Search Results (2,241)

Cancer progression is influenced by the dynamic interplay between tumor cells and the surrounding stromal microenvironment. Therapy-induced senescence (TIS) of stromal fibroblasts represents a common outcome of anticancer treatments, contributing to tumor progression through the senescence-associated secretory phenotype (SASP). While SASP cytokines promote cancer malignancy, the contribution of secreted metabolites from senescent cells remains poorly understood. Here, we investigate the role of senescent stromal metabolism in regulating prostate and ovarian cancer cell invasion. Conditioned media (CM) from TIS-induced human prostate (HPFs) and ovarian fibroblasts (HOFs) promote enhanced invasion of cancer cells. Invasion is partially preserved after exposure to boiled CM, suggesting a role for heat-stable metabolic factors. Metabolomic profiling of senescent fibroblasts-derived CM reveals a significant increase in Glutamine (Gln) levels, identifying senescent stromal fibroblasts as a previously unrecognized source of extracellular Gln in the tumor microenvironment (TME). Exposure of cancer cells to senescent CM increases Gln uptake, together with upregulation of the transporter SLC1A5 and increased intracellular Gln. This metabolic adaptation is associated with increased malignant phenotype including epithelial-to-mesenchymal transition (EMT) and stemness features. Extracellular Gln depletion, pharmacological inhibition of glutaminase-1 (GLS1) in cancer cells, or Gln synthetase (GS) silencing in fibroblasts markedly impair senescent fibroblasts CM-induced invasion, EMT markers expression, and stemness features in cancer cells. Stromal-derived Gln is associated with increased cancer cell invasion through activation of a redox-dependent NRF2/ETS1 signaling axis. Analysis of patient-derived transcriptomic datasets further suggests chemotherapy-associated upregulation of Gln metabolism and ETS1 expression. These findings identify senescent stromal-derived Gln as a key metabolic driver of prostate and ovarian cancer aggressiveness and reveal a TIS-associated metabolic vulnerability that could be explored in future preclinical studies. Full article

Background: Midkine (MDK), a secreted heparin-binding growth factor, is involved in tumor progression and metastasis. While serum MDK is widely recognized as a potential prognostic biomarker for colorectal cancer (CRC), its specific functional role and underlying mechanisms in CRC development are not fully understood. Methods: The four publicly available CRC microarray datasets—GSE41258, GSE44076, GSE81558, and GSE117606—along with TCGA-COAD and TCGA-READ datasets and their associated clinical data were obtained. MDK expression was measured at both the mRNA and protein levels using quantitative real-time PCR (qRT-PCR) and Western blotting. To investigate its oncogenic functions, a comprehensive set of assays was performed: transwell and wound healing assays for invasion and migration; CCK-8 and colony formation assays for proliferation; and tail vein/spleen injection models combined with xenograft models to study metastasis and tumor growth in vivo. To uncover underlying mechanisms, Western blotting was used to examine the involvement of epithelial–mesenchymal transition (EMT) and the PI3K/AKT signaling pathway. Results: MDK is significantly overexpressed in CRC tissues and cells compared to normal tissues and cells. Notably, patients with high MDK levels show poorer overall survival (OS). Overexpression of MDK increases CRC invasion, migration, proliferation, and metastasis both in vivo and in vitro, while its knockdown reverses these effects. Mechanistically, MDK activates the PI3K/AKT pathway, leading to increased AP2A1 expression and promotion of EMT in CRC. Conclusions: MDK promotes invasion, migration, proliferation, metastasis, and EMT in CRC cells through the PI3K/AKT pathway by inducing AP2A1 expression, which could serve as a diagnostic marker. The PI3K inhibitor LY294002 significantly reduces AP2A1 levels and inhibits MDK-induced malignant behaviors. Targeting MDK-related signaling pathways may offer new strategies for CRC treatment. Full article

Macrophages are highly plastic cells of the tumor microenvironment, and although classically activated M1 macrophages are generally regarded as anti-tumor effectors, their prolonged cytotoxic activity may also promote tumor adaptation. In this study, we investigated whether sustained exposure of prostate cancer cells to cytotoxic M1-like macrophages results in the selection of tumor cell populations with enhanced malignant properties. Macrophage-resistant derivatives of the human prostate cancer cell lines PC3 and DU145 were generated by repeated co-culture with cytotoxic THP-1-derived macrophages and characterized in vitro and in vivo. Macrophage-selected tumor cells showed increased proliferative activity and enhanced clonogenic survival. In vivo, these cells formed larger xenograft tumors with more aggressive histopathological features. At the same time, their migratory activity was not significantly increased, although they displayed partial epithelial–mesenchymal transition-like changes, including increased vimentin expression without a marked loss of epithelial markers. Transcriptomic profiling revealed coordinated inflammatory and adaptive reprogramming, characterized by the enrichment of cytokine- and immune-response pathways together with the suppression of metabolic and differentiation-associated programs. These changes were accompanied by the selective activation of p38 MAPK signaling, while sensitivity to paclitaxel remained unchanged. Taken together, the results indicate that macrophage cytotoxicity may act as a selective pressure promoting the emergence of inflammation-adapted tumor cell variants with increased malignant potential, supporting re-evaluation of the role of M1-like macrophages in tumor progression. Full article

Endometriosis is characterized by enhanced cellular proliferation, migration, and resistance to apoptosis, contributing to lesion persistence and progression. Targeting cellular plasticity and mesenchymal-associated functions may therefore represent a promising therapeutic strategy. Here, we investigated the effects of Pelargonium graveolens essential oil (PGEO) on proliferation, apoptosis, migration, cytoskeletal organization, transcriptional regulation, and metabolic alterations in human endometriotic 12Z cells. PGEO treatment suppressed proliferative capacity in a concentration-dependent manner and significantly impaired cell migration, accompanied by reduced β-tubulin expression and decreased levels of mesenchymal-associated markers CD73 and CD105. Increased GRP78 expression together with ultrastructural alterations, including cytoplasmic vacuolization and mitochondrial and endoplasmic reticulum changes, indicated activation of cellular stress responses. Although transcriptional analysis revealed increased CCND1 and PIK3CA mRNA levels, these changes did not parallel the observed suppression of proliferation, suggesting compensatory regulatory responses. Untargeted metabolomic profiling revealed alterations in energy metabolism characterized by increased levels of glycolysis-related metabolites, reduced levels of several amino acids including glutamine and histidine, and changes in lipid-associated metabolites. Collectively, these findings demonstrate that PGEO suppresses proliferative and migratory behavior in endometriotic cells while modulating cytoskeletal, transcriptional, and metabolic pathways, highlighting its potential as a candidate for further investigation in endometriosis-targeted therapeutic strategies. Full article

Cervical cancer (CC) is a complex, multistep process involving various viral, molecular, cellular, endogenous, and environmental events that transform normal cervical epithelium into a malignant tumor through a cascade of events. The contribution of high-risk human papillomavirus (HPV) to cancer is significant but involves many additional mechanisms such as oxidative stress (OS), arrested apoptosis of non-functional intraepithelial neoplastic cells, senescence-associated secretory phenotype (SASP), and the final epithelial–mesenchymal transition (EMT) of cervical epithelial neoplasia (CIN) cells. While high-risk HPV oncoproteins E6 and E7 are widely recognized as the primary triggers of CC, the critical role of E6 in degrading the p53 regulatory protein, thereby inhibiting the apoptosis of reactive oxygen species (ROS)-damaged neoplastic cells, is frequently underappreciated in the gynecological literature. Arrested apoptosis of non-functional neoplastic intraepithelial cells is a key event in cervical carcinogenesis and the biological basis of CIN progression via SASP senescence and ultimately EMT. While recent reviews touched upon each of the reviewed aspects, this review aims to provide a general understanding of all links in this complex molecular-biological chain, from HPV infection, oxidative stress, arrested apoptosis, SASP, and EMT. Beyond providing an encompassing primer for clinical researchers, we additionally review potential oxidative stress-related markers for shifting the classic diagnostic and therapeutic paradigms of CIN and cervical cancer. Full article

Bone marrow-derived mesenchymal stem cells (BMSCs), owing to their osteoblastogenic differentiation potential, are crucial for maintaining bone homeostasis and remodeling. Nevertheless, in aging and age-related bone diseases like osteoporosis, BMSCs show significantly diminished osteogenic potential, with a concomitant increase in adipogenic differentiation. The aged BMSCs also become desensitized to BMP2 stimulation to a large extent and exhibit aberrations in BMP2 signaling. However, the molecular mechanisms facilitating this shift in lineage commitment and mediating the cellular dysfunctions remain elusive. This knowledge gap hinders the development of regenerative strategies for skeletal aging and osteoporosis. This study employed an integrative tandem mass tag (TMT)-based phosphoproteomic and total proteomic profiling on BMSCs isolated from young (6-month) and aged (15-month) C57BL/6 (B6) mice to elucidate global alterations in both protein activity and expression. The analysis identified more than 500 proteins that underwent significant alterations (BH-adjusted p-value < 0.05) either in phosphorylation or expression between young and aged BMSCs. Many lineage-specific markers also underwent changes in both phosphorylation and expression with aging. Additionally, key biological processes, including cellular metabolism, clathrin-mediated endocytosis, and nucleocytoplasmic transport mechanisms, were enriched for the deregulated proteins. Signaling proteins, ERK-1/2, had increased activating phosphorylation in the aged BMSCs, while transcription factors Lrrfip1, Ruvbl1, and Ruvbl2 also exhibited dysregulated activity and abundance in the aged BMSCs. The findings from the study adds significant mechanistic insights into how aging disrupts signal transduction, metabolism, and transcriptional program in BMSCs, contributing to age-associated loss of bone mass and reduced skeletal regenerative capabilities. Through the identification of key mediators of BMSC dysfunction seen in aging, this work offers a strong foundation in devising potential therapeutic strategies to restore diminished osteogenic potential and treat osteoporosis. Full article

Gallbladder cancer (GBC) is an aggressive malignancy with limited treatment options and poor clinical outcomes. Identifying novel molecular targets is critical for improving therapeutic strategies. Sorcin (SRI), a calcium-binding protein implicated in tumor progression, has not been comprehensively investigated in GBC. SRI expression was analyzed by immunohistochemistry (IHC) in a large cohort of gallstone disease (GSD) controls (n = 85) and GBC tissues (n = 85). Functional assays, including cell proliferation, wound healing, transwell invasion, and Western blot analyses of epithelial–mesenchymal transition (EMT) markers, were performed in the NOZ GBC cell line following siRNA-mediated SRI knockdown. IHC revealed that 67% of GBC cases exhibited positive staining whereas all the GSD cases exhibited negative staining of SRI, demonstrating a significant upregulation of SRI in GBC (p < 0.001). SRI knockdown resulted in reduced proliferative capacity and markedly impaired migration and invasion. Further, SRI knockdown decreased vimentin levels, indicating suppression of EMT. SRI is significantly overexpressed in GBC and promotes key oncogenic traits, including proliferation, migration, invasion, and EMT. These findings highlight SRI as a potential therapeutic target in GBC. Further validation in animal models may facilitate translation into clinical applications. Full article

Ovarian cancer (OC) remains one of the deadliest gynecological malignancies, largely due to late diagnosis and the emergence of resistance to platinum–based chemotherapy. Long non–coding RNAs (lncRNAs) have recently emerged as key regulators of tumor progression and therapeutic adaptation. In this study, we performed integrative transcriptomic profiling of patient–derived TCGA ovarian tumor samples and carboplatin–resistant A2780 (CBDCA–R–A2780) cells to identify lncRNAs whose dysregulation overlaps between a cell–line resistance model and patient tumors. Our analyses revealed extensive transcriptional remodeling across both datasets, with MNX1–AS1 consistently emerging as a strongly deregulated transcript. Differential expression analysis showed robust upregulation of MNX1–AS1 in resistant cells and tumor tissues, accompanied by correlations with epithelial–mesenchymal transition (EMT)–related transcription factors such as FOXA1 and SNAI2 and inverse associations with epithelial markers including CDH1. Computational predictions using RIblast identified specific MNX1–AS1 binding regions with candidate miRNAs and mRNAs, prioritizing EMT–related transcripts (e.g., SNAI2, FOXA1, ZEB1) with favorable hybridization energies for future validation. Additional prioritized interactors included genes linked to stress response (IER2, FOSB) and invasion (MMP11, MMP1). Because A2780 has been discussed as an endometrioid–like/non–serous ovarian cancer model, mechanistic inferences primarily apply to this in vitro context, while TCGA analyses provide associative support rather than mechanistic validation. Collectively, these findings highlight MNX1–AS1 as a candidate regulator associated with transcriptional reprogramming in OC and a promising prognostic biomarker warranting further functional testing. Full article

Extracellular vesicles (EVs) mediate intercellular communication by delivering proteins and RNAs, with their molecular cargo often reflecting the biological context of their source. Perinatal tissues are promising sources of EV-related biomaterials with potential dermatologic applications. In this study, we compared EV-related molecular cargo from two umbilical cord-associated sources, umbilical cord mesenchymal stem cell (UCMSC)-derived EVs and cord blood plasma (CBP), to investigate whether these materials exhibit distinct functional effects on melanogenesis. UCMSC-derived EVs were isolated from conditioned culture medium and characterized using nanoparticle tracking analysis (NTA), cryo-electron microscopy (cryo-EM), and canonical EV marker detection, while cord blood samples were processed to obtain plasma following centrifugation and filtration, containing EVs together with soluble plasma components. Functional assays in the murine melanocyte cell line B16F10 demonstrated that UCMSC-derived EVs suppressed melanin production, whereas CBP treatment enhanced melanogenesis. Integrative omics analyses combining microRNAs (miRNAs) microarray profiling and proteomic characterization revealed distinct molecular signatures between UCMSC-derived EVs and CBP samples. Functional validation using miRNA mimic assays showed that selected miRNAs, including miR-6862-5p, miR-3622b-5p, miR-7847-3p, miR-6774-5p, and miR-4685-5p, reduced melanin production, whereas others, including miR-203a-3p, miR-126-3p, miR-139-5p, and miR-15b-5p, increased melanin levels. Pathway analysis using Ingenuity Pathway Analysis (IPA) (QIAGEN Inc.) associated these miRNA subsets with signaling pathways involved in melanogenesis. Together, these findings indicate that UCMSC-derived EVs and CBP exhibit opposite functional effects on melanogenesis and possess distinct miRNA and protein cargo profiles, providing potential molecular targets for modulating pigmentation and supporting the development of EV-related therapeutic strategies for pigmentation disorders. Full article

Titanium implants are widely used in orthopedic and dental fields but often face challenges such as insufficient osseointegration and peri-implant inflammation. While Strontium (Sr) possesses potent bioactive properties, achieving its controlled delivery at the implant-tissue interface remains technically challenging. To address this, we engineered a multidimensional composite coating by constructing a micro/nano-porous TiO₂ substrate via micro-arc oxidation (MAO), followed by polydopamine (PDA)-assisted Sr immobilization. This integrated architecture significantly enhanced surface hydrophilicity and facilitated high-content Sr loading with sustained release kinetics. Biological evaluations demonstrated that the PDA-mediated interface promoted superior initial adhesion and spreading of bone marrow mesenchymal stem cells (BMSCs), synergizing with released Sr²⁺ to markedly upregulate core osteogenic markers (Runx2, ALP). Crucially, the functionalized surface actively optimized the immune microenvironment by inducing M1-to-M2 macrophage polarization and comprehensively suppressing RANKL-induced osteoclastogenesis via the downregulation of TRAP and DC-STAMP. By integrating these pro-osteogenic, anti-inflammatory, and anti-resorptive capabilities, this tri-functional system effectively rebalances the bone remodeling microenvironment. Consequently, it provides a robust, universally applicable strategy for enhancing the therapeutic efficacy of next-generation orthopedic and dental implants. Full article

Undifferentiated sarcomas (USs), including undifferentiated pleomorphic sarcoma (UPS), are aggressive mesenchymal malignancies with limited molecular biomarkers for prognostic assessment and therapeutic stratification. Expression-based markers may provide insight into tumor aggressiveness and clinical outcomes. Here, we performed integrative transcriptomic and spatial analyses to identify differentially expressed genes (DEGs). By comparing normal tissues with sarcoma tumors and sarcoma tumors with cell lines. Intersection and clustering analyses were conducted to define shared expression programs, which revealed a subset of DEGs enriched in epithelial-mesenchymal transition (EMT)-related pathways. CosMx spatial transcriptomics was applied to xenograft tumors derived from two UPS cell lines to resolve tumor-intrinsic signatures. The National Cancer Center Cohort samples were used for validation, and immunohistochemistry confirmed the expression in thirty US tissues. Spatial transcriptomic profiling identified mesenchymal tissue–driven gene expression programs in UPS xenografts. Across bulk RNA-seq and spatial data, epithelial membrane protein 3 (EMP3) consistently emerged as highly expressed in US tissues and cell lines. EMP3 is a robust mesenchymal-associated biomarker linked to EMT, tumor progression, and clinical outcomes in USs, supporting its potential utility as a prognostic indicator and therapeutic target. Full article

Background and Objectives: Immunohistochemistry (IHC) is a keystone in gastric cancer (GC) management, allowing treatment customization, including for advanced or metastatic diseases. This review aims to evaluate the critical role of IHC markers, analyzing their efficiency in molecular subclassification and prediction of response to gastric cancer-targeted therapies, while also describing state-of-the-art IHC techniques and perspectives. Results: The major challenges for the GC management were structured in two main sections, as follows: (i) the current paradigm of gastric neoplasia diagnosis, which includes subsections related to the methodological and morphological foundations, the epidemiological dynamics, and risk factors, as well as differential diagnosis of poorly differentiated tumors; and (ii) the progress in 3,3′-diaminobenzidine (DAB) application and advanced reagents in gastric cancer immunohistochemistry. Discussion: Considering the role of IHC and DAB, the following topics were successively addressed in seven sections: GC key biomarkers, such as human epidermal growth factor receptor 2 (HER2), programmed death-ligand 1 (PD-L1), and DNA replication mismatch repair (MMR) system, allow direct correlation between tissue morphology and protein expression; intestinal and gastrointestinal differentiation markers; emerging and aggressive histological subtypes; epithelial–mesenchymal transition, E-cadherin, and the process of tumor budding; implementation of innovative procedures in gastric cancer immunohistochemistry; and automation, quality control, and sustainability in the pathology laboratory. Perspectives: The main directions were focused on the integration of artificial intelligence (AI) algorithms for digital quantification of the IHC signal and also on the expansion of panels to new targets, such as Claudin 18.2 (CLDN 18.2), which redefines treatment approaches in advanced stages. Conclusions: Although faced with technical and biological limitations, immunohistochemistry remains indispensable in modern gastric oncology. The evolution towards digital pathology and the refinement of scoring criteria will transform IHC from a complementary test into a visual tool that is essential for personalizing oncological treatment. Full article

Background: Uterine sarcomas are rare but highly aggressive mesenchymal malignancies associated with poor survival. Preoperative differentiation from benign leiomyomas remains a critical oncologic challenge, frequently resulting in unexpected postoperative diagnoses and potential tumour dissemination during morcellation. Reliable, accessible biomarkers to support preoperative risk assessment are lacking. This study evaluated whether CRP, a systemic inflammatory marker implicated in tumour biology, could aid in the preoperative identification of uterine sarcoma. Methods: This retrospective single-centre study included 39 patients with histologically confirmed uterine sarcoma and 39 patients with leiomyoma treated between 2010 and 2021. Preoperative serum CRP levels were compared between groups. As data were non-normally distributed, the Mann–Whitney U test was used for comparisons, and Spearman’s rank correlation was applied for association analyses. Results: Patients with sarcoma were significantly older than controls (56.2 ± 12.9 vs. 39.2 ± 6.7 years, p < 0.0001). Preoperative CRP levels were significantly higher in sarcoma patients compared with leiomyoma patients (26.4 ± 46.8 mg/L vs. 0.4 ± 1.6 mg/L; p < 0.001). Elevated CRP (>5 mg/L) was observed in 53.8% of sarcoma cases versus 2.6% of controls. Undifferentiated sarcomas demonstrated the highest CRP levels. CRP levels were not significantly associated with tumour aggressiveness. A moderate negative correlation between age and preoperative CRP was identified (r = −0.476, p = 0.029). Receiver operating characteristic analysis demonstrated a moderate discriminatory ability of preoperative CRP for differentiating uterine sarcoma from leiomyoma (AUC 0.751, 95% CI 0.668–0.834). Conclusions: Elevated preoperative CRP levels are significantly associated with uterine sarcoma and may enhance oncologic risk stratification prior to surgery. Integration of CRP into multimodal preoperative assessment algorithms could improve surgical planning and reduce the risk of inadvertent tumour dissemination. Prospective multicentre studies are required to validate its diagnostic performance and define clinically relevant cut-off values. Full article

Background: Cutaneous radiation injury arises when ionizing radiation disrupts epidermal barrier integrity, triggering persistent DNA damage, oxidative stress, and senescence-associated inflammatory signaling that drive extracellular matrix degradation and impaired regeneration. Clinical burden is rising due to dose-intensified radiotherapy, but also due to an increased use of energy-based aesthetic procedures that elicit radiation-like dermal injury. Dermal fibroblasts exhibit marked sensitivity to ionizing radiation and rapidly acquire senescence-associated secretory phenotypes that suppress collagen biosynthesis and promote chronic inflammation, underpinning the need for regenerative treatments that restore tissue homeostasis and regenerative competence. Mesenchymal stem cell–derived exosomes have emerged as a promising therapeutic strategy in this setting, with increasing preclinical evidence demonstrating their capacity to attenuate oxidative stress, enhance DNA damage-repair pathways, and normalize fibroblast metabolic function. Methods: In this study, we examine the expression profiles for 14 radiation response–associated genes of irradiated human dermal fibroblasts that were treated with bone marrow and umbilical cord MSC-derived exosomes at different timepoints using quantitative RT-PCR analysis. We also explore functional relationships among these genes through interaction network analysis, and outline a framework to organize pathway-level transcriptional responses to irradiation and exosome treatment. Results: MSC-derived exosome treatment was associated with attenuated early damage response signaling at 24 h, followed by increased expression of genes associated with DNA repair and oxidative stress recovery at intermediate timepoints. Exosome-treated cells also exhibited transcriptional changes consistent with modulation of cell-cycle regulatory pathways and reduced expression of pro-inflammatory markers by 5 d. These findings suggest that MSC-derived exosomes influence the temporal organization of the fibroblast transcriptional response to ionizing radiation and may contribute to molecular programs associated with tissue recovery following ionizing radiation exposure. Full article

Colorectal cancer (CRC) remains a major global health challenge, primarily due to late-stage diagnosis and high metastatic potential. Effective management requires novel diagnostic and prognostic strategies, with a growing focus on molecular biomarkers. A Disintegrin and Metalloproteinase (ADAM) proteins, characterized by unique proteolytic activity, play a fundamental role in tumorigenesis by regulating tumor growth, epithelial–mesenchymal transition (EMT), and metastasis. Based on recent investigations, among all ADAMs, ADAM8, ADAM9, ADAM12, ADAM15, and ADAM17 have been proved to play an important role in the CRC pathogenesis. Thus, this review underscores the potential of selected ADAM family members as promising candidates for biomarkers of CRC. Elevated ADAM8, ADAM9, ADAM12 and ADAM17 levels were observed in CRC tissues and correlated with more advanced tumor stage, while increased serum ADAM15 concentrations associated with the presence distant metastases. Moreover, ADAM9, ADAM12, ADAM15 and ADAM17 levels were associated with poorer survival, whereas ADAM8 overexpression was found to be independent prognostic factor for CRC patients’ survival. In addition, the measurement of serum ADAM15 concentrations, especially in combination with well-established tumor marker–CEA improved the diagnosis of patients with this malignancy. In conclusion, selected ADAM are critical contributors to the development and progression of CRC, affecting tumor growth, EMT, and metastasis. ADAM8, ADAM9, ADAM12, ADAM15 and ADAM17 were identified as promising biomarkers for the assessment of CRC progression and proved to be prognostic indicators for patients’ survival. Further validation through large prospective studies and standardized assays is necessary to establish their potential in clinical practice. Full article