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Management of muscle-invasive bladder cancer with radiation is associated with a 45% local relapse rate at 2 years. Concurrent treatment with mitomycin C and fluorouracil reduced recurrence to 33% and was not associated with increased late treatment-related toxicity. Bladder cancer, with more than 385,000 new cases worldwide in 2008, 1 is a major cause of cancer complications. The median age at diagnosis is over 70 years, and since the tumor often is related to smoking, many patients have a substantial number of coexisting illnesses that pose risks for radical surgical approaches. Survival rates are poor for muscle-invasive bladder cancer, with around 45% of patients surviving for 5 years regardless of the type of treatment. 2 – 4 Although surgery is considered the standard therapy, considerable interest in bladder preservation has led to the use of radiotherapy as an alternative, particularly in . . .

Prostate is the most frequent cancer in men. Prostate cancer progression is driven by androgen steroid hormones, and delayed by androgen deprivation therapy (ADT). Androgens control transcription by stimulating androgen receptor (AR) activity, yet also control pre-mRNA splicing through less clear mechanisms. Here we find androgens regulate splicing through AR-mediated transcriptional control of the epithelial-specific splicing regulator ESRP2. Both ESRP2 and its close paralog ESRP1 are highly expressed in primary prostate cancer. Androgen stimulation induces splicing switches in many endogenous ESRP2-controlled mRNA isoforms, including splicing switches correlating with disease progression. ESRP2 expression in clinical prostate cancer is repressed by ADT, which may thus inadvertently dampen epithelial splice programmes. Supporting this, treatment with the AR antagonist bicalutamide (Casodex) induced mesenchymal splicing patterns of genes including FLNB and CTNND1. Our data reveals a new mechanism of splicing control in prostate cancer with important implications for disease progression. Cancers often begin as cells that grow in connected sheets or clumps known as epithelial cells. To spread, the cancer cells need to change into cells that can break away from the group and move through the tissues. In prostate cancer, this process can happen years after successful treatment, but researchers are not sure why. Prostate cancer grows in response to testosterone. This hormone circulates around the body, and when it goes into a cell it helps select which genes are switched on or off. Testosterone-blocking drugs can help slow prostate cancer growth by changing this switching on and off of genes. But, over time, some cancers become resistant to the effects of these drugs and start to spread. This may be down to complexities in how testosterone controls gene activity. To produce a protein, a human cell first makes a copy of the corresponding gene. This copy is then modified, cutting and pasting different parts of the sequence (a process called ‘splicing’) before the protein is produced. The patterns of splicing a cell exhibits depend on splicing regulator proteins. Testosterone can change splicing patterns in prostate cancer cells, but researchers did not know how. To find out, Munkley et al. examined a set of genes that turn off in response to testosterone-blocking drugs in people with prostate cancer. This revealed that testosterone controls a master splicing regulator called ESRP2, which is normally present in epithelial cells. In prostate cancer cells in mice, extra ESRP2 slowed tumour growth. But, although ESRP2 levels are high in human prostate cancer cells to begin with, they drop in response to testosterone-blocking drugs. In the laboratory grown cells, the result was a switch away from 'epithelial-like' gene splicing patterns. Some of the new splicing patterns correlated with better patient prognosis, but other splicing patterns might help cancer cells to spread around the body. These results raise the possibility that blocking testosterone may impair prostate cancer growth, but also inadvertently prepare cancer cells to break away from tumours. A more complete understanding of how testosterone controls splicing could help explain why some tumours initially shrink when testosterone is blocked, but then later spread. Identifying the genes controlled by ESRP2 may reveal new drug targets to improve prostate cancer treatment.

Background Obesity increases breast cancer (BC) risk in post-menopausal women by mostly unknown molecular mechanisms which may partly be regulated by microRNAs (miRNAs). Methods We isolated RNA from paired benign and malignant biopsies from 83 BC patients and determined miRNA profiles in samples from 12 women at the extremes of the BMI distribution by RNA-seq. Candidates were validated in all samples. Associations between miR-10b expression and validated target transcript levels, and effects of targeted manipulation of miR-10b levels in a primary BC cell line on proliferation and invasion potential, were explored. Results Of the 148 miRNAs robustly expressed in breast tissues, the levels of miR-21, miR-10b, miR-451a, miR-30c, and miR-378d were significantly associated with presence of cancer. Of these, miR-10b showed a stronger down-regulation in the tumors of the obese subjects, as opposed to the lean. In ductal but not lobular tumors, significant inverse correlations were observed between the tumor levels of miR-10b and miR-30c and the mRNA levels of cancer-relevant target genes SRSF1, PIEZO1, MAPRE1, CDKN2A, TP-53 and TRA2B, as well as tumor grade . Suppression of miR-10b levels in BT-549 primary BC–derived cells increased cell proliferation and invasive capacity, while exogenous miR-10b mimic decreased invasion. Manipulation of miR-10b levels also inversely affected the mRNA levels of miR-10b targets BCL2L11, PIEZO1 and NCOR2 . Conclusions Our findings suggest that miR-10b may be a mediator between obesity and cancer in post-menopausal women, regulating several known cancer-relevant genes. MiR-10b expression may have diagnostic and therapeutic implications for the incidence and prognosis of BC in obese women.

Cell migration drives cell invasion and metastatic progression in prostate cancer and is a major cause of mortality and morbidity. However the mechanisms driving cell migration in prostate cancer patients are not fully understood. We previously identified the cancer-associated cell migration protein Tetraspanin 1 (TSPAN1) as a clinically relevant androgen regulated target in prostate cancer. Here we find that TSPAN1 is acutely induced by androgens, and is significantly upregulated in prostate cancer relative to both normal prostate tissue and benign prostate hyperplasia (BPH). We also show for the first time, that TSPAN1 expression in prostate cancer cells controls the expression of key proteins involved in cell migration. Stable upregulation of TSPAN1 in both DU145 and PC3 cells significantly increased cell migration and induced the expression of the mesenchymal markers SLUG and ARF6. Our data suggest TSPAN1 is an androgen-driven contributor to cell survival and motility in prostate cancer.

Background An unmet clinical need requires the discovery of new treatments for men facing advanced prostate cancer. Aberrant glycosylation is a universal feature of cancer cells and plays a key role in tumour growth, immune evasion and metastasis. Alterations in tumour glycosylation are closely associated with prostate cancer progression, making glycans promising therapeutic targets. Fucosyltransferase 8 (FUT8) drives core fucosylation by adding α1,6‐fucose to the innermost GlcNAc residue on N‐glycans. While FUT8 is recognised as a crucial factor in cancer progression, its role in prostate cancer remains poorly understood. Methods & Results Here, we demonstrate using multiple independent clinical cohorts that FUT8 is upregulated in high grade and metastatic prostate tumours, and in the blood of prostate cancer patients with aggressive disease. Using novel tools, including PhosL lectin immunofluorescence and N‐glycan MALDI mass spectrometry imaging (MALDI‐MSI), we find FUT8 underpins the biosynthesis of malignant core fucosylated N‐glycans in prostate cancer cells and using both in vitro and in vivo models, we find FUT8 promotes prostate tumour growth, cell motility and invasion. Mechanistically we show FUT8 regulates the expression of genes and signalling pathways linked to prostate cancer progression. Furthermore, we find that fucosylation inhibitors can inhibit the activity of FUT8 in prostate cancer to suppress the growth of prostate tumours. Conclusions Our study cements FUT8‐mediated core fucosylation as an important driver of prostate cancer progression and suggests targeting FUT8 activity for prostate cancer therapy as an exciting area to explore.

Background Genome wide association studies (GWAS) have identified several genetic variants that are associated with prostate cancer. Most of these variants, like other GWAS association signals, are located in non-coding regions of potential candidate genes, and thus could act at the level of the mRNA transcript. Methods We measured the expression and isoform usage of seven prostate cancer candidate genes in benign and malignant prostate by real-time PCR, and correlated these factors with cancer status and genotype at the GWAS risk variants. Results We determined that levels of LMTK2 transcripts in prostate adenocarcinomas were only 32% of those in benign tissues (p = 3.2 × 10 -7 ), and that an independent effect of genotype at variant rs6465657 on LMTK2 expression in benign (n = 39) and malignant tissues (n = 21) was also evident (P = 0.002). We also identified that whilst HNF1B(C) and MSMB2 comprised the predominant isoforms in benign tissues (90% and 98% of total HNF1B or MSMB expression) , HNF1B(B) and MSMB1 were predominant in malignant tissue (95% and 96% of total HNF1B or MSMB expression; P = 1.7 × 10 -7 and 4 × 10 -4 respectively), indicating major shifts in isoform usage. Conclusions Our results indicate that the amount or nature of mRNA transcripts expressed from the LMTK2 , HNF1B and MSMB candidate genes is altered in prostate cancer, and provides further evidence for a role for these genes in this disorder. The alterations in isoform usage we detect highlights the potential importance of alternative mRNA processing and moderation of mRNA stability as potentially important disease mechanisms.

Prostate cancer is the most common cancer in men and it is estimated that over 350,000 men worldwide die of prostate cancer every year. There remains an unmet clinical need to improve how clinically significant prostate cancer is diagnosed and develop new treatments for advanced disease. Aberrant glycosylation is a hallmark of cancer implicated in tumour growth, metastasis, and immune evasion. One of the key drivers of aberrant glycosylation is the dysregulated expression of glycosylation enzymes within the cancer cell. Here, we demonstrate using multiple independent clinical cohorts that the glycosyltransferase enzyme GALNT7 is upregulated in prostate cancer tissue. We show GALNT7 can identify men with prostate cancer, using urine and blood samples, with improved diagnostic accuracy than serum PSA alone. We also show that GALNT7 levels remain high in progression to castrate-resistant disease, and using in vitro and in vivo models, reveal that GALNT7 promotes prostate tumour growth. Mechanistically, GALNT7 can modify O -glycosylation in prostate cancer cells and correlates with cell cycle and immune signalling pathways. Our study provides a new biomarker to aid the diagnosis of clinically significant disease and cements GALNT7-mediated O -glycosylation as an important driver of prostate cancer progression.

We have investigated interstitial deletions of chromosome 8 in 70 colorectal carcinomas and 11 colonic adenomas using 11 microsatellite markers, including eight spanning the centromeric region of chromosome 8p (p11.2-p12). Allelic loss or imbalance was observed in 38 (54%) cancers and four (36%) adenomas. Twenty-eight (40%) of the cancers had deletions of 8p11.2-p12. Two distinct and independent regions of interstitial loss were found within this region. Fluorescent in situ hybridization, using an alpha satellite repeat probe to the centromere of 8p and two probes to the P1 region, was performed in four tumours that demonstrated allelic imbalance. Localized heterozygous deletions were confirmed in all four tumours. Eleven (16%) cancers had localized deletion in the region ANK-1 to D8S255 (P1) and a further eleven (16%) cancers had a less well localized deletion in the region defined by the markers D8S87 to D8S259 (P2). Loss of both centromeric loci was identified in a further six (9%) tumours. A functional significance for these two deletion regions was sought by correlation with primary and secondary tumour characteristics. Isolated P2 deletion was associated with 'early' T1 cancers (2p=0.0002), and were also identified in 3/11 adenomas. Conversely, interstitial deletions of the P1 locus were more frequently seen in 'locally invasive' T3/4 cancers (2p=0.015), and isolated P1 deletions were also associated with the presence of liver metastases (2p=0.016). Our data provide evidence of at least two genes within the 8p11.2-p12 region, mutations in which may confer different and independent roles in the pathogenesis of colorectal cancer.

Prostate is the most frequent cancer in men. Prostate cancer progression is driven by androgen steroid hormones, and delayed by androgen deprivation therapy (ADT). Androgens control transcription by stimulating androgen receptor (AR) activity, yet also control pre-mRNA splicing through less clear mechanisms. Here we find androgens regulate splicing through AR-mediated transcriptional control of the epithelial-specific splicing regulator ESRP2. Both ESRP2 and its close paralog ESRP1 are highly expressed in primary prostate cancer. Androgen stimulation induces splicing switches in many endogenous ESRP2-controlled mRNA isoforms, including a key splicing switch in the metastatic regulator FLNB which is associated with disease relapse. ESRP2 expression in clinical prostate cancer is repressed by ADT, which may thus inadvertently dampen epithelial splice programmes. Supporting this, FLNB splicing was reciprocally switched by the AR antagonist bicalutamide (Casodex®). Our data reveal a new mechanism of splicing control in prostate cancer with important implications for metastatic disease progression. Footnotes * Figure 3 did not appear correctly on our original submission