Corrigendum: mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer.

This corrects the article DOI: 10.1038/nature22964.

METTL1 promotes tumorigenesis through tRNA-derived fragment biogenesis in prostate cancer.

Newly growing evidence highlights the essential role that epitranscriptomic marks play in the development of many cancers; however, little is known about the role and implications of altered epitranscriptome deposition in prostate cancer. Here, we show that the transfer RNA N7-methylguanosine (m7G) transferase METTL1 is highly expressed in primary and advanced prostate tumours. Mechanistically, we find that METTL1 depletion causes the loss of m7G tRNA methylation and promotes the biogenesis of a novel class of small non-coding RNAs derived from 5'tRNA fragments. 5'tRNA-derived small RNAs steer translation control to favour the synthesis of key regulators of tumour growth suppression, interferon pathway, and immune effectors. Knockdown of Mettl1 in prostate cancer preclinical models increases intratumoural infiltration of pro-inflammatory immune cells and enhances responses to immunotherapy. Collectively, our findings reveal a therapeutically actionable role of METTL1-directed m7G tRNA methylation in cancer cell translation control and tumour biology.

mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer.

Activation of the PTEN-PI3K-mTORC1 pathway consolidates metabolic programs that sustain cancer cell growth and proliferation. Here we show that mechanistic target of rapamycin complex 1 (mTORC1) regulates polyamine dynamics, a metabolic route that is essential for oncogenicity. By using integrative metabolomics in a mouse model and human biopsies of prostate cancer, we identify alterations in tumours affecting the production of decarboxylated S-adenosylmethionine (dcSAM) and polyamine synthesis. Mechanistically, this metabolic rewiring stems from mTORC1-dependent regulation of S-adenosylmethionine decarboxylase 1 (AMD1) stability. This novel molecular regulation is validated in mouse and human cancer specimens. AMD1 is upregulated in human prostate cancer with activated mTORC1. Conversely, samples from a clinical trial with the mTORC1 inhibitor everolimus exhibit a predominant decrease in AMD1 immunoreactivity that is associated with a decrease in proliferation, in line with the requirement of dcSAM production for oncogenicity. These findings provide fundamental information about the complex regulatory landscape controlled by mTORC1 to integrate and translate growth signals into an oncogenic metabolic program.

Methodological aspects of the molecular and histological study of prostate cancer: focus on PTEN.

Prostate cancer is among the most frequent cancers in men, and despite its high rate of cure, the high number of cases results in an elevated mortality worldwide. Importantly, prostate cancer incidence is dramatically increasing in western societies in the past decades, suggesting that this type of tumor is exquisitely sensitive to lifestyle changes. Prostate cancer frequently exhibits alterations in the PTEN gene (inactivating mutations or gene deletions) or at the protein level (reduced protein expression or altered sub-cellular compartmentalization). The relevance of PTEN in this type of cancer is further supported by the fact that the sole deletion of PTEN in the murine prostate epithelium recapitulates many of the features of the human disease. In order to study the molecular alterations in prostate cancer, we need to overcome the methodological challenges that this tissue imposes. In this review we present protocols and methods, using PTEN as proof of concept, to study different molecular characteristics of prostate cancer.

[Inflammatory aortic aneurysm and its relationship to urological disease: a case report and a literature review]. / Aneurismas de aorta inflamatorios y su relación con la patología urológica: caso clínico y revisión de la literatura científica.

OBJECTIVE: To report a successfully treated case of inflammatory aortic aneurysm. MATERIALS AND METHODS: A 57-year-old patient reported low back pain and urinary infections. An abdominal CT scan revealed a large inflammatory aneurysm in the abdominal aorta. An aortic bypass was performed with no complications. RESULTS: Patient course since surgery has been uneventful, and currently has no symptoms. CONCLUSIONS: Contribution of the radiographic team, mainly with the CT scan, is of great value both for differential diagnosis and adequate management and follow-up. Surgery is indicated to prevent aneurysm rupture, but an increased postoperative morbidity and mortality should be assumed.

[Current treatment of small renal masses]. / Tratamiento actual de las masas renales pequeñas.

UNLABELLED: Incidental diagnosis of renal carcinoma (RC) is increasingly common due to widespread use of radiodiagnostic techniques for other conditions. In developed countries, incidental tumor account for more than 40% of detected tumors, and 80% of solid kidney tumors less than 4 cm in size are malignant. Standard treatment for these tumors is partial nephrectomy, and their relapse rate is 1%-2% The higher increase in diagnosis of this disease has occurred in patients aged 70 to 90 years, a group where associated comorbidities are very common. In the past two decades, in parallel to development of radiographic techniques, two ablation procedures achieving tumor necrosis through cold, cryotherapy, and through heat, radiofrequency, have become established. These procedures achieve 95% short- and long-term remissions in tumors less than 4 cm in size. In addition, since these procedures may be performed percutaneously, both complications and hospital stay have decreased. As early as in 1995, Bosniak, based on observation of the growth and behavior of small RCs for longer than 8 years, advocated a watchful waiting or active surveillance attitude. This article reports cryotherapy, our radiofrequency series, and a literature review. CONCLUSIONS: In the event of elderly patients, concomitant diseases advising against surgery, multiple renal tumors, a solitary kidney, or patients who reject surgery, ablation procedures may be safe and effective when performed by expert hands, achieving mid-term oncological results similar to partial nephrectomy. Active surveillance has also been shown to be safe in the mid-term in adequately informed patients. To improve indications, new diagnostic procedures that help us differentiate the potentially more aggressive tumors will be required. Larger series and longer follow-ups are neede to confirm current results.

[Does a pT0 cystectomy specimen imply being tumour-free in the long term?]. / ¿Implica el T0 en la pieza de cistectomía encontrarse libre de tumor a largo plazo?

INTRODUCTION AND OBJECTIVES: The aim of this study was to evaluate the progress of patients with a pT0 radical cystectomy specimen in order to know what factors are helpful in deciding when the bladder can be preserved. MATERIAL AND METHODS: We reviewed 153 cases of radical cystectomies performed due to bladder tumours without neoadjuvant therapy between 1995 and 2005 and with a minimum of three years of follow-up. Stage pT0 patients were selected. We considered age at time of diagnosis, sex, pathological stage and grade of the tumour at the time of transurethral resection (TUR), number of resections, surgical factors, tumour characteristics (multifocal, papillary or solid), progression-free survival, cancer-specific survival and cause of death. We ran a univariate analysis of the different factors studied along with disease progression. RESULTS: 12.8% of cystectomy specimens were pT0N0. Progression occurred in 35% between 6 months and 4 years after the cystectomy. Cancer-specific survival was 75%. Five patients died within an average of 18 months. The cause of death for all of them was tumour progression with distant metastasis. Statistical studies in the univariate analysis were only related to progression and the number of prior TURs, which is probably due to the number of cases, but the tumour multifocality, grade and stage were noteworthy. 15% of the pT0 patients had a papillary phenotype and 33% of them died. Of those with a non-papillary phenotype, 23.5% died. CONCLUSIONS: A stage pT0N0 cystectomy specimen does not define this surgery as curative, and these cases require the same follow-up as for the rest of the patients. It is of particular interest that out of all of our cases, there was no local recurrence, but there was distant metastasis. This leads us to believe that these patients could have benefitted from systemic chemotherapy with no need for radical surgery. In our study, the number of previous relapses was the only prognostic factor with statistical significance.

[Radium 223 in castration resistant prostate cancer.] / Radio 223 en cáncer de próstata resistente a la castración.

OBJECTIVE: To analyze the available evidence on Radium 223 therapy, an alfa particle emitter with specific action on bone metastases, studied on patients with castration resistant prostate cancer. EVIDENCE ACQUISITION: We review the pivotal study ALSYMPCA, that served to get the drug approval for this phase of the disease, and the new data obtained from its use. We also performed a search of ongoing studies with Radium 223 alone or in combination with other molecules. EVIDENCE SINTHESIS: According to the ALSYMPCA study, Radium 223 significantly prolongs the overall survival of patients with castration resistant prostate cancer and bone metastases; approximately 3.6 months in comparison with patients who received placebo, which turns into a median life expectancy of 14.9 months, and a 36-month survival of 46%, associated with a 30% reduction in death risk. Overall survival results were consistent both in patients who receive Docetaxel previously and those who did not. RESULTS: for secondary variables support the positive effect of Radium 223 therapy on symptomatic skeletal events (for example, the use of external beam radiotherapy to alleviate pain) and bone markers, confirming its efficacy in bone metastases. CONCLUSIONS: Radium 223 is the first treatment directed to bone that has demonstrated significant improvement on overall survival. It also prolonged the time to the first skeletal event and the median time to PSA increase significantly. All this in addition to its manageable adverse effects, lower than those appeared in the placebo arm of the pivotal study ALSYMPCA.

Metabolic alterations in urine extracellular vesicles are associated to prostate cancer pathogenesis and progression.

Urine contains extracellular vesicles (EVs) that concentrate molecules and protect them from degradation. Thus, isolation and characterisation of urinary EVs could increase the efficiency of biomarker discovery. We have previously identified proteins and RNAs with differential abundance in urinary EVs from prostate cancer (PCa) patients compared to benign prostate hyperplasia (BPH). Here, we focused on the analysis of the metabolites contained in urinary EVs collected from patients with PCa and BPH. Targeted metabolomics analysis of EVs was performed by ultra-high-performance liquid chromatography-mass spectrometry. The correlation between metabolites and clinical parameters was studied, and metabolites with differential abundance in PCa urinary EVs were detected and mapped into cellular pathways. We detected 248 metabolites belonging to different chemical families including amino acids and various lipid species. Among these metabolites, 76 exhibited significant differential abundance between PCa and BPH. Interestingly, urine EVs recapitulated many of the metabolic alterations reported in PCa, including phosphathidylcholines, acyl carnitines, citrate and kynurenine. Importantly, we found elevated levels of the steroid hormone, 3beta-hydroxyandros-5-en-17-one-3-sulphate (dehydroepiandrosterone sulphate) in PCa urinary EVs, in line with the potential elevation of androgen synthesis in this type of cancer. This work supports urinary EVs as a non-invasive source to infer metabolic changes in PCa.

Integrative analysis of transcriptomics and clinical data uncovers the tumor-suppressive activity of MITF in prostate cancer.

The dysregulation of gene expression is an enabling hallmark of cancer. Computational analysis of transcriptomics data from human cancer specimens, complemented with exhaustive clinical annotation, provides an opportunity to identify core regulators of the tumorigenic process. Here we exploit well-annotated clinical datasets of prostate cancer for the discovery of transcriptional regulators relevant to prostate cancer. Following this rationale, we identify Microphthalmia-associated transcription factor (MITF) as a prostate tumor suppressor among a subset of transcription factors. Importantly, we further interrogate transcriptomics and clinical data to refine MITF perturbation-based empirical assays and unveil Crystallin Alpha B (CRYAB) as an unprecedented direct target of the transcription factor that is, at least in part, responsible for its tumor-suppressive activity in prostate cancer. This evidence was supported by the enhanced prognostic potential of a signature based on the concomitant alteration of MITF and CRYAB in prostate cancer patients. In sum, our study provides proof-of-concept evidence of the potential of the bioinformatics screen of publicly available cancer patient databases as discovery platforms, and demonstrates that the MITF-CRYAB axis controls prostate cancer biology.

Erratum: The metabolic co-regulator PGC1α suppresses prostate cancer metastasis.

This corrects the article DOI: 10.1038/ncb3357.

Transcriptomic profiling of urine extracellular vesicles reveals alterations of CDH3 in prostate cancer.

Extracellular vesicles (EV) are emerging structures with promising properties for intercellular communication. In addition, the characterization of EV in biofluids is an attractive source of non-invasive diagnostic, prognostic and predictive biomarkers. Here we show that urinary EV (uEV) from prostate cancer (PCa) patients exhibit genuine and differential physical and biological properties compared to benign prostate hyperplasia (BPH). Importantly, transcriptomics characterization of uEVs led us to define the decreased abundance of Cadherin 3, type 1 (CDH3) transcript in uEV from PCa patients. Tissue and cell line analysis strongly suggested that the status of CDH3 in uEVs is a distal reflection of changes in the expression of this cadherin in the prostate tumor. CDH3 was negatively regulated at the genomic, transcriptional, and epigenetic level in PCa. Our results reveal that uEVs could represent a non-invasive tool to inform about the molecular alterations in PCa.

The metabolic co-regulator PGC1α suppresses prostate cancer metastasis.

Cellular transformation and cancer progression is accompanied by changes in the metabolic landscape. Master co-regulators of metabolism orchestrate the modulation of multiple metabolic pathways through transcriptional programs, and hence constitute a probabilistically parsimonious mechanism for general metabolic rewiring. Here we show that the transcriptional co-activator peroxisome proliferator-activated receptor gamma co-activator 1α (PGC1α) suppresses prostate cancer progression and metastasis. A metabolic co-regulator data mining analysis unveiled that PGC1α is downregulated in prostate cancer and associated with disease progression. Using genetically engineered mouse models and xenografts, we demonstrated that PGC1α opposes prostate cancer progression and metastasis. Mechanistically, the use of integrative metabolomics and transcriptomics revealed that PGC1α activates an oestrogen-related receptor alpha (ERRα)-dependent transcriptional program to elicit a catabolic state and metastasis suppression. Importantly, a signature based on the PGC1α-ERRα pathway exhibited prognostic potential in prostate cancer, thus uncovering the relevance of monitoring and manipulating this pathway for prostate cancer stratification and treatment.

Pelvic hydatid disease as an example of pelvic masses of uncertain aetiology.

We describe two new cases of pelvic hydatid cysts, one with a clinical profile of local compression and the other one asymptomatic. The first case is a 75 year-old man who reported difficulty in defecating and urinating. An ultrasound revealed a large pelvic cystic mass displacing the bladder and rectosigmoid region. Computed tomography showed images compatible with hydatid disease and a hydatid liver cyst. The patient underwent a surgical procedure, with the pelvic cyst being partially excised. The other case of pelvic hydatid disease was asymptomatic, and was discovered by chance while examining a 75 year-old man for a prostatic adenoma. Because he was asymptomatic, we opted for observation. The pathology confirmed the diagnosis in the first case and radiological findings confirmed the second. Both patients are now asymptomatic. Hydatid disease must be considered in the differential diagnosis of any cystic masses in the pelvic organs, especially in countries where the disease is endemic. Although there are no serological tests which are 100% specific, there are some radiological procedures which can help to confirm the disease. Surgery is the treatment of choice.

New case of an infrarenal abdominal aortic aneurysm associated with horseshoe kidney.

We review the association between surgically resolvable aortic disease and horseshoe kidney with a discussion of diagnostic problems and therapeutic options. Male patient 81 years of age with horseshoe kidney and an abdominal aortic aneurysm that was discovered by chance in an abdominal ultrasound during a check-up for his prostate condition. A retroperitoneal approach was used in order to resect the aneurysm and perform an aorto-aortic bypass with no complications occurring. Two years after the diagnosis, the patient is still asymptomatic from a vascular point of view. The co-presence of horseshoe kidney and aortic disease needing surgical correction is infrequent, but it significantly increases the technical complexity of aortic reconstruction. A literature review is included.

[Prostatic utricle ductal carcinoma. Case report and bibliographic review]. / Carcinoma ductal del utrículo prostático. Caso clínico y revisión de la literatura.

OBJECTIVE: A case of ductal carcinoma of the prostatic utricle is described, previously known as endometrial carcinoma, and literature is reviewed. METHODS: 75-years-old patient who consults for lower urinary tract obstructive symptoms, with a PSA of 8.1 ng/ml., without more symptoms. Digital rectal examination and ultrasound showed a small and stony prostate. Deobstructive transurethral resection of the prostate was performed and the biopsy revealed ductal carcinoma of the utricle. RESULTS: Nine years after diagnosis signs of dissemination are not present. CONCLUSIONS: As incidental finding in the biopsy, ductal carcinoma of the utricle is a rare tumor, the incidence of which among all prostatic carcinomas has been cited as 0.2-0.8%. We report a review about this topic for improving its knowledge. Symptoms, pathological findings and treatment of this carcinoma have been reviewed.