Prostate Growth Research Articles

Single-port Transvesical Robot-Assisted Simple Prostatectomy: Surgical Technique and Clinical Outcomes

BackgroundSurgical management of large prostatic adenomas can be performed via open, endoscopic, or robotic approaches. A low-profile single-port (SP) robot was built to work in confined areas (ie, the bladder) and regionalize surgery. ObjectiveTo describe the novel SP transvesical (TV) robot-assisted simple prostatectomy (RASP) and report clinical outcomes. Design, setting, and participantsSP TV RASP cases were performed in an academic hospital by two surgeons from 2019 to 2023. A total of 117 cases were performed, and data from patients with at least 12 mo of follow-up were analyzed. The inclusion criterion was severe obstructive urinary symptoms or catheter-dependent urinary retention due to large prostates with volume >80 ml. Surgical procedureThe procedure consisted of two main steps through a single 3-cm suprapubic incision: first, enucleation of the adenoma, and second, a 360° bladder mucosal flap reconstruction. No drains or continuous bladder irrigation was used routinely. MeasurementsIntraoperative parameters, pre- and postoperative uroflowmetry, and 1-yr clinical outcomes were assessed. We used descriptive statistics to analyze the data. Results and limitationsAll procedures were completed successfully without additional ports or conversions. The median console time and estimated blood loss were 107 min and 100 ml, respectively. Transfusion rate was 0%. Intraoperative complications included two suspected air emboli attributed to high insufflation pressures. There were no major postoperative complications. In total, 95.8% were discharged within the first 24 h, with a median length of stay and pain score of 5 h and 3/10, respectively. There was persistent improvement in the median International Prostate Symptom Score and flow rate after 1 yr. The median Sexual Score Inventory for Men score was 20 at 12 mo. Our study is limited by its retrospective nature and cohort size. ConclusionsSP TV RASP is a feasible alternative for the management of severe benign prostatic hyperplasia that promotes fast recovery and demonstrates 1-yr improvement in urinary function. Patient summarySingle-port transvesical robot-assisted simple prostatectomy is a minimally invasive alternative for the treatment of large benign prostatic growth. A single robotic arm goes through a small incision in the skin and bladder to extract the obstructive prostatic tissue. Afterward, reconstruction of the area is done to decrease bleeding and improve postoperative symptoms. We found that patients recover quickly and have excellent clinical results with a low risk of complications.

Is There Any Relation Between High-Grade Prostate Cancer and Central Obesity, Hyperinsulinemia and Dyslipidemia?

Background: Prostate Cancer (PCa) is the sixth leading cause of cancer death in men, worldwide. Incidence of prostate cancer in India is on the rise. Most studies suggest that obesity has a positive correlation with a higher risk of developing high-grade PCa and dying of PCa. Central obesity and related biochemical alterations in terms of hyperinsulinemia and dyslipidemia are associated with severity of prostate cancer in terms of high Gleason score. Materials & Methods: Central obesity was assessed using anthropometric measurements including waist hip ratio (WHR) and body mass index (BMI). Serum PSA, testosterone, and insulin levels were estimated. Serum levels of triglycerides (TG), cholesterol, low-density lipoprotein (LDL), and very low-density lipoprotein (VLDL), high-density lipoprotein (HDL) were also measured. Standard staging procedures were followed and for histopathological evaluation of PCa, Gleason grading was done on core biopsy tissue. Results: In the present population-based study, persons with high Gleason score had significantly higher WHR supporting that central obesity may predispose to high-grade prostate cancer. Study has shown a significant relationship between high Gleason score and cholesterol, TG, VLDL, and low HDL levels; however no significant relation was found with LDL levels. Testosterone is a key prostate growth factor although PCa presents at an age when testosterone levels are declining. Conclusion: In this study, there was no significant difference in testosterone levels in patients with high and low Gleason scores. Keywords: Prostate, Cancer, High grade, Low grade

Effect of TNF-α Inhibitor Therapy on Growth of the Prostate Gland

BackgroundInflammation has been linked to the development of benign prostatic hyperplasia (BPH). SRD5A2 is a pivotal enzyme in the development and growth of the prostate gland and a critical target for BPH therapy. TNF-α regulates epigenetic changes in SRD5A2, leading to suppression of SRD5A2 gene and protein expression. It is unknown whether TNF-α inhibitor therapy affects prostate growth. ObjectiveTo evaluate the effect of TNF-α inhibitor therapy on prostate growth via analysis of measurements on serial pelvic imaging scans. Design, setting, and participantsIn this retrospective cohort study, we analyzed serial pelvic cross-sectional imaging (magnetic resonance imaging or computed tomography scans) for men aged ≥18 yr receiving TNF-α inhibitors. Our inclusion/exclusion criteria yielded a treatment cohort of 99 men. An age-matched cohort was constructed with the same inclusion/exclusion criteria but without TNF-α therapy (n = 99). Outcome measurements and statistical analysisProstate growth on serial pelvic cross-sectional imaging was the primary outcome measure. Results and limitationsThere was no significant difference in total prostate volume (TPV) at baseline between the two groups. The TNF-α treatment group had a lower mean TPV on follow-up (26.21 ± 9.43 vs 32.71 ± 18.89 cm3; p = 0.002) and a lower median prostate growth rate (−0.01 vs 0.68 cm3/yr; p = 0.001). A multivariable linear regression model adjusted for age, race, initial TPV, and body mass index also revealed a significantly lower growth rate for men in the treatment group. ConclusionTNF-α inhibitor use was negatively correlated with the prostate growth rate, suggesting that inflammatory mediators regulate prostate growth. Patient summaryWe examined prostate growth rates in men taking TNF-α inhibitors and found that these drugs have a shrinking effect on the prostate. We conclude that TNF-α inhibitors may impede prostate growth.

Novel progestogenic androgens for male contraception: design, synthesis, and activity of C7 α-substituted testosterone†.

Male contraceptive development has included use of testosterone (T) with or without a progestin or the use of a single molecule such as progestogenic androgens (PA) for suppression of testicular T production. Expanding upon the vast amount of data accumulated from nortestosterone (NT), NT analogs, and their prodrugs, a new series of PA, the C7 methyl, and ethyl α-substituted T analogs 7α-Methyltestosterone (7α-MT) and 7α-Ethyltestosterone (7α-ET), respectively, were hypothesized and designed to have superior androgenic and progestogenic activities when compared with parent T. Results from androgen receptor and progesterone receptor competitive binding and transcriptional activation assays showed favorable activities for these T analogs. Additionally, 7α-MT and 7α-ET were shown to be active substrates for aromatase in vitro, mitigating a potential negative impact on bone mineral density with long-term use. In conjunction with this observation, the diminished metabolism of these T analogs by 5α-reductase may reduce potential concerns for prostatic growth. In the Hershberger in vivo rat bioassay, 7α-MT and 7α-ET showed superior androgenic and anabolic activities as compared with T. These C7 α-substituted T analogs also showed clear progestogenic activity in the McPhail bioassay which evaluated endometrial glandular arborization in a rabbit model. The discovery of aromatizable molecules with reduced metabolism by 5α-reductase that have androgenic, anabolic, and progestogenic properties indicates that the core and/or prodrugs of 7α-MT and 7α-ET are promising molecules for further development as male contraceptive PAs.

Comparison of Testosterone Level of Seminal Vesicle Fluid in Patients With Prostate Cancer Versus Other Malignancies.

Testosterone is essential for prostate cancer development and growth. This study aimed to investigate the relationship between testosterone in seminal vesicles and prostate cancer incidence and its malignant phenotype. After obtaining institutional review board approval, seminal vesicle fluid samples were collected from patients who underwent prostatectomy or cystectomy. Pathological review demonstrated that 26 patients had benign prostate tissue and 149 had prostate cancer. First, testosterone levels in seminal vesicle fluid from benign prostate and prostate cancer samples were compared. Next, the relationship between pathological stage, International Society of Urological Pathology (ISUP) score, and testosterone concentrations in seminal vesicle fluid in the prostate cancer group were examined. Testosterone in seminal vesicles was significantly higher in the prostate cancer group [median (range), 1.94 (0.17-4.32) ng/ml] than in the benign prostate group (mainly bladder cancer) [1.45 (0.60-2.78) ng/ml] (p=0.001). Testosterone in seminal vesicles showed no difference in relation to pathological stage (pT2 vs. pT3) or ISUP score (12 vs. 345) (p=0.480 and p=0.964, respectively). Neoadjuvant chemotherapy for other cancers (e.g., bladder or rectal cancer) significantly reduced testosterone in seminal vesicles (p=0.013). Multivariate regression analysis revealed that testosterone in seminal vesicles was significantly correlated with prostate cancer, and not with neoadjuvant chemotherapy (p=0.023, p=0.457, respectively). Testosterone in seminal vesicles may contribute to prostate cancer incidence, but has no relationship with pathological grading.

PLEKHS1 drives PI3Ks and remodels pathway homeostasis in PTEN-null prostate

The PIP3/PI3K network is a central regulator of metabolism and is frequently activated in cancer, commonly by loss of the PIP3/PI(3,4)P2 phosphatase, PTEN. Despite huge research investment, the drivers of the PI3K network in normal tissues and how they adapt to overactivation are unclear. We find that in healthy mouse prostate PI3K activity is driven by RTK/IRS signaling and constrained by pathway feedback. In the absence of PTEN, the network is dramatically remodeled. A poorly understood YXXM- and PIP3/PI(3,4)P2-binding PH domain-containing adaptor, PLEKHS1, became the dominant activator and was required to sustain PIP3, AKT phosphorylation, and growth in PTEN-null prostate. This was because PLEKHS1 evaded pathway-feedback and experienced enhanced PI3K- and Src-family kinase-dependent phosphorylation of Y258XXM, eliciting PI3K activation. hPLEKHS1 mRNA and activating Y419 phosphorylation of hSrc correlated with PI3K pathway activity in human prostate cancers. We propose that in PTEN-null cells receptor-independent, Src-dependent tyrosine phosphorylation of PLEKHS1 creates positive feedback that escapes homeostasis, drives PIP3 signaling, and supports tumor progression.

PHYTOCHEMICALS AND PHARMACOLOGICAL POTENTIALS OF CUCURBITA MAXIMA: A REVIEW

In ancient literature, we find references to the therapeutic use of about 500 plants; indigenous medical practices make use of about 800 plants. The pumpkin plant (Cucurbita maxima) is a creeper that is commonly seen growing on the rooftops of homes in India. Seeds, pulp, and fruit stalks are all put to good use. In addition to its potent antioxidant properties, pumpkin seed oil has been lauded for its ability to treat a variety of medical conditions, including but not limited to the prevention and reduction of prostate growth and size; the reduction of bladder and urethral pressure, the improvement of bladder compliance; the alleviation of diabetes by promoting hypoglycemic activity; and the reduction of gastric, breast, lung, and colorectal cancer. Chemical compounds can be extracted from seeds, including 24-ethyl-5-cholesta-7,22-trien-3-ol, 24-ethyl-5-cholesta-7,25-dien-3-ol, avenasterol, spinasterol, 24-dihydrospinasterol, 24-methyl lathosterol, and 25(27)-dehydrofungisterol. From the seeds, I extracted 25-(27) dehydroporiferasterol, clerosterol, isofucosterol, stigmasterol, sitosterol, campesterol, and codisterol. Traditionally, it has been utilized in headaches, nerve pain, inflammation, abscesses, and boils etc. Different parts of C. maxima have been evaluated for numerous pharmacological activities i.e., anticancer, anti-obesity, antidiabetic, hepatoprotective, diuretic, antioxidant, immunogenic, cardiotonic, antidepressant, hypolipidemic, antiarthritic and antifungal. Seed extract from the Saw Palmetto plant is used to treat benign prostatic hyperplasia, sometimes in combination with other botanicals in order to cure prostate cancer. In conclusion, the pumpkin plant is highly promising in the coming era with diverse nutritional and pharmacological properties.

N-(2-ozoazepan-3-yl)-pyrrolidine-2-carboxamide, a novel Octopus vulgaris ink-derived metabolite, exhibits a pro-apoptotic effect on A549 cancer cell line and inhibits pro-inflammatory markers.

This research aimed to chemically synthesize and evaluate the antiproliferative and anti-inflammatory potential of ozopromide (OPC), a novel compound recently isolated from O. vulgaris ink. After chemical synthesis, OPC structural characterization was confirmed by COSY2D, FTIR, and C-/H-NMR. OPC inhibited the growth of human breast (MDA-MB-231), prostate (22Rv1), cervix (HeLa), and lung (A549) cancerous cells, being the highest effect on the latter (IC50: 53.70μM). As confirmed by flow cytometry, OPC induced typical apoptosis-derived morphological features on A549cells, mostly at early and late apoptosis stages. OPC generated a dose-dependent effect inhibiting IL-6 and IL-8 on LPS-stimulated peripheral mononuclear cells (PBMCs). A major affinity of OPC to Akt-1 and Bcl-2 proteins in silico agreed with the observed pro-apoptotic mechanisms. Results suggested that OPC has the potential to alleviate inflammation and be further studied for anticancer activity. Marine-derived food products such as ink contains bioactive metabolites exhibiting potential health benefits.

Is There a Link Between Non-Alcoholic Fatty Liver Disease and Benign Prostate Hyperplasia/Lower Urinary Tract Symptoms: A Systematic Review and a Meta-Analysis.

Background: Prostatic growth has been thought to be the systemic manifestation of some metabolic derangements in recent studies. Nonalcoholic fatty liver disease (NAFLD), a hepatic manifestation of the metabolic syndrome, might be closely linked with benign prostate hyperplasia and lower urinary tract symptoms (BPH/LUTS). Several studies have been conducted regarding NAFLD and BPH/LUTS association. However, the results are yet to reach a clear conclusion. We aimed to gather these studies' results to make a more robust analysis through a systematic review and meta-analysis. Methods: We systematically searched Pubmed-Medline, Cochrane Library, and Science Direct databases. We excluded all experimental studies, case reports, and reviews. Our search was restricted to the English language. We used standard mean difference for BPH/LUTS-related parameters. We identified the study qualities by the Newcastle-Ottawa Scale. We conducted a publication bias analysis. Results: A total of six studies involving 7089 participants fulfilled the inclusion criteria. Our meta-analysis revealed that patients with NAFLD have larger prostate volume [0.553 (0.303-0.802), P ˂ 0.001; Q = 97.41; P-value for heterogeneity = P < 0.0001; I2 = 94.86%]. However, the summary effect size of the other parameters of BPH/LUTS (prostate-specific antigen and international prostate symptom score) computed in our meta-analysis did not yield significant results. Conclusions: The prostate size was larger in patients with NAFLD, but the meta-analysis did not reach a significant result for LUTS among the studies. These results should be tested with well-designed studies, in particular, to clarify the association of LUTS with NAFLD.

Identification of small-molecule inhibitors against the interaction of RNA-binding protein PSF and its target RNA for cancer treatment.

Diverse cellular activities are modulated through a variety of RNAs, including long noncoding RNAs (lncRNAs), by binding to certain proteins. The inhibition of oncogenic proteins or RNAs is expected to suppress cancer cell proliferation. We have previously demonstrated that PSF interaction with its target RNAs, such as androgen-induced lncRNA CTBP1-AS, is critical for hormone therapy resistance in prostate and breast cancers. However, the action of protein-RNA interactions remains almost undruggable to date. High-throughput screening (HTS) has facilitated the discovery of drugs for protein-protein interactions. In the present study, we developed an in vitro alpha assay using Flag peptide-conjugated lncRNA, CTBP1-AS, and PSF. We then constructed an effective HTS screening system to explore small compounds that inhibit PSF-RNA interactions. Thirty-six compounds were identified and dose-dependently inhibited PSF-RNA interaction in vitro. Moreover, chemical optimization of these lead compounds and evaluation of cancer cell proliferation revealed two promising compounds, N-3 and C-65. These compounds induced apoptosis and inhibited cell growth in prostate and breast cancer cells. By inhibiting PSF-RNA interaction, N-3 and C-65 up-regulated signals that are repressed by PSF, such as the cell cycle signals by p53 and p27. Furthermore, using a mouse xenograft model for hormone therapy-resistant prostate cancer, we revealed that N-3 and C-65 can significantly suppress tumor growth and downstream target gene expression, such as the androgen receptor (AR). Thus, our findings highlight a therapeutic strategy through the development of inhibitors for RNA-binding events in advanced cancers.

Hyperphosphorylated PTEN exerts oncogenic properties

PTEN is a multifaceted tumor suppressor that is highly sensitive to alterations in expression or function. The PTEN C-tail domain, which is rich in phosphorylation sites, has been implicated in PTEN stability, localization, catalytic activity, and protein interactions, but its role in tumorigenesis remains unclear. To address this, we utilized several mouse strains with nonlethal C-tail mutations. Mice homozygous for a deletion that includes S370, S380, T382 and T383 contain low PTEN levels and hyperactive AKT but are not tumor prone. Analysis of mice containing nonphosphorylatable or phosphomimetic versions of S380, a residue hyperphosphorylated in human gastric cancers, reveal that PTEN stability and ability to inhibit PI3K-AKT depends on dynamic phosphorylation-dephosphorylation of this residue. While phosphomimetic S380 drives neoplastic growth in prostate by promoting nuclear accumulation of β-catenin, nonphosphorylatable S380 is not tumorigenic. These data suggest that C-tail hyperphosphorylation creates oncogenic PTEN and is a potential target for anti-cancer therapy.

Neferine attenuates development of testosterone-induced benign prostatic hyperplasia in mice by regulating androgen and TGF-β/Smad signaling pathways

Benign prostatic hyperplasia (BPH) is a common urinary disease among the elderly, characterized by abnormal prostatic cell proliferation. Neferine is a dibenzyl isoquinoline alkaloid extracted from Nelumbo nucifera and has antioxidant, anti-inflammatory and anti-prostate cancer effects. The beneficial therapeutic effects and mechanism of action of neferine in BPH remain unclear.A mouse model of BPH was generated by subcutaneous injection of 7.5 mg/kg testosterone propionate (TP) and 2 or 5 mg/kg neferine was given orally for 14 or 28 days. Pathological and morphological characteristics were evaluated. Prostate weight, prostate index (prostate/body weight ratio), expression of type Ⅱ 5α-reductase, androgen receptor (AR) and prostate specific antigen were all decreased in prostate tissue of BPH mice after administration of neferine. Neferine also downregulated the expression of pro-caspase-3, uncleaved PARP, TGF-β1, TGF-β receptor Ⅱ (TGFBR2), p-Smad2/3, N-cadherin and vimentin. Expression of E-cadherin, cleaved PARP and cleaved caspase-3 was increased by neferine treatment.1–100 μM neferine with 1 μM testosterone or 10 nM TGF-β1 were added to the culture medium of the normal human prostate stroma cell line, WPMY-1, for 24 h or 48 h. Neferine inhibited cell growth and production of reactive oxygen species (ROS) in testosterone-treated WPMY-1 cells and regulated the expression of androgen signaling pathway proteins and those related to epithelial-mesenchymal transition (EMT). Moreover, TGF-β1, TGFBR2 and p-Smad2/3, N-cadherin and vimentin expression were increased but E-cadherin was decreased after 24 h TGF-β1 treatment in WPMY-1 cells. Neferine reversed the effects of TGF-β1 treatment in WPMY-1 cells. Neferine appeared to suppress prostate growth by regulating the EMT, AR and TGF-β/Smad signaling pathways in the prostate and is suggested as a potential agent for BPH treatment.

The prognostic value of androgen to PSA ratio in predictive modeling of prostate cancer

Prostate specific antigen (PSA) is the ubiquitous biomarker used in mathematical and artificial intelligence models of prostate cancer. Yet, it is imperfect. The growth of prostate and cancer cells produces PSA, but their growth is dependent on androgen in most cases. Thus, looking at PSA by itself ignores the impact of androgen. Here, we propose the use of androgen as a reference framework for better integration of PSA in prostate cancer models. The binding of androgen to androgen receptors activates signals that promote prostate cancer growth and the production of PSA, so higher levels of androgen should correlate to higher growth of the tumor and higher production of PSA. Thus, PSA and androgen fall and rise almost synchronously during the start and stop of androgen deprivation therapy (ADT), respectively. Yet, when cancer cells become resistant to ADT, we observe a divergence to this trend, leading to a high level of PSA even during ADT. Therefore, we hypothesize that the cancer evolutionary dynamics can be represented by the ratio of androgen to PSA and its integration into prostate cancer models may help improve their predictive power.

Inhibition of growth and contraction in human prostate stromal cells by silencing of NUAK1 and -2, and by the presumed NUAK inhibitors HTH01-015 and WZ4003.

Background: NUAKs promote myosin light chain phosphorlyation, actin organization, proliferation and suppression of cell death in non-muscle cells, which are critical for smooth muscle contraction and growth. In benign prostatic hyperplasia (BPH), contraction and growth in the prostate drive urethral obstruction and voiding symptoms. However, a role of NUAKs in smooth muscle contraction or prostate functions are unknown. Here, we examined effects of NUAK silencing and the presumed NUAK inhibitors, HTH01-015 and WZ4003 on contraction and growth-related functions in prostate stromal cells (WPMY-1) and in human prostate tissues. Methods: Effects of NUAK1 and -2 silencing, HTH01-015 and WZ4003 on matrix plug contraction, proliferation (EdU assay, Ki-67 mRNA), apoptosis and cell death (flowcytometry), viability (CCK-8) and actin organization (phalloidin staining) were examined in cultured WPMY-1 cells. Effects of HTH01-015 and WZ4003 on smooth muscle contraction were assessed in organ bath experirments with human prostate tissues. Results: Effects of silencing were most pronounced on proliferation and cell death, resulting in decreases of proliferation rate by 60% and 70% by silencing of NUAK1 and NUAK2 (compared to scramble siRNA-transfected controls), decreases in Ki-67 by 75% and 77%, while numbers of dead cells after silencing of NUAK1 and NUAK2 amounted to 2.8 and 4.9 fold of scramble-transfected controls. Silencing of each isoform was paralleled by reduced viability, breakdown in actin polymerization, and partial decreases in contractility (maximally 45% by NUAK1 silencing, 58% by NUAK2 silencing). Effects of silencing were mimicked by HTH01-015 and WZ4003, with numbers of dead cells amounting up to 16.1 fold or 7.8 fold with HTH01-015 or WZ4003, compared to solvent-treated controls. Using concentrations of 500nM, neurogenic contractions of prostate tissues were inhibited partly by HTH01-015 and U46619-induced contractions were inhibited partly by HTH01-015 and WZ4003, while α1-adrenergic and endothelin-1-induced contractions remained unaffected. Using 10μM, inhibition of endothelin-1-induced contractions by both inhibitors and inhibition of α1-adrenergic contractions by HTH01-015 added to effects seen by 500nM. Conclusion: NUAK1 and -2 suppress cell death and promote proliferation in prostate stromal cells. A role in stromal hyperplasia appears possible in BPH. Effects of NUAK silencing are mimicked by HTH01-015 and WZ4003.

Preferred methods of Diagnosis and Treatment of Benign Prostatic Hyperplasia adopted by Ayurveda practitioners - A Survey Study

Introduction: Benign Prostatic Hyperplasia (BPH) refers to the nonmalignant growth of prostate gland. In Ayurveda, it can be correlated with Mutraaghata or Mutradosha. Currently used common oral medications such as 5α-reductase inhibitors, α1-Blockers as well as surgical treatment methods such as Transurethral Resection of the Prostate (TURP) have well-known side effects. Ayurveda case studies on BPH show evidence of a potential alternative to these current methods. Objectives: To conduct a survey to know the diagnostic methods and treatment modalities used by different Ayurveda Practitioners in BPH treatment. Materials &amp; Methods: A survey comprising 7 questions in the form of multiple-choice questions on the diagnosis and treatment methods of BPH adopted by Ayurveda Physicians was done. The answers were recorded and interpreted in the form of graphs and pie charts. Results: A total of 57 different Ayurveda practitioners participated in the survey. Prevalence of BPH was seen more in the age group of 60-70 years. Ultrasonography (USG) and Prostate Specific Antigen (PSA) were among the most commonly used diagnostic methods for BPH. Most common symptoms observed were increased frequency of urine, urine incontinence and urine urgency. Uttara Basti (administration of medicine through the urethra) was the most recommended type of treatment procedure preferred, followed by Matra Basti (enema). Avagaha Swedana (Sitz bath) was recommended by most practitioners. The course duration of treatment is advised to be around half to one month. Around 40-60% relief was claimed in patients with BPH by the participants. Conclusion: BPH is a condition that is currently being treated by various Ayurveda practitioners using classical treatment methods such as Uttara Basti, Matra Basti etc. with claimed relief of about 40-60% by the participants.

Long non-coding RNAs in bone metastasis: progresses and perspectives as potential diagnostic and prognostic biomarkers.

In a precision medicine perspective, among the biomarkers potentially useful for early diagnosis of cancers, as well as to define their prognosis and eventually to identify novel and more effective therapeutic targets, there are the long non-coding RNAs (lncRNAs). The term lncRNA identifies a class of non-coding RNA molecules involved in the regulation of gene expression that intervene at the transcriptional, post-transcriptional, and epigenetic level. Metastasis is a natural evolution of some malignant tumours, frequently encountered in patients with advanced cancers. Onset and development of metastasis represents a detrimental event that worsen the patient's prognosis by profoundly influencing the quality of life and is responsible for the ominous progression of the disease. Due to the peculiar environment and the biomechanical properties, bone is a preferential site for the secondary growth of breast, prostate and lung cancers. Unfortunately, only palliative and pain therapies are currently available for patients with bone metastases, while no effective and definitive treatments are available. The understanding of pathophysiological basis of bone metastasis formation and progression, as well as the improvement in the clinical management of the patient, are central but challenging topics in basic research and clinical practice. The identification of new molecular species that may have a role as early hallmarks of the metastatic process could open the door to the definition of new, and more effective, therapeutic and diagnostic approaches. Non-coding RNAs species and, particularly, lncRNAs are promising compounds in this setting, and their study may bring to the identification of relevant processes. In this review, we highlight the role of lncRNAs as emerging molecules in mediating the formation and development of bone metastases, as possible biomarkers for cancer diagnosis and prognosis, and as therapeutic targets to counteract cancer spread.

VSSP-activated macrophages mediate senescence and tumor inhibition in a preclinical model of advanced prostate cancer

Androgen deprivation therapy (ADT) is a standard therapy for prostate cancer (PCa). Though disseminated disease is initially sensitive to ADT, an important fraction of the patients progresses to castration-resistant prostate cancer (CRPC). For this reason, the identification of novel effective therapies for treating CRPC is needed. Immunotherapeutic strategies focused on macrophages as antitumor effectors, directly enhancing their tumoricidal potential at the tumor microenvironment or their adoptive transfer after ex vivo activation, have arisen as promising therapies in several cancer types. Despite several approaches centered on the activation of tumor-associated macrophages (TAMs) in PCa are under investigation, to date there is no evidence of clinical benefit in patients. In addition, the evidence of the effectiveness of macrophage adoptive transfer on PCa is poor. Here we find that VSSP, an immunomodulator of the myeloid system, decreases TAMs and inhibits prostatic tumor growth when administered to castrated Pten-deficient prostate tumor-bearing mice. In mice bearing castration-resistant Ptenpc−/−; Trp53pc−/− tumors, VSSP administration showed no effect. Nevertheless, adoptive transfer of macrophages activated ex vivo with VSSP inhibited Ptenpc−/−; Trp53pc−/− tumor growth through reduction of angiogenesis and tumor cell proliferation and induction of senescence. Taken together, our results highlight the rationale of exploiting macrophage functional programming as a promising strategy for CRPC therapy, with particular emphasis on ex vivo-activated proinflammatory macrophage adoptive transfer.Graphical abstract5rwXuKXp78386xwRRkt56hVideo abstract

Abstract 5281: Role of TMEM97/Sigma-2 receptor in prostate cancer

Abstract Introduction: Prostate cancer is the most common cancer in men. About one in eight men will be diagnosed with prostate cancer in his lifetime, and one in forty-one men will die of it. Sigma 2 receptor (σ2R) has been implicated in carcinogenesis including prostate cancer. Its molecular identity remained elusive until 2017 that transmembrane protein 97 (TMEM97) was identified as the bona fide sigma 2 receptor. Past studies have shown that σ2R is highly expressed in various mammalian tumors and TMEM97 works as an oncogene in different cancers. In this study, we examined the expression of TMEM97/σ2 receptor in prostate cancer, evaluated its interaction with androgen receptor (AR), and determined its functions in tumor cell growth and progression. Methods: The expression of TMEM97 at mRNA levels and its association with clinical parameters were queried in the TCGA database using cBioportal. Its expression pattern in prostate tumor tissues was examined by IHC using a commercially validated antibody. A correlation analysis of TMEM97 with AR was conducted utilizing both PCTA and TCGA databases. To determine its roles in tumor proliferation, clonogenicity, and responses to hormone deprivation and chemo-therapy, TMEM97 expression was overexpressed and knocked down, and the subsequent effects were determined by cell proliferation MTS assay, colony formation assay with and without enzalutamide treatment. A xenograft model of nu/nu mice was used to assess the impact of TMEM97 overexpression on tumor formation and growth in vivo. The effects of TMEM97 overexpression and knockdown on AR transcriptional activity were examined. Results: A significant elevation of TMEM97 mRNA levels, with a Z-Score above 2.0, was found in 5% of the prostate cancer patients and was associated with significantly reduced survival. TMEM97 protein was detected in prostate tumor tissues of all stages and grades. Its expression is highly correlated with the expression of AR in prostate cancer. Prostate cancer cells with TMEM97 overexpression showed growth advantage over the control cells both in normal culture conditions and also under treatment of enzalutamide. TMEM97 knockdown weakened growth, and sensitized castration resistant 22Rv1 toward enzalutamide, which is linked to the decrease of AR-V7. TMEM97 overexpression in LNCaP cells also significantly increased tumor formation and growth when xenografted into nu/nu mice. In LNCaP cells, TMEM97 overexpression elevated AR target genes expression. Parallelly, these genes were all significantly downregulated in TMEM97 knockdown cells. A compound with a high affinity to TMEM97 was found to induce apoptosis of prostate cancer cells with preferential degradation of AR-V7. Conclusion: The observations suggest that TMEM97/sigma2 receptor plays a role in prostate tumor cell proliferation and the increased expression of TMEM97 can elevate AR activity and stimulate prostate tumor formation and growth. Citation Format: Xiangwei Fang, Yuanqin Zhang, Jiuhui Wang, Paul Cacioppo, Michael Crider, Daotai Nie. Role of TMEM97/Sigma-2 receptor in prostate cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5281.

PD02-08 ESR1+ LUMINAL EPITHELIAL CELLS DRIVE THE PROSTATE GROWTH AND SURVIVAL IN THE ABSENCE OF SRD5A2

You have accessJournal of UrologyCME1 Apr 2023PD02-08 ESR1+ LUMINAL EPITHELIAL CELLS DRIVE THE PROSTATE GROWTH AND SURVIVAL IN THE ABSENCE OF SRD5A2 Christina Sharkey, Xingbo Long, Ra'ad Al-Faouri, Aria F. Olumi, and Zongwei Wang Christina SharkeyChristina Sharkey More articles by this author , Xingbo LongXingbo Long More articles by this author , Ra'ad Al-FaouriRa'ad Al-Faouri More articles by this author , Aria F. OlumiAria F. Olumi More articles by this author , and Zongwei WangZongwei Wang More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003219.08AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Steroid 5α reductase 2 (SRD5A2) is the predominant enzyme responsible for prostatic development and growth. 5α reductase inhibitors (5ARI) are the only class of benign prostate hyperplasia-related medications that reduce prostate size. However, why the patients respond variably to 5ARI therapies is still largely unknown. We previously demonstrated that 30% of adult human prostatic tissues do not express the SRD5A2 gene and protein via epigenetic modifications. We established a SRD5A2 null (Srd5a2-/-) mouse model and through single cell RNA sequencing, we identified LE2, a sub-cell population of ESR1+ luminal epithelial that is upregulated in Srd5a2-/- mice. Our goal in this study is to characterize the spatial expression of LE2 markers and its functional phenotype when SRD5A2 is absent. METHODS: Homozygous Srd5a2-/- mice and littermate control heterozygous SRD5A2+/- mice were generated and differentially expressed gene profiles of LE2 were obtained from single-cell RNA sequencing (scRNA seq). Spatial expression of LE2 markers was evaluated by RNA fluorescence in-situ hybridization (RNA-FISH). Cell proliferation was detected by Ki67 and BrdU staining. The Cell Death and ER signaling pathways were evaluated with RT2 PCR profiler arrays (84 genes per array) and downstream signaling pathways were analyzed by western blot. Prostate biopsies from the clinical trial of 5ARI for Medical Therapy of Prostatic Symptoms (MTOPS) were used for immunohistochemistry. RESULTS: The prostate weight of Srd5a2-/- mice was significantly decreased compared to Srd5a2+/- littermate control mice (p<0.001). The prostate cell proliferation was suppressed in Srd5a2-/- mice (p=0.05). The cell death signaling akt1, caspase 7, caspase 9, and ER target genes cyp1a1 and vegfa were downregulated (p<0.05). On the other hand, in the anterior lobe of prostate of Srd5a2-/- mice, the cell proliferation was higher than that in control. scRNA seq showed that ESR1 was expressed mainly in the prostate anterior lobe and the number of ESR1+ LE2 cells was significantly increased upon SRD5A2 absence. This was confirmed by RNA-FISH using the probes of LE2 cell markers ESR1 and PVT1. Co-staining of LE2 cell markers ESR1 and PKCa in prostate biopsies of MTOPS further confirmed the existence of an equivalent LE2 cell population in the human prostate with BPH. CONCLUSIONS: Our data demonstrate that LE2, the subpopulation of prostate cells may play an important role in alternative pathways for prostate growth and survival in absence of SRD5A2 and androgen deprivation. Understanding the underlying androgen-independent pathways contributing to prostate growth can help identify novel therapeutic targets for the management of prostatic diseases. Source of Funding: NIH/R01 DK124502 © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e71 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Christina Sharkey More articles by this author Xingbo Long More articles by this author Ra'ad Al-Faouri More articles by this author Aria F. Olumi More articles by this author Zongwei Wang More articles by this author Expand All Advertisement PDF downloadLoading ...

PD02-07 ALTERNATE ANDROGEN-INDEPENDENT PATHWAYS FOR PROSTATE GROWTH IN THE ABSENCE OF SRD5A2

You have accessJournal of UrologyCME1 Apr 2023PD02-07 ALTERNATE ANDROGEN-INDEPENDENT PATHWAYS FOR PROSTATE GROWTH IN THE ABSENCE OF SRD5A2 Christina Sharkey, Xingbo Long, Ra'ad Al-Faouri, Aria F. Olumi, and Zongwei Wang Christina SharkeyChristina Sharkey More articles by this author , Xingbo LongXingbo Long More articles by this author , Ra'ad Al-FaouriRa'ad Al-Faouri More articles by this author , Aria F. OlumiAria F. Olumi More articles by this author , and Zongwei WangZongwei Wang More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003219.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Benign prostatic hyperplasia (BPH) is a heterogeneous disease that results from the nonmalignant proliferation of both the prostate epithelial and stromal compartments. Steroid 5α reductase 2 (SRD5A2) is the predominant enzyme responsible for prostatic development and growth. Despite the introduction of steroid 5α-reductase inhibitors (5ARI) for benign prostatic hyperplasia (BPH), the progression of LUTS is only slowed by 34% with 5ARI-response. Therefore, we hypothesize that there are alternative pathways driving prostate growth and development when SRD5A2 is absent. To address this question we generated SRD5A2 null (Srd5a2-/-) mouse model and demonstrated that luminal cells with lineage signature and progenitor signature diminished, whereas luminal cells with estrogen response genetic signature stably survived when SRD5A2 is absent. Here we further aim to identify whether the cell-cell interactions between stromal cells and luminal cells with WNT5A are the critical modulators in absence of SRD5A2. METHODS: Single cell RNA sequencing (scRNA seq) and bulk RNA seq was performed with prostate tissues from Srd5a2-/- and Srd5a2+/- littermate control mice. Unbiased scRNA seq with 10x genomics platform, followed by unsupervised clustering, was utilized to generate cell clusters based on differentially expressed (DE) gene profiles. The heterotypic cell-cell communication was analyzed using CellphoneDB2. Identified ligand-receptor pairs were validated by qPCR in BHPrS1 human prostatic stromal cell line and human prostatic tissues with BPH. RNAscope was performed to identify the transcription expression of target genes. RESULTS: The expression of SRD5A2 was exclusively identified in fibroblasts and myofibroblasts. The absence of SRD5A2 induced the increase of stromal cells (11.3% vs. 18.0%) but decrease of luminal cells (53.2% vs. 31.8%). Analysis of ligand-receptor pairs indicated that stromal cells were the most prolific interactors, and myofibroblasts were the most "outbound" cells. Meanwhile, in Srd5a2-/- mice the fibroblasts had the most significantly increased weighted value (366 vs. 493), and LE1, one subset of luminal cells had most significantly decreased weighted value (205 vs. 96). Myofibroblast and muscle system processes were most significantly upregulated in Srd5a2-/- mice as assessed by bulk RNA-seq analysis. Nine highly significant interactions were identified which regulate stromal–luminal cell communication, including WNT5A/PTPRK, TGFB2/TGFBR1, and (NRP1, NRP2, FLT1)/VEGFA. RNAscope data showed a significant upregulation of WNT5A in the anterior prostate of Srd5a2-/- mice (p<0.0001). CONCLUSIONS: Our data suggest that the heterotypic cell-cell communication is substantially changed in the absence of SRD5A2. The stroma-niched signaling, particularly WNT5A and WNT signaling pathway might serve as a therapeutic target for managing BPH patients who lack SRD5A2 expression and may be unresponsive to 5ARI therapies. Source of Funding: NIH/R01 DK124502 © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e71 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Christina Sharkey More articles by this author Xingbo Long More articles by this author Ra'ad Al-Faouri More articles by this author Aria F. Olumi More articles by this author Zongwei Wang More articles by this author Expand All Advertisement PDF downloadLoading ...