Search Results (1,618)

Bone metastases continue to be a major cause of morbidity and mortality in patients with advanced cancers, driven by the dynamic remodeling of the bone marrow niche. Traditionally viewed as passive space-fillers, bone marrow adipocytes (BMAs) are now recognized as active regulators of tumor growth, therapeutic resistance, and skeletal pathology. BMAs comprise a significant portion of the adult marrow space, particularly in aging and obesity, and facilitate metastatic colonization through various mechanisms. These include metabolic coupling, where adipocyte-derived fatty acids fuel tumor oxidative phosphorylation; the secretion of adipokines such as leptin and IL-6, which promote epithelial-to-mesenchymal transition, invasion, and immune evasion; regulation of osteoclastogenesis via RANKL expression; and the release of extracellular vesicles that reprogram cancer cell metabolism. Clinical and experimental studies show that BMA expansion correlates with increased tumor burden and poorer outcomes in breast, prostate, lung cancers, and multiple myeloma. Additionally, BMAs actively promote therapeutic resistance through metabolic rewiring and drug sequestration. Experimental models, ranging from in vitro co-cultures to in vivo patient-derived xenografts, demonstrate the complex roles of BMAs and also reveal important translational gaps. Despite promising preclinical approaches such as metabolic inhibitors, PPARγ modulation, adipokine blockade, and lifestyle changes, no therapies directly targeting BMAs have yet reached clinical practice. This review compiles current evidence on the biology of BMAs, their tumor-promoting interactions, and potential therapeutic strategies, while also highlighting unresolved questions about BMA heterogeneity, lipid flux, and immunometabolic crosstalk. By revealing how bone marrow adipocytes actively shape the metastatic niche through metabolic, endocrine, and immunological pathways, this review highlights their potential as novel biomarkers and therapeutic targets for improving the management of bone metastases. Full article

Uveal melanoma is a melanocyte-derived malignancy of the eye with a high propensity for liver metastasis. Metastatic uveal melanoma is associated with high mortality and is poorly responsive to currently available therapies. Most uveal melanoma cases are driven by activating mutations in GNAQ and GNA11 genes, which convey oncogenic signaling through the mitogen-activated protein kinase (MAPK) pathway. Despite promising early results, safe doses of pharmacological inhibitors of the MAPK cascade failed to effectively control uveal melanoma in human trials. Considering the role of the RAC/PAK signaling axis as a co-regulator of the MAPK cascade, we set forth to investigate whether the efficacy of MAPK cascade inhibitors in pre-clinical models may be enhanced by direct inhibition of RAC and PAK proteins, or by indirect control of RAC via inhibition of guanylate biosynthesis. We observed that pharmacological inhibition of RAC, PAK and the key guanylate biosynthesis enzyme IMPDH significantly synergized with various inhibitors of the MAPK cascade in suppressing oncogenic signaling and the growth of uveal melanoma cells. In a mouse model, the addition of an IMPDH inhibitor to the treatment regimen significantly enhanced the ability of a MAPK cascade inhibitor to improve the survival of tumor-bearing animals. Targeting of the RAC/PAK axis provides a new strategy to increase the efficacy of targeted therapies in uveal melanoma. While RAC and PAK inhibitors are still undergoing pre-clinical development, clinically available inhibitors of IMPDH offer an opportunity to test the efficacy of this novel synergistic combination in the context of human disease. Full article

Sepsis is a life-threatening condition driven by a dysregulated host response to infection, with high mortality and few treatment options. Decades of failed drug development underscore the urgent need for therapies with novel mechanisms of action. Vimentin, an intermediate filament protein, acts as a network hub that senses and integrates cellular signals. Its involvement in key sepsis pathologies, including infection, hyperinflammation, immunosuppression, coagulopathy and metabolic dysregulation, positions it as a potential therapeutic target. This study evaluated the efficacy of ALD-R491, a novel small-molecule vimentin modulator, in a murine model of polymicrobial sepsis induced by cecal ligation and puncture (CLP). Mice received ALD-R491 prophylactically or therapeutically, alone or with ceftriaxone. The treatment significantly reduced serum levels of key biomarkers of sepsis, including C-reactive protein (CRP), lactate (Lac), tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), and dose-dependently improved the survival of septic mice. Organ-specific analysis confirmed the effects of ALD-R491 in mitigating hyperinflammation and multi-organ injury. The treatment reduced pulmonary edema and inflammation; preserved liver tissue architecture and improved hepatic function with lowered alanine aminotransferase/aspartate aminotransferase (ALT/AST); decreased kidney tubular damage; and improved renal function with lowered creatinine/blood urea nitrogen (BUN). These preclinical findings indicate that the vimentin-targeting agent ALD-R491 represents a promising therapeutic candidate for sepsis and merits further clinical investigation. Full article

Fusobacterium nucleatum (Fn) has been increasingly recognized as a crucial mediator of colorectal cancer (CRC) biology, particularly in microsatellite-stable (MSS) tumors, where immune checkpoint inhibitors (ICIs) have shown limited efficacy. Rather than representing a passive microbial passenger, Fn actively shapes tumor behavior by adhering to epithelial cells, activating oncogenic signaling, and promoting epithelial–mesenchymal transition (EMT). At the same time, it remodels the tumor microenvironment, driving immune suppression through inhibitory receptor engagement, accumulation of myeloid-derived cells, and metabolic reprogramming of tumor-associated macrophages. These mechanisms converge to impair cytotoxic immunity and contribute to both intrinsic and acquired resistance to ICIs. Beyond immune escape, Fn interferes with conventional chemotherapy by sustaining autophagy and blocking ferroptosis, thereby linking microbial colonization to multidrug resistance. Most of these mechanisms derive from preclinical in vitro and in vivo models, where causal relationships can be inferred. In contrast, human data are mainly observational and provide correlative evidence without proving causality. No interventional clinical studies directly targeting Fn have yet been conducted. Its enrichment across the adenoma–carcinoma sequence and consistent detection in both tumor and fecal samples highlight its potential as a biomarker for early detection and patient stratification. Importantly, multidimensional stool assays that integrate microbial, genetic, and epigenetic markers are emerging as promising non-invasive tools for CRC screening. Therapeutic strategies targeting Fn are also under exploration, ranging from antibiotics and bacteriophages to multifunctional nanodrugs, dietary modulation, and natural microbiota-derived products. These approaches may not only reduce microbial burden but also restore immune competence and enhance the efficacy of immunotherapy in MSS CRC. Altogether, current evidence positions Fn at the intersection of microbial dysbiosis, tumor progression, and therapy resistance. A deeper understanding of its pathogenic role may support the integration of microbial profiling into precision oncology frameworks, paving the way for innovative diagnostic and therapeutic strategies in CRC. Full article

Hydrogels are hydrophilic, soft polymer networks with high water content and mechanical properties that are tunable; they are also biocompatible. Therefore, as biomaterials, they are of interest to modern medicine. In this review, the main applications of hydrogels in essential clinical applications are discussed. Chemical, physical, or hybrid crosslinking of either synthetic or natural polymers allow for the precise control of hydrogels’ physicochemical properties and their specific characteristics for certain applications, such as stimuli-responsiveness, drug retention and release, and biodegradability. Hydrogels are employed in gynecology to regenerate the endometrium, treat infections, and prevent pregnancy. They show promise in cardiology in myocardial infarction therapy through injectable scaffolds, patches in the heart, and medication delivery. In rheumatoid arthritis, hydrogels act as drug delivery systems, lubricants, scaffolds, and immunomodulators, ensuring effective local treatment. They are being developed, among other applications, as antimicrobial coatings for stents and radiotherapy barriers for urology. Ophthalmology benefits from the use of hydrogels in contact lenses, corneal bandages, and vitreous implants. They are used as materials for chemoembolization, tumor models, and drug delivery devices in cancer therapy, with wafers of Gliadel presently used in clinics. Applications in abdominal surgery include hydrogel-coated meshes for hernia repair or Janus-type hydrogels to prevent adhesions and aid tissue repair. Results from clinical and preclinical studies illustrate hydrogels’ diversity, though problems remain with mechanical stability, long-term safety, and mass production. Hydrogels are, in general, next-generation biomaterials for regenerative medicine, individualized treatment, and new treatment protocols. Full article

Background/Objectives: Neuroblastoma (NB) is an aggressive pediatric malignancy that accounts for nearly 15% of all childhood cancer-related deaths, with high-risk cases showing a poor 20% prognosis and limited response to current therapies. Survivin, encoded by the BIRC5 gene, is an anti-apoptotic protein frequently overexpressed in NB and linked to treatment resistance and unfavorable clinical outcomes. Methods and Results: An analysis of 1235 NB patient datasets revealed a significant association between elevated BIRC5 expression and reduced overall and event-free survival, highlighting survivin as an important therapeutic target in NB. To explore this strategy, we evaluated the efficacy of YM-155, a small-molecule survivin inhibitor, across multiple NB cell lines. YM-155 displayed potent cytotoxic activity in six NB cell lines with IC₅₀ values ranging from 8 to 212 nM and significantly inhibited colony formation and 3D spheroid growth in a dose-dependent manner. Mechanistic analyses revealed that YM-155 downregulated survivin at both mRNA and protein levels, induced apoptosis by about 2–7-fold, and caused G0/G1 phase cell cycle arrest. Moreover, YM-155 treatment enhanced p53 expression, suggesting reactivation of tumor suppressor pathways. Notably, combining YM-155 and the chemotherapeutic agent etoposide resulted in synergistic inhibition of NB growth with ED75 values ranging from 0.17 to 1, compared to either agent alone. In the xenograft mouse model, YM-155 inhibited tumor burden in contrast to controls by about 3-fold, and without any notable toxic effects in vivo. Conclusion: Overall, our findings identify YM-155 as a promising therapeutic agent for high-risk NB by directly targeting survivin and enhancing chemosensitivity. These results support continued preclinical development of survivin inhibitors as part of rational combination strategies in pediatric cancer treatment. Full article

Purpose: Renal angiomyolipomas (AMLs) are benign renal neoplasms that may lead to spontaneous hemorrhage. Transcatheter arterial embolization (TAE) is a nephron-sparing treatment option, yet data on predictors of hemorrhage and re-intervention remain limited. This study evaluates clinical and radiologic outcomes of TAE and identifies predictors of hemorrhage and repeat embolization. Materials and Methods: A retrospective review of 66 patients (69 AMLs) undergoing TAE between 2010 and 2024 was conducted. Clinical, radiological, and procedural variables were analyzed. Tumor size, vascularity, and aneurysmal features were assessed pre- and post-embolization. Logistic regression models identified predictors of hemorrhage and repeat TAE. Results: Pre-treatment tumor diameter was the only significant predictor of hemorrhage (p = 0.011), with a threshold of 6.8 cm yielding 84.6% sensitivity and 71.3% specificity. All hemorrhagic tumors measured ≥4 cm. Post-embolization tumor volume predicted repeat TAE (p = 0.001), with a 248 mL cutoff. TAE significantly reduced tumor diameter (−33.5%) and volume (−60%) (p < 0.001). Radiologic success was achieved in 97% of cases, with a durable success rate of 84%. Clinical success was 94%, and complications occurred in 7.2% of patients, including two major events. Conclusions: TAE is a safe and effective treatment for renal AMLs. Tumor diameter >6.8 cm is a strong predictor of hemorrhage, while larger post-embolization volumes predict the need for re-intervention. These findings challenge the conventional 4 cm treatment threshold and support more individualized management strategies incorporating tumor morphology and response to embolization. Full article

Background: Cervical cancer remains a major global health concern, with high recurrence rates in advanced stages. [¹⁸F]FDG PET/CT provides prognostic biomarkers such as SUV, MTV, and TLG, though these are not routinely integrated into clinical protocols. Radiomics offers quantitative analysis of tumor heterogeneity, supporting risk stratification. Purpose: To evaluate the prognostic value of clinical and radiomic features for disease-free survival (DFS) in locoregionally advanced cervical cancer using machine learning (ML). Methods: Sixty-three patients (mean age 47.9 ± 14.5 years) were diagnosed between 2015 and 2020. Radiomic features were extracted from pre-treatment PET/CT (IBSI-compliant PyRadiomics). Clinical variables included age, T-stage, Dmax, lymph node involvement, SUVmax, and TMTV. Forty-two models were built by combining six feature-selection techniques (UCI, MD, MI, VH, VH.VIMP, IBMA) with seven ML algorithms (CoxPH, CB, GLMN, GLMB, RSF, ST, EV) using nested 3-fold cross-validation with bootstrap resampling. External validation was performed on 95 patients (mean age 50.6 years, FIGO IIB–IIIB) from an independent cohort with different preprocessing protocols. Results: Recurrence occurred in 31.7% (n = 20). SUVmax of lymph nodes, lymph node involvement, and TMTV were the most predictive individual features (C-index ≤ 0.77). The highest performance was achieved by UCI + EV/GLMB on combined clinical + radiomic features (C-index = 0.80, p < 0.05). For single feature sets, IBMA + RSF performed best for clinical (C-index = 0.72), and VH.VIMP + GLMN for radiomics (C-index = 0.71). External validation confirmed moderate generalizability (best C-index = 0.64). Conclusions: UCI-based feature selection with GLMB or EV yielded the best predictive accuracy, while VH.VIMP + GLMN offered superior external generalizability for radiomics-only models. These findings support the feasibility of integrating radiomics and ML for individualized DFS risk stratification in cervical cancer. Full article

This research focuses on developing innovative nanoparticle-based drug delivery systems to enhance therapeutic efficacy while minimizing adverse effects. We engineered biocompatible polymeric nanoparticles capable of encapsulating various therapeutic agents, demonstrating improved stability, prolonged circulation times, and preferential accumulation in target tissues. Surface functionalization with targeting ligands achieved unprecedented specificity in drug delivery. Our nanoparticle formulations exhibited superior tumor accumulation in preclinical cancer models, enhancing therapeutic efficacy and reducing systemic toxicity. Additionally, we developed stimuli-responsive nanoparticles for precise spatiotemporal control over drug release. These advanced delivery systems promise to improve patient outcomes and advance personalized nanomedicine. Full article

Copper plays a critical role in cancer biology, with tumor cells exhibiting abnormal copper metabolism that drives proliferation and tumor growth. A limited number of preclinical and clinical studies have reported promising theranostic potential of copper-based radionuclides, such as ⁶⁴Cu, for both diagnostic imaging and targeted radiotherapy in diverse cancers, including prostate cancer (PCa). In this work, we evaluated the cellular uptake and antitumor efficacy of [⁶⁴Cu]Cu-acetate using both cellular and animal models of PCa. Uptake assays revealed that ~70% of the administered dose (10 kBq) was internalized by PC-3 cells within 24 h, predominantly localizing to the cytoplasm, with around 9% detected in the nucleus. These results were corroborated by comparable natural Cu-acetate uptake levels (at equimolar dose) in PC-3 cells, as quantified by ICP-MS. Clonogenic assays revealed a dose-dependent reduction in survival following treatment with [⁶⁴Cu]Cu-acetate (3 and 6 MBq), whereas its non-radioactive counterpart [^NatCu]Cu-acetate, even at excess concentrations (10 µM), had no significant effect. Ex vivo biodistribution studies showed selective tumor accumulation/retention alongside expected hepatic uptake. Clear tumor visualization was achieved using μPET imaging with [⁶⁴Cu]Cu-acetate (10 MBq iv). A single higher dose (65 MBq iv) effectively reduced tumor growth in a subcutaneous PC-3 xenograft mouse model, without systemic toxicity, as evidenced by stable body weight. Together, these results further support the theranostic potential of [⁶⁴Cu]Cu in PCa. Full article

Background/Objectives: Head and neck cancer (HNC) is the sixth most common cancer worldwide, with a high mortality, particularly from head and neck squamous cell carcinoma (HNSCC). Although some therapeutic strategies are available, they might cause severe side effects. For example, surgery may result in disfigurement and functional loss, severely impacting the patient’s quality of life. Thus, minimally invasive and more effective alternatives are needed. Gold nanoparticle (AuNP)-mediated photothermal therapy (PTT) is a promising approach for HNC, which relies on AuNP photothermal efficiency and tumor localization. This study aimed to synthesize and characterize AuNPs, evaluate their safety without laser activation, and assess their efficacy with laser activation. Methods and Results: Their physicochemical and photostability over three months and sterility were confirmed. In vitro safety was tested using human non-cancerous and HNC cell lines, while in vivo biocompatibility was evaluated in the hen’s egg chorioallantoic membrane (CAM) model, with no adverse effects observed. Upon laser activation, AuNPs reduced HNC cell viability by 50–70%, including HNSCC lines. In vivo biodistribution studies showed that AuNPs remained at the injection site for up to one month without toxicity. Conclusions: Overall, the developed AuNP formulation demonstrates stability, biocompatibility, and prolonged local retention, key attributes for effective and targeted PTT. These findings support the potential of AuNP-mediated photothermal therapy as a promising treatment modality for HNC, although further preclinical and clinical studies are needed to optimize treatment parameters. Full article

Background: Tumor-associated macrophages (TAMs) are important contributors to tumor progression and metastasis. Therefore, the identification of molecules that mediate these cells’ tumor-promoting functions is highly warranted. VSIG4 has been proposed as a macrophage immune checkpoint. Hence, we aim to investigate this marker in preclinical models. Methods: Publicly available scRNAseq datasets of human colorectal (CRC) and triple-negative breast (TNBC) carcinomas and their murine counterparts were reanalyzed to investigate the expression of VSIG4 in the different TAM populations. Moreover, tumors were grown in Vsig4-deficient mice to evaluate the effect on primary tumor characteristics. Finally, since liver Kupffer cells and large peritoneal macrophages are at least partly VSIG4-high, and are implicated in metastasis to those organs, the dissemination of CRC cancer cells to those sites was assessed in the Vsig4-deficient mice. Results: We demonstrate that VSIG4 expression in human CRC and TNBC is mostly restricted to TAMs, and that its expression correlates with a worse prognosis. However, a striking finding was that no Vsig4 mRNA nor protein could be detected in the microenvironment of primary CRC and TNBC murine tumors, resulting in a similar tumor growth in wild type versus Vsig4-deficient mice. Moreover, no major differences were observed in metastatic tumor load in the liver and peritoneal cavity, apart from a reduced metastasis to the omentum in Vsig4-deficient animals. Conclusions: Murine cancer models are not suitable to investigate the role of VSIG4 in primary tumors and VSIG4 deficiency did not alter liver nor peritoneal cavity metastasis in murine models, with the exception of the omentum. Full article

Breast cancer remains a leading cause of morbidity and mortality among women globally, with increasing incidence projected in the coming years. Despite advances in standard oncologic therapies, there is a growing interest in supportive interventions that enhance treatment efficacy and reduce adverse effects. This review critically evaluates preclinical and clinical data on the medicinal mushroom Coriolus versicolor and its bioactive compounds—primarily polysaccharide-K, polysaccharopeptide, and laccase—as potential adjuvants in breast cancer therapy. A systematic PubMed search identified 11 original studies from 2010 to 2025 examining the impact of C. versicolor on breast cancer cell lines, animal models, and human subjects. Findings consistently demonstrate antiproliferative, pro-apoptotic, necroptotic, anti-invasive, and immunomodulatory effects across various breast cancer subtypes, including triple-negative breast cancer. One phase I clinical trial also reported good tolerability and immunological benefits in patients post-chemotherapy. The review highlights molecular mechanisms involving apoptosis, necroptosis, and modulation of the tumor microenvironment. While promising, these results underscore the need for standardized preparations, pharmacokinetic data, and larger placebo-controlled trials. Overall, C. versicolor shows potential as a safe, natural adjunct to conventional therapy, offering prospects for integrative strategies in breast cancer management. Full article

Ovarian cancer (OCa) remains the most lethal gynecologic malignancy in the United States, with low-grade serous and mucinous subtypes frequently driven by KRAS mutations. These mutations activate downstream MAPK and PI3K/AKT signaling pathways, contributing to tumor progression and resistance to therapy. Although the MEK inhibitor trametinib is used to target these pathways, its efficacy is limited in KRAS-mutant OCa due to compensatory activation of the leukemia inhibitory factor (LIF)/LIF receptor (LIFR) axis. In this study, we evaluated the therapeutic potential of combining trametinib with EC359, a selective LIFR inhibitor, in Ras/Raf-driven OCa models. EC359 significantly reduced cell viability, clonogenic survival, and induced cell death via ferroptosis in vitro. Mechanistic studies revealed that EC359 suppressed trametinib-induced activation of LIFR downstream signaling. RNA-seq analysis showed that combination therapy downregulated mitochondrial translation and MYC target genes while upregulating apoptosis-related genes. In vivo, EC359 and trametinib co-treatment significantly reduced tumor growth in xenograft and PDX models without inducing toxicity. Our studies identify LIFR signaling as a critical vulnerability in Ras/Raf-mutant and low grade serous OCa. Further, it provides strong preclinical rationale for EC359 and trametinib combination therapy as a new therapeutic strategy for treating Ras/Raf-driven OCa and low-grade serous OCa. Full article

Cells of the innate immune system, particularly natural killer (NK) cells, serve as the first line of defense against tumor development and play a critical role in antitumor immunity. Characterizing the immune cell pool and its functional state is essential for understanding immunotherapy mechanisms and identifying key cellular players. However, defining NK cell populations in mice, the primary model for cancer immunotherapy, is challenging due to strain-specific marker variability and the absence of a universal NK cell marker, such as human CD56. This study evaluates surface markers of NK and other peripheral blood immune cells in both humans and mice, associating these markers with specific functional profiles. Bioinformatic approaches are employed to visualize these markers, enabling rapid immunoprofiling. We explore the translational relevance of these markers in assessing immunotherapy efficacy, including their gene associations, ligand interactions, and interspecies variations. Markers compatible with rapid flow-cytometry-based detection are prioritized to streamline experimental workflows. We propose a standardized immunoprofiling strategy for monitoring systemic immune status and evaluating the effectiveness of immunotherapy in preclinical and clinical settings. This approach facilitates the design of preclinical studies that aim to identify predictive biomarkers for immunotherapy outcomes by monitoring immune status. Full article