Search Results (1,396)

Background: Homeobox transcription factors regulate developmental programs, cellular plasticity, and tumor progression, yet the role of H2.0-like homeobox (HLX) in prostate cancer (PCa) remains poorly defined. We investigated the clinical significance of HLX and its relationship to the pro-metastatic transcription factor TBX2. Methods: Transcriptomic and clinical datasets from TCGA, MET500, and SU2C/PCF cohorts were analyzed to assess HLX expression, clinicopathologic associations, and its relationship with TBX2. Functional studies in human PCa cell lines included TBX2 gain- and loss-of-function, HLX knockdown, chromatin immunoprecipitation (ChIP), and expression analyses. Shared HLX- and TBX2-associated pathways were evaluated by Reactome enrichment analysis, and Hallmark Gene Set Enrichment Analysis compared castration-resistant prostate cancer (CRPC) bone metastases with high versus low HLX expression (GSE77930; n = 5/group). In vivo relevance was assessed in an orthotopic TBX2 dominant-negative PCa xenograft model. Results: Human PCa datasets showed that HLX expression was elevated in PCa versus normal prostate tissue and associated with higher Gleason grade, lymph node involvement, aggressive molecular subtypes, and shorter disease-free survival. HLX expression also positively correlated with TBX2 across human PCa cohorts. HLX- and TBX2-associated transcriptional programs converged on extracellular matrix organization, cell adhesion, NOTCH, and VEGF-MAPK signaling pathways. Furthermore, HLX-high CRPC bone metastases were enriched for epithelial–mesenchymal transition, NOTCH, TGF-β, inflammatory, angiogenic, hypoxic, and KRAS signaling pathways. Mechanistic studies showed that HLX knockdown suppressed extracellular matrix-associated genes and key NOTCH pathway components. ChIP demonstrated direct TBX2 binding to the HLX promoter, and genetic modulation of TBX2 expression established HLX as a downstream target of TBX2. Consistent with these findings, reduced HLX expression in orthotopic TBX2 dominant-negative xenografts was associated with loss of metastatic progression. Conclusions: HLX is a candidate biomarker of aggressive PCa and a direct transcriptional target of TBX2. These findings identify a previously unrecognized TBX2–HLX regulatory axis associated with metastatic transcriptional programs and aggressive disease in advanced PCa. Full article

Prostate cancer is among the most frequently diagnosed cancers in men globally, with metastatic disease contributing substantially to morbidity and mortality. While conventional therapies remain the standard of care, dietary and lifestyle behaviors are increasingly explored as potentially modifiable factors influencing clinical outcomes, although their role in advanced disease is not well established. We report a 60-year-old, physically active male, lifelong non-smoker without significant comorbidities, diagnosed with de novo metastatic prostate adenocarcinoma (Gleason score 9) and an initial prostate-specific antigen (PSA) of 808.3 µg/L. The patient received standard androgen deprivation therapy. By personal choice, he adopted a whole-food, low-fat (WFLF) vegan diet, structured physical activity, and periodic fasting-mimicking diet cycles. These interventions complemented, but did not replace or delay, conventional treatment. During the 14-month follow-up period, serial PSA measurements, laboratory tests, blood pressure monitoring, dietary assessment, body composition analysis, imaging, and germline genetic testing were performed. PSA declined from 808.3 µg/L to 1.7 µg/L (>99.8%), and remained suppressed throughout follow-up. Concurrent improvements were observed in body composition and metabolic biomarkers. The WFLF vegan diet increased fiber and micronutrient intake while reducing saturated fat and cholesterol. This case demonstrates the successful application and execution of an integrative oncology approach and highlights metastatic prostate cancer managed with standard therapy alongside patient-initiated lifestyle modifications. The findings should be interpreted as descriptive, exploratory, and hypothesis-generating. Given the single-patient design, the independent impact of lifestyle interventions cannot be determined. Controlled studies are warranted to clarify their potential role in advanced prostate cancer management. Full article

Background: Prognostic assessment in metastatic castration-resistant prostate cancer (mCRPC) remains important, but metastatic burden is not routinely captured as a simple combined measure. This exploratory study developed the Metastatic Integrated Risk Assessment (MIRA) score using disease burden and routine variables. Methods: Anonymised placebo-arm individual patient data from D4320C00014/ENTHUSE-M1 were analysed. Baseline variables were assessed for association with overall survival (OS) using Cox regression. A hierarchical composite tumour-burden variable combined bone-metastasis categories with RECIST target-lesion presence and sum of longest diameters (SLD). Selected variables formed an additive score, stratified into three risk groups, and were compared with the reconstructed Halabi classification using Harrell’s C-index. The final multivariate Cox model underwent internal validation using 1000 bootstrap resamples. Results: Among 266 placebo-treated patients, 133 deaths occurred, and median OS was 22.21 months. Composite tumour burden showed the strongest prognostic association and remained independently associated with OS. MIRA risk groups showed clear OS separation. In this derivation cohort, MIRA showed higher apparent discrimination than the reconstructed Halabi classification, with C-indices of 0.755 and 0.646, respectively; the paired difference was statistically significant (p < 0.001). For the final multivariate Cox model, the apparent C-index was 0.779, and the optimism-corrected C-index was 0.760; the optimism-corrected calibration slope was 0.841. Conclusions: These exploratory findings support metastatic tumour burden as a relevant prognostic factor in mCRPC and suggest that a simple combined measure of skeletal and measurable soft-tissue disease may have value for risk stratification. Refinement and independent external validation of MIRA are required before clinical use. Full article

Prostate cancer is formed of a heterogeneous population of cancer cells with different biological properties. They initially form a small part of the normal stromal microenvironment but are able, through cell-to-cell contact and via exosomes, small nanoparticles containing DNA, mRNA, microRNA, long non-coding RNA, enzymes, and chemokines and cytokines, to transform the normal stromal cells into tumour-associated cells to create an immunosuppressive environment as well as inhibit the antitumour immune response. Matrix metalloproteinases are able to degrade not only the basement membrane but also the extracellular matrix, allowing the exosomes to disseminate via the circulation. Exosomes are organotrophic, homing in to specific tissues such as bone. Here, they create the premetastatic niche devoid of cancer cells and cause an immunosuppressive environment, as well as induce changes in the host cells and produce myeloid-derived suppressor cells, of which some migrate to the primary tumour inhibiting the antitumour immune response further. Prostate cancer cells can disseminate even before the cancer is detected and thus escape curative therapy. If they survive the shear forces of the circulation and the antitumour immune response, they are able to implant in the premetastatic niche, transforming it into the metastatic niche. Here, they enter a latent state or dormancy period, which may last for months or years but later can “awake” to form metastasis. This review critically analyses the cellular and molecular mechanisms, which produce this process from cellular aspects to the signalling pathways responsible for this process. Multiple mechanisms are involved in a coordinated fashion to permit the survival of the cancer cells, from cellular changes in host cells and immunomodulation via chemokines and cytokines. It emphasizes the role of microRNAs and long non-coding RNAs in this process, and that patients with higher Gleason scores have a worse prognosis in terms of biochemical free survival at 10 years. Therefore, a precision medical approach may improve the biochemical free survival rate without affecting the role of the signalling pathways in normal cells. This includes the modulation of interleukin expression, elimination of exosomes, or the inhibition of important enzymes, such as MMP-2, thus mitigating the residual recurrence risk that persists with conventional therapy. Full article

Objectives: Eligibility for Lutetium-177 labeled prostate-specific membrane antigen ([¹⁷⁷Lu]Lu-PSMA) radioligand therapy depends on PSMA PET/CT interpretation and may vary across observers and centres. We aimed to identify imaging and clinical correlates of VISION-like PSMA PET-defined eligibility and to compare exploratory clinical, PET-based, and combined models. Materials and Methods: Seventy-six consecutive patients with de novo metastatic prostate cancer undergoing PSMA PET/CT were retrospectively assessed for [¹⁷⁷Lu]Lu-PSMA eligibility. Candidacy was determined by consensus of two nuclear medicine physicians using VISION-like criteria. Three stepwise logistic regression models used clinical variables, PSMA PET/CT variables, or both, and were internally validated with bootstrap out-of-bag predictions. Results: Forty-three patients (56.6%) met VISION-like criteria for RLT. Internally validated area under the curve (AUC) values were 0.731, 0.817, and 0.829 for the clinical, PSMA PET/CT, and combined models. PET-defined candidacy was associated with higher PSMA-positive lesion count, greater PET-derived tumour burden, and higher mean standardised uptake value (SUVmean). Clinically, CHAARTED low-volume disease and prior docetaxel exposure were linked to lower probability, whereas disease state at imaging was not significant. In the combined multivariable model, SUVmean was independently associated with higher candidacy (odds ratio [OR]: 1.22, 95% confidence interval [CI]: 1.04–1.42; p = 0.015), whereas prior docetaxel showed the opposite association (OR: 0.10, 95% CI: 0.0129–0.776; p = 0.028). Conclusions: PSMA-positive lesion count and SUVmean were the most reproducible determinants of VISION-like eligibility. Prior docetaxel exposure was associated with lower candidacy in the combined model, although the exposed subgroup was small and the confidence interval wide. Whether systemic therapy modifies PSMA expression, and with it access to subsequent PSMA-targeted lines, requires paired imaging before and after treatment in the same patients. Full article

The management of oligometastatic disease has undergone a significant paradigm shift over the past two decades. Once considered uniformly incurable, selected patients with metastatic disease can now achieve prolonged progression-free survival, durable disease control, and, in carefully selected cases, long-term remission or cure through metastasis-directed therapies. Advances in stereotactic ablative radiotherapy (SABR), surgery, systemic therapies, and the emerging concept of Curative Oligometastatic Radiotherapy (CORT) have challenged the traditional distinction between curative and palliative treatment. Concurrent developments in imaging, including PET/CT, prostate-specific membrane antigen (PSMA) PET, whole-body MRI, and MR-guided adaptive radiotherapy (MR-linac), together with evolving biomarker research, are improving disease characterisation, refining patient selection, and treatment personalisation. As survival improves, an increasing number of patients are living with durably controlled metastatic cancer and experience long-term physical, psychological, cognitive, functional, and financial consequences of treatment. Despite these challenges, evidence-based survivorship pathways for patients with oligometastatic disease remain poorly defined. Supportive oncology is becoming an essential component of modern radiation oncology rather than an adjunct to cancer treatment. This emerging discipline focuses on optimising symptom control, minimising toxicity, and delivering structured survivorship care. Rather than being limited to end-of-life care, supportive oncology is embedded throughout the patient journey; from diagnosis and treatment selection to prehabilitation, rehabilitation, patient-reported outcome (PRO) monitoring, surveillance for late effects, multidisciplinary follow-up, and long-term survivorship. This review discusses how advances in precision radiotherapy, molecular imaging, biomarkers, and emerging treatment technologies are reshaping the management of oligometastatic disease while simultaneously creating a growing population of long-term survivors with increasingly complex supportive care needs. It highlights the expanding role of supportive oncology in the care of patients with oligometastatic disease, encompassing multidisciplinary symptom management and argues that improvements in disease control must now be matched by the development of evidence-based multidisciplinary survivorship pathways that integrate supportive oncology to optimise quality of life (QoL), functional independence, and patient-centred outcomes. Finally, this review highlights current evidence gaps and proposes future research priorities for developing evidence-based survivorship models for this rapidly expanding patient population. Full article

Prostate cancer remains one of the most frequently diagnosed malignancies in men worldwide, and despite favorable outcomes for localized disease, progression to castration-resistant prostate cancer (CRPC) represents a major clinical challenge associated with poor prognosis. CRPC is characterized by disease progression despite castrate levels of circulating testosterone and is most commonly diagnosed in the metastatic setting. Although the introduction of second-generation androgen receptor-targeted therapies has improved survival, resistance inevitably emerges. This review overviews the most recent findings in the field of CRPC with particular emphasis on the current understanding of the biological mechanisms of hormone-resistant cancer as well as the evidence on treatment strategies. A comprehensive literature search was conducted across PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar, focusing mainly on studies published between 2015 and 2025 that investigated molecular and cellular mechanisms of resistance to androgen deprivation therapy and androgen receptor (AR)-targeted treatments. Seventy-eight relevant articles were included in the final synthesis. The reviewed evidence highlights four major categories of resistance mechanisms. First, AR-dependent alterations remain predominant, including AR gene amplification, activating mutations, dysregulation of co-regulators, and expression of constitutively active AR splice variants such as androgen receptor variant 7 (AR-V7). Second, AR-independent or bypass pathways, most notably phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR), wingless-related integration site (WNT)/β-catenin, mitogen-activated protein kinase (MAPK), and glucocorticoid receptor signaling, enable tumor survival despite AR blockade. Third, lineage plasticity and transdifferentiation to neuroendocrine prostate cancer represent a distinct and increasingly recognized resistance mechanism driven by loss of tumor protein 53 (TP53) and retinoblastoma 1 (RB1) and epigenetic reprogramming. Finally, additional contributors, including intratumoral androgen synthesis, metabolic reprogramming, and tumor microenvironment interactions, further support disease progression. Together, these interconnected mechanisms underscore the biological complexity of CRPC and emphasize the need for biomarker-guided, combination-based therapeutic strategies to overcome resistance and improve patient outcomes. Full article

This report presents a within-patient comparison of ¹⁸F-rhPSMA-7.3 and ¹⁸F-PSMA-1007 PET/CT in a 71-year-old man with Gleason score 4 + 3 = 7, pT3bN1 metastatic castration-resistant prostate cancer after robot-assisted radical prostatectomy, multiple androgen-deprivation and androgen receptor-directed treatments, and radiotherapy for para-aortic nodal metastases. The scans showed concordant PSMA-avid cervical-to-mediastinal lymphadenopathy and an ill-defined right lower-lobe pulmonary lesion with a recorded SUVmax > 15, despite distinct physiologic biodistributions. Infection or inflammation remained a relevant differential diagnosis, and the patient declined biopsy. Antibiotics did not improve the CT findings. After enrollment in a clinical trial of systemic therapy, the last available pretreatment prostate-specific antigen (PSA) level of 42.4 ng/mL decreased to 3.1 ng/mL, with marked disease regression. The concordant dual-tracer findings, lack of response to antibiotics, and subsequent radiographic and biochemical response to systemic therapy favored nodal and pulmonary metastases from prostate cancer. However, without histopathologic confirmation, the diagnosis remains presumptive, highlighting the need to integrate PET biodistribution, semiquantitative uptake, anatomic imaging, and longitudinal clinical findings. Full article

In metastatic prostate cancer, there have been pronounced survival gains driven by the introduction of combination and intensification strategies. Consequently, many patients now experience prolonged survival with metastatic disease. While these advances represent a major therapeutic success, prolonged exposure to systemic therapies is associated with a broad spectrum of adverse effects. These side effects affect multiple domains, including bone health, cardiovascular risk, physical function, and psychological well-being. As a result, survivorship has emerged as a critical and increasingly relevant aspect of care in metastatic prostate cancer. In parallel, the importance of patient-reported outcomes in clinical trials, alongside traditional oncologic endpoints, is increasingly acknowledged. Overall, survivorship care in metastatic disease remains incompletely conceptualized as the long-term impact of cumulative treatment burden is often underrecognized. This narrative review examines key survivorship challenges in metastatic prostate cancer in an era of improving survival, with a focus on treatment-related toxicities, quality of life, and unmet needs in supportive care. We highlight current evidence, identify gaps in knowledge, and discuss future directions for integrating survivorship into routine clinical practice. Full article

Background/Objectives: To date there is a lack of an integrative review literature on redox homeostasis, oxidative stress and the influence on metabolic pathways and plasticity in uveal melanoma (UM), since most literature findings are from cutaneous melanoma (CM), a genetically and behaviorally distinct cancer. Furthermore, UM metabolic pathway comparison to other cancers could provide more insight into metastatic UM, a difficult-to-treat malignancy. Methods: A wide-ranging multi-step literature search of PubMed and Web of Science for redox balance, oxidative stress, antioxidants and metabolic plasticity in UM, with expanded search terms for connections with other cancers. Results: UM cells maintain redox homeostasis via several redox loops: glutathione, thioredoxin, peroxiredoxins, peroxisomal catalase and the mitochondrial antioxidative network. NADPH plays a key role in regenerating UM antioxidative capabilities. Key redox signaling pathways are the subject of ongoing research in UM: NRF2 signaling, AMPK, mTOR, MAPK, FoxO. These pathways are less studied versus CM and present behavior differences in UM. PON2, studied in CM, represents a literature gap in UM. Inside the tumoral microenvironment, UM presents high metabolic plasticity and easy switching from glycolysis to oxidative phosphorylation (OXPHOS). Thus, UM eschews the classic Warburg effect loop and instead presents high oxidative phosphorylation (OXPHOS) gene expression, which generates additional lactate, which in turn produces cascade reprogramming in the metabolic pathways and lactate metabolism particularities associated in experimental studies with immune-escape phenomena. Uveal melanoma’s OXPHOS capabilities confer survival advantages and subdivide tumoral populations into OXPHOS-high and OXPHOS-low variants. Glycolysis/OXPHOS metabolic plasticity is an ongoing research field in other cancers with common and different elements vs. UM: cutaneous melanoma, small cell lung carcinoma, pancreatic cancer, breast cancer, acute myeloid leukemia, prostate cancer, renal cell carcinoma and glioblastoma. Uveal melanoma cells are susceptible to deleterious effects of prooxidants, a metabolic vulnerability which helps to create genetic pleomorphism, selecting higher proliferation and dissemination variants. Conclusions: Uveal melanoma is an oncogenic mutation and mitochondrial metabolism-driven malignancy, with metabolic connections to other malignancies. Emerging understanding of redox homeostasis, redox pathway signaling, mitochondrial oxidative and oncogenic metabolism could lead to better understanding of therapeutic response and new therapeutic targets. This review novelly integrates the general and CM redox literature with the UM literature, painting a complex redox signaling and metabolic plasticity picture of UM. Full article

Background: Germline and somatic variants in DNA Damage Repair (DDR) genes are found in approximately one-fourth of patients with metastatic prostate cancer (PC). However, their precise prognostic role and predictive impact on standard therapies remain controversial. Methods: This retrospective, single-center study evaluated the prevalence of germline/somatic DDR aberrations in 287 eligible patients with metastatic prostate cancer (mPC), treated between 2017 and 2022. Clinical characteristics and treatment outcomes (PFS and OS) for chemotherapy (taxanes) or next-generation hormonal therapies (NHT) were compared between DDR-mutated (DDRmut) and wild-type (DDRwt) cohorts. Results: Sixty-three patients (21.9%) were DDRmut, with BRCA2 (12.5%), ATM (3.1%), and BRCA1 (1.39%) being the most common alterations. A family history of breast, ovarian, or prostate cancer strongly predicted DDRmut status (47.0% vs. 14.0%, p = 0.0001). Tissue samples remained evaluable for sequencing up to 180 months from collection. Overall baseline characteristics were similar between cohorts, and BRCA1/2- and ATM-mutated patients treated with first-line taxanes for mCRPC presented with non significantly highermedian OS compared to DDRwt patients (70 vs. 36 months; p = 0.30). On the contrary, the DDRmut subgroup showed a trend toward shorter PFS (12 vs. 18 months; p = 0.04) when treated with first-line NHT. No significant differences were observed with third-line Cabazitaxel. Conclusions: Formalin-fixed paraffin-embedded (FFPE) prostate tissue is highly reliable for DDR, possibly integrating novel liquid biopsy approaches for DDR evaluation. In a real-world setting, BRCA1/2 and ATM variants identify a distinct molecular subgroup that derives preferential survival benefit from first-line taxanes over standard hormonal intensification. Full article

Background/Objectives: Lutetium (¹⁷⁷Lu) TLX591 (¹⁷⁷Lu-TLX591) is a radio antibody–drug conjugate (rADC) that utilizes a novel monoclonal antibody-based approach for treatment of patients with prostate-specific membrane antigen (PSMA)-expressing metastatic castration-resistant prostate cancer (mCRPC). ProstACT SELECT (NCT04786847) was a multicenter, single-arm, open-label Phase 1 trial evaluating patient selection for ¹⁷⁷Lu-TLX591 therapy using ⁶⁸Ga-PSMA-11 PSMA positron emission tomography (PET) in a heterogenous sample of patients with mCRPC. Primary and key secondary objectives were to evaluate safety and tolerability, biodistribution, and organ radiation dosimetry of ¹⁷⁷Lu-TLX591 in combination with the best standard of care (SOC) for patients with PSMA-expressing mCRPC who progressed despite prior treatment with an androgen receptor pathway inhibitor. Methods: Thirty patients received ¹⁷⁷Lu-TLX591 intravenously in combination with investigator-determined SOC. Cohort 1 (n = 5) received an imaging dose of ¹⁷⁷Lu-TLX591 (1 GBq [27 mCi]), followed 14 days later by one therapeutic dose (2.8 GBq [76 mCi]). Cohort 2 received two therapeutic doses of ¹⁷⁷Lu-TLX591, 14 days apart. Baseline ⁶⁸Ga-PSMA-11 PET was performed to confirm eligibility and was qualitatively compared with serial ¹⁷⁷Lu-TLX591 single-photon emission computed tomography (SPECT)/CT, which was performed at five timepoints following the first ¹⁷⁷Lu-TLX591 administration and also used to evaluate organ radiation dosimetry. Safety assessments included monitoring for treatment-emergent adverse events and collection of laboratory samples at specified timepoints used for biomarker analyses. Results: Tumor targeting observed on ¹⁷⁷Lu-TLX591 SPECT/CT imaging was qualitatively consistent with uptake observed on ⁶⁸Ga-PSMA-11 PET imaging. No new safety signals were observed. Radiation exposure was within safety limits, with the highest absorbed dose to liver (clearance organ; 2.44 ± 0.56 Gy/GBq) and with lower exposure to salivary glands (0.07 ± 0.03 Gy/GBq) and kidneys (0.64 ± 0.17 Gy/GBq). Activity was retained in tumor lesions through to the final protocol-specified imaging timepoint (312 h) following administration. Conclusions: In this Phase 1, single-arm study, ⁶⁸Ga-PSMA-11 PET supported patient selection for ¹⁷⁷Lu-TLX591 therapy. In a heterogenous population representative of a real-world setting, ¹⁷⁷Lu-TLX591 therapy in combination with SOC demonstrated a manageable and predictable safety profile, durable retention, and low salivary gland radiation exposure. Further evaluation in larger, randomized studies is warranted. Full article

Chimeric antigen receptor (CAR) therapies are emerging as promising strategies, particularly for metastatic castration-resistant prostate cancer (PCa), as they can act independently of the androgen receptor axis. Adapter CAR-T cell platforms, such as the RevCAR system, offer precise therapeutic control and tumor targeting via small, rapidly eliminated tumor-specific adapters. To enable more convenient late-stage RevCAR-T therapy in PCa patients, allowing for discontinuous reverse target module (RevTM) infusion, we developed novel, larger IgG4-based RevTMs targeting prostate stem cell antigen (PSCA) and benchmarked them against previously described smaller adapter formats. Within the RevCAR system, PSCA-IgG4 RevTMs effectively mediated PCa killing at low effector-to-target ratios and low RevTM concentrations in a strictly antigen-dependent manner. Oncolytic activity was accompanied by a rapid and pronounced release of proinflammatory cytokines across a broad RevTM concentration range, which is particularly advantageous for immunologically cold PCa. Finally, anti-tumor activity was confirmed in a short-term mouse model. Preliminary PET studies further indicate slow blood elimination and tumor-specific accumulation of novel IgG4-RevTMs. Together, these data position PSCA-IgG4 RevTMs as promising candidates for stepwise RevCAR-T treatment in PCa, in which short-lived scFv-RevTMs are initially used to ensure a rapid safety switch, followed by larger IgG4-RevTMs once the risk profile is known. Full article

Background and Objectives: Cornerstone therapies for metastatic prostate cancer include androgen deprivation and androgen receptor pathway inhibition, but cognitive impairment is a recognized, life-altering potential adverse effect of this treatment. Abiraterone acetate (AA), an androgen receptor pathway and CYP17A1 inhibitor, suppresses androgen synthesis and may contribute to cognitive changes. This cell culture-based study uses the BE(2)M17 human male neuroblastoma model to investigate AA-induced alterations in gene and protein expression that may underlie cognitive decline, laying the foundation for a mechanistic investigation aimed at identifying molecular targets to mitigate cognitive impairment in men with prostate cancer receiving androgen-directed therapies. Materials and Methods: BE(2)M17 cells were pretreated for 12 h with dihydrotestosterone (DHT; 5 nM) or vehicle control, then exposed to AA (0, 5, 10 µM, 24 h). RNA and protein were analyzed by qRT-PCR and Western blot for markers of amyloid processing, neuronal health, and mitochondrial function. Results: AA significantly altered multiple neurobiological markers. BACE1 mRNA increased in DHT + 10 µM AA compared to control and DHT alone (p = 0.0416 and p = 0.0118). However, BACE1 protein decreased in 10 µM AA + DHT versus DHT alone (p = 0.0132). Immunoblot revealed reduced amyloid precursor protein (APP) in 10 µM AA versus control (p = 0.0057) and 10 µM versus 5 µM (p = 0.0263). APP was reduced in 10 µM AA + DHT versus control (p = 0.0015) and versus DHT alone (p = 0.0467). LRP1 and BDNF were significantly reduced with 10 µM AA versus 5 µM AA (p = 0.0092 and p = 0.0081), while synaptophysin decreased in 10 µM AA + DHT versus DHT alone (p = 0.0049). BDNF also declined in 10 µM AA + DHT compared to 5 µM AA + DHT (p = 0.0301). PGC1α mRNA increased in AA + DHT versus DHT alone (p = 0.0332). MitoTracker analysis showed reduced fluorescence with 5 µM AA alone but increased fluorescence with 5 µM AA + DHT relative to control and DHT (p = 0.0019; p < 0.0001), while 10 µM AA + DHT reduced fluorescence compared to 5 µM AA + DHT (p = 0.0003). Conclusions: AA, alone or combined with DHT, disrupts key pathways involved in neuronal health, amyloid processing, and mitochondrial function. These findings suggest a potential mechanistic link between AA treatment and cognitive impairment. Full article

Background: Bone metastasis is a frequent and debilitating complication of advanced cancer, particularly in breast and prostate cancer, and is driven by complex interactions among tumor cells, bone-resident cells, immune populations, vascular components, and the extracellular matrix. Within this specialized microenvironment, proteoglycans have emerged as key molecular regulators of tumor–bone crosstalk, matrix remodeling, metastatic niche formation, dormancy, and therapeutic resistance. Methods: We conducted a narrative review using targeted searches of PubMed and Google Scholar for studies published through 31 May 2026. Search terms included combinations of proteoglycan- and glycosaminoglycan-related concepts, including “proteoglycans,” “glycosaminoglycans,” “heparan sulfate proteoglycans,” “hyaluronan,” “heparanase,” “syndecans,” “glypicans,” “perlecan/HSPG2,” “versican,” and “decorin,” with disease- and process-related terms such as “bone metastasis,” “extracellular matrix,” “tumor–bone crosstalk,” “breast cancer,” “prostate cancer,” “metastatic niche,” “osteolytic metastasis,” “osteoblastic metastasis,” “dormancy,” “reactivation,” “immune regulation,” and “therapy resistance.” Original studies, reviews, and translational reports were selected according to their relevance to cell-surface, pericellular, and extracellular proteoglycans in bone metastatic progression. Results: Proteoglycans and associated GAG/ECM axes are implicated in multiple processes involved in skeletal metastasis, including growth factor availability, extracellular matrix organization, osteolytic and osteoblastic niche formation, angiogenesis, immune evasion, metastatic dormancy, reactivation, and therapy resistance. These functions are highly context-dependent and are influenced by proteoglycan localization, core protein structure, glycosaminoglycan composition, sulfation patterns, proteolytic processing, and cellular source. Conclusions: Proteoglycans represent critical molecular nodes in the bone metastatic microenvironment and hold potential as biomarkers, therapeutic targets, and tools for stratifying metastatic niche heterogeneity. Their clinical translation will require validation in human bone metastasis samples, improved models that reproduce the mineralized and immune-rich bone niche, and a clearer distinction between causal mechanisms and correlative associations. Future studies should integrate matrisome profiling, spatial proteomics, single-cell and spatial transcriptomics, glycosaminoglycan omics, degradomics, and three-dimensional bone niche models to define actionable proteoglycan-dependent mechanisms and improve therapeutic targeting of metastatic bone disease. Full article