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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 -
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 -
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 -
Medicina (Kaunas, Lithuania) Sep 2023Image-guided focal therapy has increased in popularity as a treatment option for patients with primary and locally recurrent prostate cancer. This review will cover the... (Review)
Review
Image-guided focal therapy has increased in popularity as a treatment option for patients with primary and locally recurrent prostate cancer. This review will cover the basic indications, evaluation, treatment algorithm, and follow-up for patients undergoing image-guided ablation of the prostate. Additionally, this paper will serve as an overview of some technical approaches to cases so that physicians can familiarize themselves with working in this space. While the focus of this paper is prostate cryoablation, readers will obtain a basic literature overview of some of the additional available image-guided treatment modalities for focal prostate therapy.
Topics: Male; Humans; Cryosurgery; Prostate; Algorithms; Pelvis; Physicians
PubMed: 37763708
DOI: 10.3390/medicina59091589 -
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 -
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 -
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 Cell Biology Dec 2023Lineage transitions are a central feature of prostate development, tumourigenesis and treatment resistance. While epigenetic changes are well known to drive prostate...
Lineage transitions are a central feature of prostate development, tumourigenesis and treatment resistance. While epigenetic changes are well known to drive prostate lineage transitions, it remains unclear how upstream metabolic signalling contributes to the regulation of prostate epithelial identity. To fill this gap, we developed an approach to perform metabolomics on primary prostate epithelial cells. Using this approach, we discovered that the basal and luminal cells of the prostate exhibit distinct metabolomes and nutrient utilization patterns. Furthermore, basal-to-luminal differentiation is accompanied by increased pyruvate oxidation. We establish the mitochondrial pyruvate carrier and subsequent lactate accumulation as regulators of prostate luminal identity. Inhibition of the mitochondrial pyruvate carrier or supplementation with exogenous lactate results in large-scale chromatin remodelling, influencing both lineage-specific transcription factors and response to antiandrogen treatment. These results establish reciprocal regulation of metabolism and prostate epithelial lineage identity.
Topics: Male; Humans; Prostate; Monocarboxylic Acid Transporters; Cell Differentiation; Epithelial Cells; Androgen Antagonists; Lactates
PubMed: 38049604
DOI: 10.1038/s41556-023-01274-x -
Cancer Research Dec 2023Prostate cancer remains the second leading cause of cancer death in men in Western cultures. A deeper understanding of the mechanisms by which prostate cancer cells...
UNLABELLED
Prostate cancer remains the second leading cause of cancer death in men in Western cultures. A deeper understanding of the mechanisms by which prostate cancer cells divide to support tumor growth could help devise strategies to overcome treatment resistance and improve survival. Here, we identified that the mitotic AGC family protein kinase citron kinase (CIT) is a pivotal regulator of prostate cancer growth that mediates prostate cancer cell interphase progression. Increased CIT expression correlated with prostate cancer growth induction and aggressive prostate cancer progression, and CIT was overexpressed in prostate cancer compared with benign prostate tissue. CIT overexpression was controlled by an E2F2-Skp2-p27 signaling axis and conferred resistance to androgen-targeted treatment strategies. The effects of CIT relied entirely on its kinase activity. Conversely, CIT silencing inhibited the growth of cell lines and xenografts representing different stages of prostate cancer progression and treatment resistance but did not affect benign epithelial prostate cells or nonprostatic normal cells, indicating a potential therapeutic window for CIT inhibition. CIT kinase activity was identified as druggable and was potently inhibited by the multikinase inhibitor OTS-167, which decreased the proliferation of treatment-resistant prostate cancer cells and patient-derived organoids. Isolation of the in vivo CIT substrates identified proteins involved in diverse cellular functions ranging from proliferation to alternative splicing events that are enriched in treatment-resistant prostate cancer. These findings provide insights into the regulation of aggressive prostate cancer cell behavior by CIT and identify CIT as a functionally diverse and druggable driver of prostate cancer progression.
SIGNIFICANCE
The poorly characterized protein kinase citron kinase is a therapeutic target in prostate cancer that drives tumor growth by regulating diverse substrates, which control several hallmarks of aggressive prostate cancer progression. See related commentary by Mishra et al., p. 4008.
Topics: Humans; Male; Cell Line, Tumor; Cell Proliferation; Prostate; Prostatic Neoplasms; Protein Kinases; Signal Transduction
PubMed: 37801613
DOI: 10.1158/0008-5472.CAN-23-0883 -
Development (Cambridge, England) Jul 2023The reactivation of developmental genes and pathways during adulthood may contribute to pathogenesis of diseases such as prostate cancer. Analysis of the mechanistic...
The reactivation of developmental genes and pathways during adulthood may contribute to pathogenesis of diseases such as prostate cancer. Analysis of the mechanistic links between development and disease could be exploited to identify signalling pathways leading to disease in the prostate. However, the mechanisms underpinning prostate development require further characterisation to interrogate fully the link between development and disease. Previously, our group developed methods to produce prostate organoids using induced pluripotent stem cells (iPSCs). Here, we show that human iPSCs can be differentiated into prostate organoids using neonatal rat seminal vesicle mesenchyme in vitro. The organoids can be used to study prostate development or modified to study prostate cancer. We also elucidated molecular drivers of prostate induction through RNA-sequencing analyses of the rat urogenital sinus and neonatal seminal vesicles. We identified candidate drivers of prostate development evident in the inductive mesenchyme and epithelium involved with prostate specification. Our top candidates included Spx, Trib3, Snai1, Snai2, Nrg2 and Lrp4. This work lays the foundations for further interrogation of the reactivation of developmental genes in adulthood, leading to prostate disease.
Topics: Male; Humans; Rats; Animals; Prostate; Rodentia; Urogenital System; Prostatic Neoplasms; Cell Differentiation; Organoids; Induced Pluripotent Stem Cells
PubMed: 37376888
DOI: 10.1242/dev.201328