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Nature Nov 2023Inflammation is a hallmark of cancer. In patients with cancer, peripheral blood myeloid expansion, indicated by a high neutrophil-to-lymphocyte ratio, associates with...
Inflammation is a hallmark of cancer. In patients with cancer, peripheral blood myeloid expansion, indicated by a high neutrophil-to-lymphocyte ratio, associates with shorter survival and treatment resistance across malignancies and therapeutic modalities. Whether myeloid inflammation drives progression of prostate cancer in humans remain unclear. Here we show that inhibition of myeloid chemotaxis can reduce tumour-elicited myeloid inflammation and reverse therapy resistance in a subset of patients with metastatic castration-resistant prostate cancer (CRPC). We show that a higher blood neutrophil-to-lymphocyte ratio reflects tumour myeloid infiltration and tumour expression of senescence-associated mRNA species, including those that encode myeloid-chemoattracting CXCR2 ligands. To determine whether myeloid cells fuel resistance to androgen receptor signalling inhibitors, and whether inhibiting CXCR2 to block myeloid chemotaxis reverses this, we conducted an investigator-initiated, proof-of-concept clinical trial of a CXCR2 inhibitor (AZD5069) plus enzalutamide in patients with metastatic CRPC that is resistant to androgen receptor signalling inhibitors. This combination was well tolerated without dose-limiting toxicity and it decreased circulating neutrophil levels, reduced intratumour CD11bHLA-DRCD15CD14 myeloid cell infiltration and imparted durable clinical benefit with biochemical and radiological responses in a subset of patients with metastatic CRPC. This study provides clinical evidence that senescence-associated myeloid inflammation can fuel metastatic CRPC progression and resistance to androgen receptor blockade. Targeting myeloid chemotaxis merits broader evaluation in other cancers.
Topics: Humans; Male; Chemotaxis; Disease Progression; Drug Resistance, Neoplasm; Inflammation; Lewis X Antigen; Myeloid Cells; Neoplasm Metastasis; Prostate; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Androgen Receptor Antagonists; Antineoplastic Agents
PubMed: 37844613
DOI: 10.1038/s41586-023-06696-z -
Journal of Translational Medicine Aug 2023Benign prostatic hyperplasia (BPH) is a common disease in elderly men, mainly resulted from an imbalance between cell proliferation and death. Glutathione peroxidase 3...
Glutathione Peroxidase 3 induced mitochondria-mediated apoptosis via AMPK /ERK1/2 pathway and resisted autophagy-related ferroptosis via AMPK/mTOR pathway in hyperplastic prostate.
BACKGROUND
Benign prostatic hyperplasia (BPH) is a common disease in elderly men, mainly resulted from an imbalance between cell proliferation and death. Glutathione peroxidase 3 (GPX3) was one of the differentially expressed genes in BPH identified by transcriptome sequencing of 5 hyperplastic and 3 normal prostate specimens, which had not been elucidated in the prostate. This study aimed to ascertain the mechanism of GPX3 involved in cell proliferation, apoptosis, autophagy and ferroptosis in BPH.
METHODS
Human prostate tissues, GPX3 silencing and overexpression prostate cell (BPH-1 and WPMY-1) models and testosterone-induced rat BPH (T-BPH) model were utilized. The qRT-PCR, CCK8 assay, flow cytometry, Western blotting, immunofluorescence, hematoxylin and eosin, masson's trichrome, immunohistochemical staining and transmission electron microscopy analysis were performed during in vivo and in vitro experiments.
RESULTS
Our study indicated that GPX3 was localized both in the stroma and epithelium of prostate, and down-regulated in BPH samples. Overexpression of GPX3 inhibited AMPK and activated ERK1/2 pathway, thereby inducing mitochondria-dependent apoptosis and G0/G1 phase arrest, which could be significantly reversed by MEK1/2 inhibitor U0126 preconditioning. Moreover, overexpression of GPX3 further exerted anti-autophagy by inhibiting AMPK/m-TOR and up-regulated nuclear factor erythroid 2-related factor 2 (Nrf2)/glutathione peroxidase 4 (GPX4, mitochondrial GPX4 and cytoplasmic GPX4) to antagonize autophagy-related ferroptosis. Consistently, GPX3 deficiency generated opposite changes in both cell lines. Finally, T-BPH rat model was treated with GPX3 indirect agonist troglitazone (TRO) or GPX4 inhibitor RAS-selective lethal 3 (RSL3) or TRO plus RSL3. These treatments produced significant atrophy of the prostate and related molecular changes were similar to our in vitro observations.
CONCLUSIONS
Our novel data manifested that GPX3, which was capable of inducing apoptosis via AMPK/ERK1/2 pathway and antagonizing autophagy-related ferroptosis through AMPK/m-TOR signalling, was a promising therapeutic target for BPH in the future.
Topics: Aged; Animals; Humans; Male; Rats; AMP-Activated Protein Kinases; Apoptosis; Ferroptosis; Glutathione Peroxidase; Hyperplasia; MAP Kinase Signaling System; Mitochondria; Prostate; Prostatic Hyperplasia; TOR Serine-Threonine Kinases
PubMed: 37633909
DOI: 10.1186/s12967-023-04432-9 -
Frontiers in Cellular and Infection... 2023To explore whether type III prostatitis is related to bacterial infection by detecting the composition and function of microorganisms in expressed prostatic secretion...
OBJECTIVE
To explore whether type III prostatitis is related to bacterial infection by detecting the composition and function of microorganisms in expressed prostatic secretion (EPS) of patients with chronic prostatitis (CP) and healthy people.
METHODS
According to the inclusion and exclusion criteria, 57 subjects were included in our study, divided into the healthy group, type II prostatitis group, and type III prostatitis group. 16s rRNA sequencing technique was used to detect and analyze the microbial composition of EPS in each group. Additionally, the metagenomics sequencing technique was used to further explore the function of different bacteria in the type III prostatitis group. Data analysis was performed by bioinformatics software, and the results were statistically significant when P<0.05.
RESULTS
Many microorganisms exist in EPS in both CP patients and healthy populations. However, the relative abundance of , , , , and in CP patients (including type II and III) were significantly different. Still, the relative abundance of different bacteria in type II prostatitis patients was much higher than in type III. The metagenomics sequencing results for the type III prostatitis group showed that the different bacteria had certain biological functions.
CONCLUSION
Based on our sequencing results and previous studies, we suggest that type III prostatitis may also be caused by bacterial infection.
Topics: Male; Humans; Prostatitis; RNA, Ribosomal, 16S; Chronic Disease; Bacterial Infections; Bacteria
PubMed: 37465760
DOI: 10.3389/fcimb.2023.1189081 -
Mathematical Biosciences and... Jul 2023At present, the incidence of prostate cancer (PCa) in men is increasing year by year. So, the early diagnosis of PCa is of great significance. Transrectal... (Review)
Review
At present, the incidence of prostate cancer (PCa) in men is increasing year by year. So, the early diagnosis of PCa is of great significance. Transrectal ultrasonography (TRUS)-guided biopsy is a common method for diagnosing PCa. The biopsy process is performed manually by urologists but the diagnostic rate is only 20%-30% and its reliability and accuracy can no longer meet clinical needs. The image-guided prostate biopsy robot has the advantages of a high degree of automation, does not rely on the skills and experience of operators, reduces the work intensity and operation time of urologists and so on. Capable of delivering biopsy needles to pre-defined biopsy locations with minimal needle placement errors, it makes up for the shortcomings of traditional free-hand biopsy and improves the reliability and accuracy of biopsy. The integration of medical imaging technology and the robotic system is an important means for accurate tumor location, biopsy puncture path planning and visualization. This paper mainly reviews image-guided prostate biopsy robots. According to the existing literature, guidance modalities are divided into magnetic resonance imaging (MRI), ultrasound (US) and fusion image. First, the robot structure research by different guided methods is the main line and the actuators and material research of these guided modalities is the auxiliary line to introduce and compare. Second, the robot image-guided localization technology is discussed. Finally, the image-guided prostate biopsy robot is summarized and suggestions for future development are provided.
Topics: Male; Humans; Prostate; Robotics; Reproducibility of Results; Biopsy; Prostatic Neoplasms
PubMed: 37679175
DOI: 10.3934/mbe.2023678 -
Nature Reviews. Urology Sep 2023Prostate cancer is a leading cause of death in men worldwide. For over 30 years, growing interest has focused on the development of vaccines as treatments for prostate... (Review)
Review
Prostate cancer is a leading cause of death in men worldwide. For over 30 years, growing interest has focused on the development of vaccines as treatments for prostate cancer, with the goal of using vaccines to activate immune cells capable of targeting prostate cancer to either eradicate recurrent disease or at least delay disease progression. This interest has been prompted by the prevalence and long natural history of the disease and by the fact that the prostate is an expendable organ. Thus, an immune response elicited by vaccination might not need to target the tumour uniquely but could theoretically target any prostate tissue. To date, different vaccine approaches and targets for prostate cancer have been evaluated in clinical trials. Overall, five approaches have been assessed in randomized phase III trials and sipuleucel-T was approved as a treatment for metastatic castration-resistant prostate cancer, being the only vaccine approved to date by the FDA as a treatment for cancer. Most vaccine approaches showed safety and some evidence of immunological activity but had poor clinical activity when used as monotherapies. However, increased activity has been observed when these vaccines were used in combination with other immune-modulating therapies. This evidence suggests that, in the future, prostate cancer vaccines might be used to activate and expand tumour-specific T cells as part of combination approaches with agents that target tumour-associated immune mechanisms of resistance.
Topics: Male; Humans; Prostatic Neoplasms; Cancer Vaccines; Immunotherapy; Prostate
PubMed: 36879114
DOI: 10.1038/s41585-023-00739-w -
Theranostics 2024Neuroendocrine prostate cancer (NEPC) typically implies severe lethality and limited treatment options. The precise identification of NEPC cells holds paramount...
Neuroendocrine prostate cancer (NEPC) typically implies severe lethality and limited treatment options. The precise identification of NEPC cells holds paramount significance for both research and clinical applications, yet valid NEPC biomarker remains to be defined. Leveraging 11 published NE-related gene sets, 11 single-cell RNA-sequencing (scRNA-seq) cohorts, 15 bulk transcriptomic cohorts, and 13 experimental models of prostate cancer (PCa), we employed multiple advanced algorithms to construct and validate a robust NEPC risk prediction model. Through the compilation of a comprehensive scRNA-seq reference atlas (comprising a total of 210,879 single cells, including 66 tumor samples) from 9 multicenter datasets of PCa, we observed inconsistent and inefficient performance among the 11 published NE gene sets. Therefore, we developed an integrative analysis pipeline, identifying 762 high-quality NE markers. Subsequently, we derived the NE cell-intrinsic gene signature, and developed an R package named NEPAL, to predict NEPC risk scores. By applying to multiple independent validation datasets, NEPAL consistently and accurately assigned NE feature and delineated PCa progression. Intriguingly, NEPAL demonstrated predictive capabilities for prognosis and therapy responsiveness, as well as the identification of potential epigenetic drivers of NEPC. The present study furnishes a valuable tool for the identification of NEPC and the monitoring of PCa progression through transcriptomic profiles obtained from both bulk and single-cell sources.
Topics: Male; Humans; Neuroendocrine Cells; Prostatic Neoplasms; Prostate; Gene Expression Profiling; Transcriptome
PubMed: 38250042
DOI: 10.7150/thno.92336 -
Molecular Cancer Oct 2023Genetic signatures have added a molecular dimension to prognostics and therapeutic decision-making. However, tumour heterogeneity in prostate cancer and current sampling...
Genetic signatures have added a molecular dimension to prognostics and therapeutic decision-making. However, tumour heterogeneity in prostate cancer and current sampling methods could confound accurate assessment. Based on previously published spatial transcriptomic data from multifocal prostate cancer, we created virtual biopsy models that mimic conventional biopsy placement and core size. We then analysed the gene expression of different prognostic signatures (OncotypeDx®, Decipher®, Prostadiag®) using a step-wise approach with increasing resolution from pseudo-bulk analysis of the whole biopsy, to differentiation by tissue subtype (benign, stroma, tumour), followed by distinct tumour grade and finally clonal resolution. The gene expression profile of virtual tumour biopsies revealed clear differences between grade groups and tumour clones, compared to a benign control, which were not reflected in bulk analyses. This suggests that bulk analyses of whole biopsies or tumour-only areas, as used in clinical practice, may provide an inaccurate assessment of gene profiles. The type of tissue, the grade of the tumour and the clonal composition all influence the gene expression in a biopsy. Clinical decision making based on biopsy genomics should be made with caution while we await more precise targeting and cost-effective spatial analyses.
Topics: Male; Humans; Prostate; Transcriptome; Biopsy; Prostatic Neoplasms; Genomics
PubMed: 37789377
DOI: 10.1186/s12943-023-01863-2 -
International Journal of Biological... 2023Benign prostatic hyperplasia (BPH) is a condition that becomes more common with age and manifests itself primarily as the expansion of the prostate and surrounding...
Benign prostatic hyperplasia (BPH) is a condition that becomes more common with age and manifests itself primarily as the expansion of the prostate and surrounding tissues. However, to date, the etiology of BPH remains unclear. In this respect, we performed single-cell RNA sequencing of prostate transition zone tissues from elderly individuals with different prostate volumes to reveal their distinct tissue microenvironment. Ultimately, we demonstrated that a reduced Treg/CD4+ T-cell ratio in the large-volume prostate and a relatively activated immune microenvironment were present, characterized partially by increased expression levels of granzymes, which may promote vascular growth and profibrotic processes and further exacerbate BPH progression. Consistently, we observed that the prostate gland of patients taking immunosuppressive drugs usually remained at a smaller volume. Furthermore, in mouse models, we confirmed that both suppression of the immune system with rapamycin and induction of Treg proliferation with low doses of IL-2 therapy indeed prevented the progression of BPH. Taken together, our findings suggest that an activated immune microenvironment is necessary for prostate volume growth and that Tregs can reverse this immune activation state, thereby inhibiting the progression of BPH.
Topics: Humans; Male; Animals; Mice; Prostatic Hyperplasia; Interleukin-2; Sirolimus; Prostate; Disease Models, Animal
PubMed: 37497009
DOI: 10.7150/ijbs.85089 -
JPMA. the Journal of the Pakistan... Dec 2023Here we discuss the interactions between prostatic health and diabetes. Diabetes may be associated with changes in prostatic anatomy, physiology, clinical morbidity, and...
Here we discuss the interactions between prostatic health and diabetes. Diabetes may be associated with changes in prostatic anatomy, physiology, clinical morbidity, and clinical outcomes. Certain glucose-lowering drugs may impact prostatic health, and some prostato-tropic medications can influence glycaemic control. One should be vigilant for symptoms and signs of prostate health in diabetes.
Topics: Male; Humans; Prostate; Erectile Dysfunction; Prostatic Hyperplasia; Diabetes Mellitus; Lower Urinary Tract Symptoms
PubMed: 38083941
DOI: 10.47391/JPMA.23-101 -
International Journal of Molecular... Jul 2023Benign prostatic hyperplasia (BPH) is a chronic proliferative disease showing stromal-dominant proliferation. However, the detailed proliferation mechanism has remained... (Review)
Review
Benign prostatic hyperplasia (BPH) is a chronic proliferative disease showing stromal-dominant proliferation. However, the detailed proliferation mechanism has remained unclear. Although aging and androgen have been reported as definitive risk factors for BPH, recent studies have focused on the involvement of androgen-independent factors. Androgen-independent factors include ischemia, oxidative stress, metabolic syndrome, infection, autoimmune reactions, and inflammation, with inflammation in BPH tissues playing a central role in the BPH proliferative process. Inflammation in BPH tissues by various factors finally leads to tissue remodeling and stromal proliferation through the wound healing process of the prostate. To elucidate the proliferative mechanism of BPH, a study using whole-genome gene expression analysis in a stromal-dominant BPH rat model was performed and showed that immune response-related pathways and complement classical pathways are activated. Furthermore, expression analysis using this BPH rat model showed that the autoimmune reaction triggered complement pathway activation in the proliferative process of BPH. BPH is a multifactorial disease, and understanding the role of androgen-independent factors including immune responses contributes to elucidating the pathogenesis of BPH. Androgen-independent factors may lead to new therapeutic targets for BPH, and further development of this research is expected.
Topics: Humans; Male; Rats; Animals; Prostatic Hyperplasia; Androgens; Prostate; Inflammation; Cell Proliferation
PubMed: 37511400
DOI: 10.3390/ijms241411634