Search Results (332)

Background/Objectives: Cancer cachexia (CC) is a metabolic syndrome characterized by the progressive loss of skeletal muscle and adipose tissue during tumor progression. Despite its clinical prevalence, effective therapeutic options are currently lacking. Phloretin, a natural flavonoid with potent anti-inflammatory and antioxidant properties, has unclear efficacy against CC. This study investigates the therapeutic potential of phloretin in ameliorating cancer cachexia. Methods: Mouse models of CC were established using BALB/c mice implanted with C26 colon carcinoma cells and C57BL/6 mice implanted with Lewis lung carcinoma (LLC) cells. Upon the detection of palpable tumors, phloretin (10 mg/kg) was administered daily via intraperitoneal injection. At the endpoint, hind limb skeletal muscle, inguinal white adipose tissue (iWAT), and hearts were harvested and weighed. Lean body mass was assessed by analyzing the weight of the carcass following the excision of skin, subcutaneous fat, and visceral organs. Gene expression and protein levels in muscle tissues were subsequently quantified. Results: Phloretin administration significantly alleviated tumor-induced loss of tumor-free body weight. It effectively preserved skeletal muscle mass in both C26 and LLC cachexia models, while significantly attenuating adipose tissue depletion in the C26 model. In vitro, phloretin treatment mitigated myotube atrophy induced by C26 conditioned medium. Mechanistically, phloretin inhibited STAT3 activation in skeletal muscle. This inhibition suppressed the expression of the E3 ubiquitin ligases MuRF-1 and Atrogin-1. Furthermore, phloretin concurrently modulated the autophagy pathway. Conclusions: Phloretin effectively ameliorates cancer cachexia-induced muscle wasting by targeting STAT3-mediated protein degradation and autophagy pathways. These findings suggest that phloretin represents a promising therapeutic agent for the clinical management of cancer-associated cachexia. Full article

Background: The early detection of prostate and testicular tumors remains challenging as standard diagnostic tools often lack sensitivity and produce ambiguous results. Seminal fluid is a biologically rich medium that closely reflects the state of male reproductive tissues and has therefore emerged as a promising source of non-invasive molecular biomarkers. Objective: This study aimed to critically evaluate the evidence regarding cell-free DNA, RNA, proteins and metabolites in seminal fluid, and to assess their potential for improving the early detection of male reproductive cancers. Methods: A systematic review was performed according to PRISMA guidelines. Comprehensive searches of the PubMed and Scopus databases were conducted to identify original clinical studies analyzing molecular biomarkers in seminal fluid from patients with prostate or testicular tumors. For each study, data were extracted on biomarker types, cohort characteristics, analytical methods and diagnostic performance. Results: Forty-two eligible studies were included, covering multiple biomarker classes. Most were observational, single-center investigations classified as level 3b evidence. Across the different types of biomarkers, seminal fluid was associated with tumor-associated molecular changes. Alterations in the concentration, fragmentation and methylation patterns of cell-free DNA (e.g., GSTP1, RARβ2, LGALS3 and OCT3/4) distinguished malignant from benign conditions with sensitivities of up to 80–100%. RNA-based markers, including microRNAs, small non-coding RNAs, and tRNA fragments, showed improved performance in several studies, with multimarker models achieving areas under the curve (AUCs) of 0.85–0.93. Proteomic analyses identified high-specificity candidates such as TGM4, AMACR, PROS1 and DKK3. Metabolomic profiling further strengthened the diagnostic potential; reduced seminal citrate outperformed prostate-specific antigen (AUC 0.748 vs. 0.548), and reproducible shifts in amino acid and lipid profiles were observed in testicular tumors. However, substantial heterogeneity in study design, patient selection, and analytical platforms was observed. Risk of bias varied, and large prospective validation cohorts were lacking. Conclusions: Current evidence suggests that seminal fluid contains molecular signals associated with tumors that could be used for diagnosis. However, the available data are predominantly exploratory and methodologically heterogeneous. Before seminal fluid-based biomarkers can be considered for routine clinical implementation, robust prospective studies with standardized protocols are required. Full article

Background/Objectives: Inflammatory mediators within the tumor microenvironment contribute to lung cancer progression by enhancing cellular motility and invasive capacity through cytokine-dependent signaling networks. Modulation of these inflammation-associated pathways by dietary bioactive compounds may provide complementary strategies for limiting cancer aggressiveness. Our objective was to examine the inhibitory effects of a cyanidin-3-O-glucoside (C3G)-rich fraction from Kum Akha pigmented black rice (CKAB-P1) on inflammation-stimulated A549 cancer cell progression. Methods: CKAB-P1 was obtained through solvent-partition extraction and chemically characterized using the pH differential method and high-performance liquid chromatography. A549 cells were pretreated with CKAB-P1 or C3G, followed by stimulation with conditioned medium predominantly containing IL-6 and IL-1β derived from LPS-exposed THP-1 macrophages (THP-1-CS). Effects on cancer cell migration and invasion were evaluated using wound-healing, Transwell invasion, gelatin zymography, and Western blot analyses. Results: CKAB-P1 contained 106.62 ± 3.54 mg/g extract of total anthocyanins, with C3G representing the major constituent (59.42 ± 2.54 mg/g extract). Exposure of THP-1-CS stimulated migration and invasion of A549 lung cancer, and neutralization of IL-6 and IL-1β reduced these pro-migratory effects, confirming cytokine involvement. Treatment with CKAB-P1 (10–40 μg/mL) or C3G (2.5–20 μg/mL) markedly attenuated inflammation-enhanced migration and invasion (p < 0.05). A reduction in MMP-2 and MMP-9 activity, along with decreased expression of invasion-associated protein expressions (uPA, uPAR, and MT1-MMP), was observed. Furthermore, both CKAB-P1 and C3G attenuated phosphorylation of JAK1 and STAT3. Conclusions: These findings suggest that anthocyanin-enriched black rice fraction may limit inflammation-driven A549 lung cancer cell aggressiveness through modulation of the cytokine-driven JAK1/STAT3 signaling cascade, indicating its potential relevance as a bioactive dietary component targeting tumor-associated inflammatory signaling. Full article

Glioblastoma cells sustain tumor growth by releasing inflammatory cytokines that modulate the tumor microenvironment (TME). Targeting the cytokine expression profile of glioblastoma multiforme (GBM) and tumor-supportive cells represents a promising therapeutic strategy. Lactoferrin, a natural compound with recognized anticancer properties, has been poorly investigated regarding its role in modulating GBM cytokine profiles and TME cellular activity. This study evaluated lactoferrin’s ability to modulate GBM inflammatory signaling and pro-tumorigenic functions of tumor-associated astrocytes. U87MG glioblastoma cells were treated with human lactoferrin (10 μg/mL) for 72 h, and DI-TNC1 astrocytes were exposed to conditioned medium from treated and untreated U87MG cells for 24 h. Results demonstrate that lactoferrin inhibits GBM cell proliferation, migration, and stemness-related pathways while modulating inflammatory profiles through NF-κB pathway interference, downregulating pro-tumorigenic cytokines IL-6, IL-1β, IL-4, and IL-10. Increased TGF-β expression in lactoferrin-treated cells likely reflects a compensatory mechanism rather than enhanced malignancy. Furthermore, lactoferrin attenuates pro-tumorigenic effects of tumor-associated astrocytes by reducing NF-κB activation and expression of TGF-β, TNF-α, IL-4, and IL-10. This innovative study provides evidence supporting non-cytotoxic approaches targeting GBM-TME interactions, highlighting lactoferrin’s potential to attenuate glioblastoma malignancy and astrocyte inflammatory signaling, suggesting its therapeutic potential for GBM treatment. Full article

Copper–organic compounds are being investigated as antitumor candidates. Besides their efficacy as cytotoxic agents alone, the oxidative potential of electrochemical Cu²⁺-to-Cu¹⁺ transition emerges as an attractive approach for elimination of tumor cells otherwise resistant to chemotherapy. To minimize side effects of the potent oxidative burst upon Cu(II) reduction, the metal cations should be delivered to the tumor site. Taking advantage of the ability of bisphosphonates to accumulate in the bone, we synthesized a Cu(II) complex of zoledronic acid (ZA), an FDA-approved drug for prevention of bone destruction. The CuZA complex obtained upon precipitation of ZA and different copper salts (sulfate, chloride or perchlorate) were structurally identical, consisting of two organic moieties coordinated by three metal cations. Combined treatment with water-soluble formulations of CuZA and cysteine triggered rapid death in human cell lines. This effect was achievable with non-toxic concentrations of CuZA and cysteine alone. Importantly, the K562 chronic myelogenous leukemia cells that demonstrated an attenuated response to the 3d generation Bcr-Abl tyrosine kinase inhibitor in the medium conditioned by bone marrow-derived fibroblasts, were readily killed by CuZA–cysteine combination. Thus, oxidative burst upon metal reduction in CuZA complexes emerges as a promising method of eradication of tumor cells in the bone microenvironment. Full article

Monoacylglycerol lipase (MAGL) is a key regulator of lipid signaling networks implicated in tumor progression and represents an attractive anticancer target. To combine MAGL inhibition with potentially enhanced uptake by highly glycolytic cancer cells, we designed glycoconjugated analogs of a N-benzoylpiperidine MAGL inhibitor scaffold bearing a glucopyranose unit. An alkyne-functionalized benzoylpiperidine intermediate was prepared and coupled to azido sugars through a CuAAC “click” reaction to afford two triazole-linked glycoconjugates. In a colorimetric assay on human MAGL, the new compounds 17 and 18 inhibited the enzyme with IC₅₀ values of 43.3 and 68.8 μM, respectively, confirming compatibility with MAGL inhibition albeit with reduced potency versus reference triazole-substituted benzoylpiperidine 13 (IC₅₀ = 4.1 μM). In PANC-1 pancreatic cancer cells, both glycoconjugates were inactive in high-glucose medium, but displayed antiproliferative activity under low-glucose conditions (GI₅₀ 17 = 129 μM; GI₅₀ 18 = 12 μM), consistent with glucose-dependent uptake/competition. Overall, these first-in-class MAGL-targeting glycoconjugates provide a starting point for optimizing dual MAGL inhibition and metabolically driven cellular selectivity. Full article

Background/Objectives: Natural polysaccharides have many bio-pharmacological effects, which make them compounds with potential in healthcare. Limnospira platensis (Spirulina), a well-known blue–green cyanobacterium with relevance in the market of nutraceuticals, produces polysaccharides with recognized antioxidant and anti-inflammatory activities. Noteworthy, the growth of the cyanobacterium biomass may be obtained in a more sustainable manner under mixotrophic conditions. In the present study, we compared the antioxidant and anti-inflammatory effects of polysaccharide-enriched extracts from the cyanobacterium cultured under autotrophism (Auto−P extract) or mixotrophism (Mixo−P extract); this latter was realized using medium added with brewery wastewater (BWW). Methods and Results: Non-cellular investigation showed a better antioxidant profile for Mixo−P extract in the OH radical scavenging assay and a similar activity between the extracts in ABTS and ferrous chelation assays. The antioxidant protective activity of L. platensis extracts investigated on HaCat cells in the range of 0.3–10 μg/mL (not cytotoxic concentrations), against hydrogen peroxide (H₂O₂, 600 μM)-induced damage, revealed a similar activity by the two extracts. When tested against the inflammatory stimuli with lipopolysaccharide (LPS, 10 μg/mL) or tumor necrosis factor-α (TNF-α, 10 ng/mL), both Auto−P and Mixo−P showed an ability to prevent the effects of the inflammatory agents on cell viability and on interleukin-1β (IL-1β) and interleukin-6 (IL-6) release, with a slightly greater potency by Mixo−P extract. Conclusions: In conclusion, our data suggest the possible use of L. platensis polysaccharide-enriched extracts in biological-made pharmaceuticals for skin disorders or in cosmeceuticals. In addition, this study demonstrates that mixotrophic cultivation of L. platensis may be an alternative and sustainable way for biotechnological applications of the cyanobacterium biomass. Full article

Background: The solid Ehrlich tumor (SET) is a transplantable experimental neoplasm that mimics mammary adenocarcinoma in female mice, widely used to investigate tumor physiology, behavior, and therapeutic interventions. Among emerging approaches, ozone therapy has gained attention in human and veterinary medicine, prompting studies to clarify its mechanisms and potential applications. This study evaluated vascular and tumor cell proliferation in SET of mice treated with ozonated water under different protocols. Methods: A total of 99 animals were allocated into four groups: ozonated water at 104 mM/5 ppm (G1, n = 30), 208 mM/8 ppm (G2, n = 30), vehicle control with 0.9% saline (G3, n = 30), and negative control (GCN, n = 9). Subgroups were established according to administration routes (intratumoral or peritumoral), number of applications (one or two), and observation periods (24 h, five days, or 30 days). Immunohistochemistry with anti-CD31 and anti-Ki-67 antibodies assessed vascular and cellular proliferation, respectively, considering peri- and intratumoral regions. Results: Increased CD31 expression was detected at 30 days in treated groups compared to controls, particularly after two intratumoral applications and in all peritumoral (PT) protocols. Ki-67 expression was reduced after five days in the treated groups, indicating decreased cell proliferation relative to controls. A positive correlation was observed between peri- and intratumoral CD31 immunostaining. Conclusion: Ozonated water reduced tumor cell proliferation in the medium term, but treatment discontinuation favored increased vascular density in the long term. These findings suggest caution in the oncological use of ozone, as it may present both antineoplastic and tumor-promoting effects depending on treatment conditions. Full article

Ovarian cancer remains the most lethal gynecological malignancy, largely due to its early dissemination and extensive peritoneal metastasis. The tumor microenvironment (TME), particularly tumor-associated macrophages, promotes this invasive phenotype; however, the precise molecular effectors linking immune-to-tumor signaling remain unclear. We identified FRY, a microtubule-binding protein previously uncharacterized in ovarian pathology, as a critical mediator of macrophage-driven invasion. We observed that conditioned medium from ovarian cancer-stimulated macrophages (OCM) robustly induced FRY expression in ovarian cancer cells. Clinically, elevated FRY levels correlate with advanced tumor stage and poor patient survival. Functionally, FRY knockdown significantly abrogated OCM-induced invasion without affecting cell viability, highlighting its specific role in motility. Mechanistically, FRY facilitates epithelial–mesenchymal transition (EMT) and acts as an essential downstream effector of the PI3K/AKT signaling cascade; notably, FRY was required for AKT1-driven invasive behaviors. Furthermore, we identified the transcription factor NFIX as a key regulator of FRY expression. Macrophage-derived signals upregulate NFIX, which directly regulates FRY transcription. Pharmacological inhibition of the CXCR1/2 axis with reparixin effectively blocked OCM-mediated induction of both NFIX and FRY, suggesting that chemokine signaling initiates this pro-invasive loop. Collectively, these findings suggest that FRY is a macrophage-driven mediator of invasion and underscore its potential relevance in ovarian cancer. Full article

Advanced prostate cancer frequently metastasizes to bone, but no effective therapy exists. To seek a novel treatment option and identify a new drug target, we took an induced tumor-suppressing (iTS) cell-based approach and produced tumor-suppressing proteins and conditioned medium (CM). Notably, the overexpression of Lrp5 and β-catenin, as well as the pharmacological Wnt activator, converted osteocytes, Murine mesenchymal stem cells, mononuclear cells, and monocytes into iTS cells. While Lrp5 conditional knockout mice presented severe bone loss, Lrp5-overexpressing osteocyte-derived CM rescued tumor-induced bone damage. Whole-genome proteomics analysis revealed that Moesin (MSN), which acted as an oncogene in tumor cells, was enriched in CM as an extracellular tumor-suppressing protein. Its anti-tumor action was mediated primarily by the interaction with CD44. Consistently, FRET live-cell imaging demonstrated that extracellular MSN reduced Src tyrosine kinase activity and nuclear localization of β-catenin. Collectively, we demonstrated herein the iTS cell-based approach to protect bone from prostate cancer and showed MSN as a potent extracellular tumor-suppressing protein. Full article

Colorectal cancer (CRC) progression and therapy resistance are driven in part by metabolic reprogramming and the persistence of cancer stem-like cells (CSCs). The seven in absentia homolog 2 (SIAH2)/with-no-lysine kinase 1 (WNK1) signaling axis has emerged as a potential regulator of these processes, yet its functional role in CRC metabolism and tumor–stroma crosstalk remains incompletely understood. Integrated analyses of The Cancer Genome Atlas–Colon Adenocarcinoma (TCGA-COAD) and Gene Expression Omnibus (GEO, GSE17538) datasets revealed significant upregulation of SIAH2 and WNK1 in CRC tissues, with strong positive correlations to glycolysis- and hypoxia-associated genes, including PFKP, LDHA, BPGM, ADH1A, ADH1B, and HIF-1α. Single-cell and clinical profiling further demonstrated preferential enrichment of SIAH2 in undifferentiated, stem-like tumor cell populations. Functional studies across multiple CRC cell lines showed that SIAH2 silencing suppressed proliferation, clonogenic growth, tumor sphere formation, and cell-cycle progression, whereas SIAH2 overexpression exerted opposite effects. Seahorse extracellular flux analyses established that SIAH2 promotes glycolytic capacity and metabolic flexibility. At the protein level, SIAH2 regulated glycolytic enzymes and WNK1/hypoxia-inducible factor-1α (HIF-1α) signaling, effects that were amplified by cancer-associated fibroblast (CAF)-derived conditioned medium. CAF exposure enhanced SIAH2 expression, CSC spheroid growth, and resistance to fluorouracil, leucovorin, and oxaliplatin (FOLFOX) chemotherapy, whereas SIAH2 depletion effectively abrogated these effects. Collectively, these findings identify the SIAH2/WNK1 axis as a central metabolic regulator linking glycolysis, CSC maintenance, and microenvironment-driven therapy resistance in CRC, highlighting its potential as a therapeutic target. Full article

Bone metastasis in breast cancer remains a major therapeutic challenge because current osteoclast-targeted therapies do not fully disrupt the tumor–bone vicious cycle. Osteocytes, the most abundant bone cells, are increasingly recognized as key regulators of bone–tumor crosstalk. Previous work has shown that osteocyte-specific overexpression of the Wnt co-receptor LRP5 inhibits breast cancer-induced osteolysis and generates conditioned medium (CM) with tumor-suppressive activity. Proteomic analysis identified LIM domain and actin-binding protein 1 (LIMA1) as a central mediator that interacts with Myosin Vb (MYO5B), suggesting the role of the LIMA1/MYO5B regulatory axis. This study demonstrates that CM derived from LRP5-overexpressing osteocytes suppresses EO771 breast cancer cell proliferation, migration, and invasion, and downregulates tumor-promoting proteins, including MMP9, Snail, IL-6, and TGF-β1, while upregulating the apoptosis-related protein cleaved caspase-3. These effects were largely reversed by knockdown of LIMA1 or MYO5B. In syngeneic mouse models of mammary tumors and bone metastasis, systemic administration of LRP5-overexpressing osteocyte-derived CM reduced tumor burden and osteolytic bone destruction, whereas genetic knockdown of LIMA1 in osteocytes or MYO5B in tumor cells abrogated these protective effects. Collectively, these findings indicate that LRP5 activation in osteocytes engages the LIMA1/MYO5B signaling axis that inhibits breast cancer progression and osteolysis, disrupts tumor–stromal interactions, and restores bone–tumor homeostasis, thereby providing a potential therapeutic strategy to break the vicious cycle of bone metastasis in breast cancer. Full article

Personalized treatment strategies for seminoma, a germ cell tumor, are crucial due to inherent tumor heterogeneity. Existing in vitro models often inadequately represent the native tumor microenvironment. Ex vivo organ culture (EVOC) offers a potential solution by preserving the tumor’s original architecture and cellular interactions. This study presents the pilot study for adaptation of the EVOC platform specifically for non-metastatic seminoma, focusing on short-term tissue maintenance and an assessment of viability markers, examining intraoperative biopsies from 12 patients with non-metastatic seminoma (cT1–2, cN0–3, M0) undergoing orchifuniculectomy. Tissues were cultured in DMEM/F12 medium supplemented with fetal bovine serum and antibiotics. Histological and immunohistochemical analyses were performed on days 0, 3, 7, and 10. We analyzed the proliferative index (PI), using Ki-67; total cell number (OCN); and tumor cell number (TCN; PLAP-positive cells). The area under the curve (AUC) for PI was calculated to evaluate tumor viability. Statistical analyses included repeated measures ANOVA and post-hoc tests. Histological examination confirmed the preservation of the native seminoma histoarchitecture up to day 7. OCN showed a median decrease of 32.6% on day 7 (p = 0.002) and 55.1% on day 10 (p = 0.0004) compared with the baseline. TCN showed a median decrease of 27.5% on day 7 (p = 0.0033) and 53.2% on day 10 (p = 0.00018) compared with the baseline. The PI decreased significantly from day 3 to day 10 (p < 0.05). The AUC for PI was identified as a representative marker of tumor viability. An “EVOC score” calculation method was proposed to compare the effects of different treatments. This proof-of-concept work confirms that seminoma tissue can be maintained ex vivo for up to ten days under optimized conditions. The EVOC system developed here will serve as a methodological basis for further improving culture stability and exploring its broader applications in tumor biology and pharmacological testing. Full article

Background: Fluid shear stress (FSS) is a biomechanical force that can produce phenotypic changes in the cells that are directly in contact with the flow of fluid. Accumulating evidence indicates high FSS to possess the potential ability to prevent tumor development and suppress cancer growth. However, the exact mechanism of its antitumorigenic effects is still not clear. Objective: In this study, we aimed to investigate the effect of FSS on breast cancer microenvironment via macrophage modulation. Methods: We exposed THP-1 like-macrophages to different levels of FSS. The supernatant from THP1-like-macrophages after exposure to FSS was used as conditioned medium (FSS-CM). Subsequently, we analyzed human breast cancer cells, MCF-7, and endothelial cells, as well as HUVECs cultured with FSS-CM. Results: Study outcomes have demonstrated that low FSS-CM inhibited apoptosis as well as induced tumor migration in MCF-7 cells. Conversely, high FSS-CM promoted apoptosis, inhibited tumor migration, and induced G1-phase arrest in MCF-7 cells. Furthermore, low FSS-CM was found to promote proliferation of HUVECs. Conclusions: In conclusion, this study highlights the complex interplay between FSS and cancer cell behavior. Our findings provide in vitro evidence that high FSS exerts an anti-cancer effect by promoting THP-1-like macrophage polarization toward an anti-tumor phenotype, leading to increased apoptosis and reduced migration in MCF-7 cells. These results suggest that the modulation of macrophage polarization may underlie the therapeutic potential of high FSS in suppressing breast cancer progression. Full article

Mesothelial cells (MCs) are highly relevant for studying the pathogenesis of serosal diseases, fibrosis, inflammation, and tumor progression. However, the isolation and maintenance of an epithelial-like phenotype of MCs in vitro remain methodologically challenging due to their tendency to undergo mesothelial-to-mesenchymal transition (MMT). In this work, we propose a combined protocol utilizing collagen IV coating, conditioned medium, and short-term ROCK inhibitor treatment, which improves cell survival. This approach enables the establishment of primary human cultures suitable for investigating mesothelial cell functional activity and for assessing the efficacy of potential therapeutic strategies. Full article