. The highest sensitivity, 94%, was observed for transmembrane protein 256 (TM256; chromosome 17 open reading frame 61). LAMTOR proteins were also distinctly enriched with very high specificity for patient samples. TM256 and LAMTOR1 could be used to augment the sensitivity to 100%. Other prominent proteins were V-type proton ATPase 16 kDa proteolipid subunit (VATL), adipogenesis regulatory factor (ADIRF), and several Rab-class members and proteasomal proteins. In conclusion, this study clearly shows the potential of using urinary exosomes in the diagnosis and clinical management of prostate cancer.     

Socio-economic and lifestyle factors associated with the risk of prostate cancer

International and interethnic differences in prostate cancer incidence suggest an environmental aetiology, and lifestyle and socio-economic factors have been studied, but with divergent results. Information on a cohort of 22,895 Norwegian men aged 40 years and more was obtained from a health examination and two self-administered questionnaires. Information on incident cases of prostate cancer was made available from the Cancer Registry. We used the Cox proportional hazards model to calculate incidence rate ratios as estimates of the relative risk (RR) with 95% confidence interval (CI). Reported P-values are two-sided. During a mean follow-up of 9.3 years, 644 cases were diagnosed. Risk was elevated among men in occupations of high compared to low socio-economic status (RR = 1.30; 95% CI 1.05-1.61), and among men with high education compared to the least educated (RR = 1.56; 95% CI 1.11-2.19). A RR of 1.56 (95% CI 0.97-2.44) suggests a higher risk among divorced or separated men, compared with married men. We also found indications of a weak negative association with leisure-time physical activity (RR = 0.80; 95% CI 0.62-1.03 for high vs low activity), a weak positive association with increasing number of cigarettes (P = 0.046), while alcohol consumption was not related to the risk of prostate cancer. These results show that high socio-economic status is associated with increased risk of prostate cancer, and that divorced or separated men might be at higher risk than married men. Data from this study also indicate that high levels of physical activity may reduce prostate cancer risk.     

肠道菌群对肿瘤治疗的影响

肠道菌群是寄居在人体肠道内的正常微生物群落,维持着宿主肠道微生态的稳态,肠道微生态失调促进肿瘤的发生,但特异的肠道共生菌及其代谢产物可能抑制肿瘤的发生。肠道菌群对宿主固有免疫和适应性免疫系统的成熟与调节具有重要作用,其可增强烷化剂、Toll 样受体（Toll-like receptor,TLR ）激动剂、免疫检验点抑制剂、过继性细胞免疫治疗等的抗肿瘤作用。肠道菌群主要通过调节肿瘤浸润髓源细胞的分化和功能影响抗肿瘤免疫反应,重新编程肿瘤浸润髓源细胞可能是一种理想的肿瘤治疗方法。肠道菌群为肿瘤治疗提供了新的策略,但其临床应用还面临着较多问题。本文就肠道菌群对肿瘤的发生和肿瘤治疗的有益影响进行综述。