Cellular landscape of tumour microenvironment in prostate cancer

Prostate cancer is still a public health priority in men and the impact of this disease will be more pronounced with the ageing of the world's population. Clinical heterogeneity of prostate cancer is reflected in spatial and clonal genomic diversity. Accumulating evidence demonstrates that the malignant behaviour of cancer is not only attributed to cancer cells but also fundamentally affected by stromal activity and controlled by various mechanisms of the tumour microenvironment. Data on prostate cancer in this study was derived from seven GEO datasets and the TCGA database. We analyzed the tumour microenvironment of prostate cancer in terms of clinical process, T stage and Gleason score using EPIC and xCell algorithms. We also analyzed the common immune checkpoints. In this study, we confirmed remarkable tumour tissue remodelling in the development of prostate cancer and further demonstrated the importance of cancer-related fibroblasts in the biochemical recurrence and metastasis for patients with prostate cancer undergoing radical radiotherapy or prostatectomy. In addition, we found that NRP1, CD200, TNFSF18 and CD80 might be the potential targets for prostate cancer.     

Macrophages direct tumour histology and clinical outcome in a colon cancer model

Macrophages generally constitute a major component of the tumour stroma. Although conventionally considered to be cytotoxic effector cells, macrophages have recently been described as promoters of tumour progression. The present study shows that selective depletion of peritoneal or liver macrophages prior to CC531 tumour cell inoculation resulted in highly differentiated tumours in rats. In contrast, tumours from control rats, in which macrophages are abundantly present, showed a desmoplastic stromal reaction with hallmark features of malignancy, such as neovascularization and matrix remodelling, indicating that the presence of macrophages is associated with malignant histopathological differentiation. Remarkably, macrophage-depleted rats, bearing highly differentiated tumours, had a worse prognosis, as they displayed a higher tumour load and poorer survival. Thus, while macrophages direct tumours towards malignant tumour histology, their role in anti-tumour defence is important. The selective inhibition of macrophage functions involved in malignant progression without interfering with cytotoxic ability may therefore identify important new targets for cancer therapy.     

Metallothionein 1 h tumour suppressor activity in prostate cancer is mediated by euchromatin methyltransferase 1

Metallothioneins (MTs) are a group of metal binding proteins thought to play a role in the detoxification of heavy metals. Here we showed by microarray and validation analyses that MT1h, a member of MT, is down‐regulated in many human malignancies. Low expression of MT1h was associated with poor clinical outcomes in both prostate and liver cancer. We found that the promoter region of MT1h was hypermethylated in cancer and that demethylation of the MT1h promoter reversed the suppression of MT1h expression. Forced expression of MT1h induced cell growth arrest, suppressed colony formation, retarded migration, and reduced invasion. SCID mice with tumour xenografts with inducible MT1h expression had lower tumour volumes as well as fewer metastases and deaths than uninduced controls. MT1h was found to interact with euchromatin histone methyltransferase 1 (EHMT1) and enhanced its methyltransferase activity on histone 3. Knocking down of EHMT1 or a mutation in MT1h that abrogates its interaction with EHMT1 abrogated MT1h tumour suppressor activity. This demonstrates tumour suppressor activity in a heavy metal binding protein that is dependent on activation of histone methylation. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Aberrant CpG island hypermethylation of multiple genes in prostate cancer and prostatic intraepithelial neoplasia

To date, several reports have been published about CpG island methylation of various genes in prostate cancer. However, most of these studies have focused on cancer tissue only or a single gene and data about concurrent methylation of multiple genes in prostate cancer or prostatic intraepithelial neoplasia (PIN) are limited. The aim of the present study was to determine the methylation profile of 11 tumour-related genes in prostate cancer and PIN. Seventy-one samples, including 37 prostate cancers, 14 PINs, and 20 normal prostates, were examined for the methylation status of 11 tumour-related genes using methylation-specific PCR. The mean number of genes methylated was significantly higher in prostate cancer and PIN than in non-neoplastic prostate (4.4, 3, and 0.2, respectively; p < 0.001). In prostate cancer, APC, GSTP1, MGMT, and RASSF1A were frequently methylated at a frequency of 56.8%, 86.5%, 75.7%, and 83.8%, respectively. These genes were methylated in more than 30% of PINs. Prostate cancers with high serum prostate-specific antigen (PSA) (more than 8 ng/ml) or a high Gleason score (GS) (3 + 4 or more) showed higher numbers of methylated genes than those with low serum PSA (8 or less) or low GS (3 + 3 or less) (5.4 versus 2.5 and 5.4 versus 3.1, respectively; p < 0.05). The methylation frequency of APC, RASSF1A, and RUNX3 was higher in prostate cancers with high serum PSA or with high GS than in those with low PSA or with low GS, respectively, the differences reaching statistical significance (p < 0.05). A strong association between MGMT methylation and loss of MGMT expression was demonstrated by immunohistochemistry. CpG island methylation is a frequent event, occurs early, and accumulates during multi-step prostatic carcinogenesis. High levels of CpG island hypermethylation might serve as a potential biological marker for aggressive prostate cancer.     

Expression of hedgehog pathway components in prostate carcinoma microenvironment: shifting the balance towards autocrine signalling

Tzelepi V, Karlou M, Wen S, Hoang A, Logothetis C, Troncoso P & Efstathiou E
(2011) Histopathology 58, 1037–1047
Expression of hedgehog pathway components in prostate carcinoma microenvironment: shifting the balance towards autocrine signalling Aims: The hedgehog (Hh) signalling pathway has been implicated in the pathogenesis and aggressiveness of prostate cancer through epithelial–mesenchymal interactions. The aim of this study was to elucidate the cell‐type partitioned expression of the Hh pathway biomarkers in the non‐neoplastic and tumour microenvironments and to correlate it with the grade and stage of prostate cancer. Methods and results: Expression of the Hh pathway components (Shh, Smo, Ptch, Gli1) in the microenvironment of non‐neoplastic peripheral zone (n = 119), hormone‐naive primary prostate carcinoma (n = 141) and castrate‐resistant bone marrow metastases (n = 53) was analysed using immunohistochemistry in tissue microarrays and bone marrow sections. Results showed that epithelial Shh, Smo and Ptch expression was up‐regulated, whereas stromal Smo, Ptch, and Gli1 expression was down‐regulated in prostate carcinomas compared to non‐neoplastic peripheral zone tissue. Ptch expression was modulated further in high‐grade and high‐stage primary tumours and in bone marrow metastases. Hh signalling correlated with ki67 and vascular endothelial growth factor (VEGF) but not with CD31 expression. Conclusion: Our results highlight the importance of Hh‐mediated epithelial–mesenchymal interactions in the non‐neoplastic prostate and imply that shifting the balance from paracrine towards autocrine signalling is important in the pathogenesis and progression of prostate carcinoma.     

GSTP1在前列腺癌组织中的表达及其甲基化检测

目的寻找前列腺癌患者血清中的生物标志物,为临床前列腺癌的早期无创性诊断提供依据。方法采用免疫组化SP染色法检测前列腺癌组织中GSTP1表达;运用甲基化特异性聚合酶链反应(MSP)方法检测前列腺癌患者癌组织和相应血清GSTP1基因启动子区5’端CpG岛甲基化程度。结果免疫组化结果:GSTP1在88例前列腺癌组仅有2例呈阳性反应且均为石蜡包埋标本;49例前列腺增生组均为阳性反应,其中38例呈现为强阳性反应。MSP检测结果:38例新鲜前列腺癌组织中,GSTP1基因高甲基化29例,此29例相应血清GSTP1基因高甲基化28例。对照组19例前列腺增生标本和对应的血清均没有检测到GSTP1基因甲基化。结论前列腺癌组织中GSTP1基因的表达与其启动子区甲基化程度呈负相关。前列腺癌患者的组织和血清中GSTP1甲基化检测结果相一致,检测血清中GSTP1的甲基化程度可反应癌组织中GSTP1基因的表达的情况。     

Loss of caveolin‐1 in prostate cancer stroma correlates with reduced relapse‐free survival and is functionally relevant to tumour progression

Levels of caveolin‐1 (Cav‐1) in tumour epithelial cells increase during prostate cancer progression. Conversely, Cav‐1 expression in the stroma can decline in advanced and metastatic prostate cancer. In a large cohort of 724 prostate cancers, we observed significantly decreased levels of stromal Cav‐1 in concordance with increased Gleason score (p = 0.012). Importantly, reduced expression of Cav‐1 in the stroma correlated with reduced relapse‐free survival (p = 0.009), suggesting a role for stromal Cav‐1 in inhibiting advanced disease. Silencing of Cav‐1 by shRNA in WPMY‐1 prostate fibroblasts resulted in up‐regulation of Akt phosphorylation, and significantly altered expression of genes involved in angiogenesis, invasion, and metastasis, including a > 2.5‐fold increase in TGF‐β1 and γ‐synuclein (SNCG) gene expression. Moreover, silencing of Cav‐1 induced migration of prostate cancer cells when stromal cells were used as attractants. Pharmacological inhibition of Akt caused down‐regulation of TGF‐β1 and SNCG, suggesting that loss of Cav‐1 in the stroma can influence Akt‐mediated signalling in the tumour microenvironment. Cav‐1‐depleted stromal cells exhibited increased levels of intracellular cholesterol, a precursor for androgen biosynthesis, steroidogenic enzymes, and testosterone. These findings suggest that loss of Cav‐1 in the tumour microenvironment contributes to the metastatic behaviour of tumour cells by a mechanism that involves up‐regulation of TGF‐β1 and SNCG through Akt activation. They also suggest that intracrine production of androgens, a process relevant to castration resistance, may occur in the stroma. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

''Pseudoadenomatoid'' tumour of prostate

A prostatic nodule with the histological appearance of an adenomatoid tumour is described. Mucin and immunohistochemical stains, however, revealed striking differences from five classical adenomatoid tumours and from mesothelium but similarities with prostatic glandular epithelium. It is concluded that the prostatic nodule was a localized area of florid epithelial hyperplasia and not a true adenomatoid tumour despite its appearance.     

APC gene hypermethylation and prostate cancer: a systematic review and meta-analysis

Prostate cancer (PCa) is a worldwide disease that affects a large number of males. Although prostate-specific antigen (PSA) screening is used, the specificity is limited. This study analyzes the sensitivity and specificity of adenomatous polyposis coli (APC) methylation for PCa detection in body fluids and tissues. Combining search results from PubMed and Embase, 19 studies were included, 5 involving body fluids and 14 involving prostate tissue, with 2344 subjects. In body fluid subgroups, the pooled sensitivity and specificity was 0.53 (95% confidence interval (CI): 0.28–0.78) and 0.92 (95% CI: 0.86–0.95), respectively. From tissue studies, the results presented as 0.84 (95% CI: 0.70–0.92) and 0.91 (95% CI: 0.77–0.97). To confirm the results, we conducted a further analysis by removing studies which introduced high heterogeneity due to the type of cases and controls. The same degree of sensitivity and specificity was presented in two subgroups (urine: sensitivity 0.46, 95% CI: 0.39–0.53; specificity 0.87, 95% CI: 0.64–0.96; tissue: sensitivity 0.87, 95% CI: 0.72–0.94; specificity 0.89, 95% CI: 0.68–0.97). In addition, analysis of the interaction between APC methylation and PCa showed strong association in the whole data set (odds ratio (OR)=24.91, 95% CI: 12.86–48.24, I²=72.5%). Pooling the same two main subgroups (tissue/fluid) gave a pooled OR of 33.54 (95% CI: 14.88–75.59; I²=70.7%) and 8.20 (95% CI: 2.84–23.74, I²=64.2%), respectively. From this study, the results suggest that APC promoter methylation may be the potential testing for PCa diagnosis and provide a new viewpoint in the treatment of PCa.     

前列腺癌细胞中NSBP1基因表达上调

明确用mRNA差异显示技术（mRNA-DD）筛选出的前列腺癌相关基因（Nucleosomal Binding Protein 1）在前列腺癌细胞系的表达情况。在GenBank NR数据库中对筛选出的5条差异表达序列标签（EST）进行同源性分析,其中1条与已知基因NSBP1高度同源（97%）。半定量RT-PCR结果显示在LNCaP、DU145及PC-3前列腺癌细胞系中NSBP1 mRNA的表达水平分别高于正常前列腺组织2.5倍,3.4倍和3.6倍,与Northern杂效分析结果趋势一致。7例前列腺癌组织的PT-PCR结果也体现了相同的表达趋势,NSBP1表达较配对正常前列腺癌组织增高,差异有统计学意义。以上结果表明NSBP1基因在前列腺癌组织系和组织中的表达均明显高于正常列腺癌组织,NSBP1表达上调可能参与了前列腺癌的发生发展过程。     

The tumour–stroma ratio in colon cancer: the biological role and its prognostic impact

The tumour microenvironment consists of a complex mixture of non‐neoplastic cells, including fibroblasts, immune cells and endothelial cells embedded in the proteins of the extracellular matrix. The tumour microenvironment plays an active role in tumour behaviour. By interacting with cancer cells, it influences disease progression and the metastatic capacity of the tumour. Tumours with a high amount of stroma correspond to poor patient prognosis. The tumour–stroma ratio (TSR) is a strong independent prognostic tool in colon cancer and provides additional value to the current clinically used tumour–node–metastasis classification. The TSR is assessed on conventional haematoxylin and eosin‐stained paraffin sections at the invasive front of the tumour. Here we review studies demonstrating the prognostic significance of the TSR in solid epithelial tumours with a focus on colon cancer. Moreover, the biological role of the tumour microenvironment during tumour progression and invasion will be discussed, as well as the attempts to target the tumour stroma for therapeutic purposes. We suggest that the TSR can be implemented with little effort and without additional costs in current routine pathology diagnostics owing to its simplicity and reliability.     

Molecular pathology of prostate cancer

The incidence of prostate cancer has increased in Japan recently and is developing into a life-threatening disease for many Japanese men. This is a result of several convergent factors including the adoption of a Western lifestyle, the widespread use of prostate-specific antigen (PSA) testing, and an increased population of advanced years in Japanese men. Although there is much information to date relating to molecular events underlying the etiology of prostate cancer, it is still unclear as to how and when these genetic alterations occur in each step of tumorigenesis. One fruitful area of investigation has been in the analysis of chromosomal abnormalities commonly observed in prostate cancer. However, no single candidate gene has been definitely identified in cancer initiation and/or progression; in addition, less research has been devoted to understanding the molecular events that underlie tumor histogenesis in terms of likely precursor lesions, such as prostatic intraepithelial neoplasia (PIN). This article reviews the current knowledge of the molecular pathology of prostate cancer, including its histogenesis, genetic and epigenetic alterations, and hereditary factors.     

The PTEN gene in locally progressive prostate cancer is preferentially inactivated by bi-allelic gene deletion

PTEN is frequently inactivated during the development of many cancers, including prostate cancer, and both bi-allelic and mono-allelic PTEN inactivation may contribute to tumorigenesis. PTEN mutations in clinical cancer specimens can easily be recorded but mono- or bi-allelic gene deletions are often difficult to assess. We performed a comprehensive study to detect PTEN inactivation in 40 locally progressive clinical prostate cancer specimens obtained by transurethral resection of the prostate, utilizing a variety of complementary technical approaches. The methods to detect PTEN deletion included allelotype analysis, dual-colour FISH and array-based CGH. We also applied a novel semi-quantitative approach, assessing the PTEN-WT (wild-type): PTEN-Psi (pseudogene) ratio (WPR). Structural analysis of PTEN was performed by single-strand conformational polymorphism (PCR-SSCP) and sequencing. PTEN protein expression was assessed by immunohistochemistry. Our data predict complete PTEN inactivation in 12 samples (30%), nine of these by bi-allelic deletion. Loss of one PTEN copy was also detected by several methodologies but the number could not be accurately assessed. Immunohistochemistry indicated the absence of PTEN protein in 15 samples, and heterogeneous expression of the protein in eight tumours. Taken together, these data show that bi-allelic deletion is a major mechanism of PTEN inactivation in locally progressive prostate cancer.     

Basaloid carcinoma of the prostate gland: histogenesis and review of the literature

The clinicopathological features of a basaloid carcinoma of the prostate gland are described in a 28-year-old man, and the management and prognosis discussed. Basaloid tumours of the prostate are very rare and only a few cases have been described in detail. Those cases which have been reported as adenoid cystic carcinoma, adenoid cystic-like carcinoma and adenoid basal cell tumour are reviewed.     

Cytology of metastatic prostate cancer following orchiectomy and antiandrogen therapy: a diagnostic challenge

Androgen deprivation therapy induces apoptosis and decreases both cell proliferation and angiogenesis in prostate adenocarcinoma. The molecular alterations following androgen ablation translate into unique cytologic features in both primary and metastatic prostate adenocarcinoma. We describe the cytologic appearance of metastatic prostate carcinoma following both surgical castration and androgen deprivation therapy.