Search Results (1,021)

Endometriosis is a disease characterized by the presence of endometrial glands and stroma outside of the uterine corpus, often clinically presenting with pain and/or infertility. Ectopic lesions exhibit features characteristic of epithelial-to-mesenchymal transition (EMT), a process in which epithelial cells lose polarity and acquire mesenchymal traits, including migratory and invasive capabilities. During the process of EMT, epithelial traits are downregulated, while mesenchymal traits are acquired, with cells developing migratory ability, increasing proliferation, and resistance to apoptosis. EMT is promoted by exposure to hypoxia and stimulation by transforming growth factor-β (TGF-β), platelet-derived growth factor (PDGF), and estradiol. Signaling pathways that promote EMT are activated in most ectopic lesions and involve transcription factors such as Snail, Slug, ZEB-1/2, and TWIST-1/2. EMT-specific molecules present in the serum of women with endometriosis appear to have diagnostic potential. Strategies targeting EMT in animal models of endometriosis have demonstrated regression of ectopic lesions, opening the door for novel therapeutic approaches. This review summarizes the current understanding of the role of EMT in endometriosis and highlights potential targets for EMT-related diagnosis and therapeutic interventions. Full article

Bone is the most frequent site of distant metastasis in advanced prostate cancer (PCa), contributing substantially to patient morbidity and mortality. Hypoxia, a defining feature of the solid tumour microenvironment, plays a pivotal role in driving bone-tropic progression by promoting epithelial-to-mesenchymal transition (EMT), cancer stemness, extracellular matrix (ECM) remodelling, and activation of key signalling pathways such as Wingless/Integrated (Wnt) Wnt/β-catenin and PI3K/Akt. Hypoxia also enhances the secretion of extracellular vesicles (EVs), enriched with pro-metastatic cargos, and upregulates bone-homing molecules including CXCR4, integrins, and PIM kinases, fostering pre-metastatic niche formation and skeletal colonisation. In this review, we analysed current evidence on how hypoxia orchestrates PCa dissemination to bone, focusing on the molecular crosstalk between HIF signalling, Wnt activation, EV-mediated communication, and cellular plasticity. We further explore therapeutic strategies targeting hypoxia-related pathways, such as HIF inhibitors, hypoxia-activated prodrugs, and Wnt antagonists, with an emphasis on overcoming therapy resistance in castration-resistant PCa (CRPC). By examining the mechanistic underpinnings of hypoxia-driven bone metastasis, we highlight promising translational avenues for improving patient outcomes in advanced PCa. Full article

Prostate cancer continues to be the most common cause of cancer-related disease and mortality among men worldwide, especially in the advanced stages, notably metastatic castration-resistant prostate cancer (mCRPC), which poses significant treatment challenges. Docetaxel, a widely used chemotherapeutic agent, has long served as the standard treatment, offering survival benefits and mitigation. However, its clinical impact is frequently undermined by the development of chemoresistance, which is a formidable challenge that leads to treatment failure and disease progression. The mechanisms driving docetaxel resistance are diverse and complex, encompassing modifications in androgen receptor signaling, drug efflux transporters, epithelial-mesenchymal transition (EMT), microtubule alterations, apoptotic pathway deregulation, and tumor microenvironmental influences. Recent evidence suggests that extracellular RNAs influence drug responses, further complicating the resistance landscape. This review offers a broad discussion on the mechanisms of resistance and explores novel therapeutic approaches to address them. These include next-generation taxanes, targeted molecular inhibitors, immunotherapies, and combination regimens that can be designed to counteract specific resistance pathways. By broadening our understanding of docetaxel resistance, this review highlights potential strategies to improve therapeutic efficacy and the potential to enhance outcomes in patients with advanced treatment-resistant prostate cancer. Full article

Bone metastasis remains a significant cause of morbidity and diminished quality of life in patients with advanced breast, prostate, and lung cancers. Emerging research highlights the pivotal role of reversible epigenetic alterations, including DNA methylation, histone modifications, chromatin remodeling complex dysregulation, and non-coding RNA networks, in orchestrating each phase of skeletal colonization. Site-specific promoter hypermethylation of tumor suppressor genes such as HIN-1 and RASSF1A, alongside global DNA hypomethylation that activates metastasis-associated genes, contributes to cancer cell plasticity and facilitates epithelial-to-mesenchymal transition (EMT). Key histone modifiers, including KLF5, EZH2, and the demethylases KDM4/6, regulate osteoclastogenic signaling pathways and the transition between metastatic dormancy and reactivation. Simultaneously, SWI/SNF chromatin remodelers such as BRG1 and BRM reconfigure enhancer–promoter interactions that promote bone tropism. Non-coding RNAs, including miRNAs, lncRNAs, and circRNAs (e.g., miR-34a, NORAD, circIKBKB), circulate via exosomes to modulate the RANKL/OPG axis, thereby conditioning the bone microenvironment and fostering the formation of a pre-metastatic niche. These mechanistic insights have accelerated the development of epigenetic therapies. DNA methyltransferase inhibitors (e.g., decitabine, guadecitabine) have shown promise in attenuating osteoclast differentiation, while histone deacetylase inhibitors display context-dependent effects on tumor progression and bone remodeling. Inhibitors targeting EZH2, BET proteins, and KDM1A are now advancing through early-phase clinical trials, often in combination with bisphosphonates or immune checkpoint inhibitors. Moreover, novel approaches such as CRISPR/dCas9-based epigenome editing and RNA-targeted therapies offer locus-specific reprogramming potential. Together, these advances position epigenetic modulation as a promising axis in precision oncology aimed at interrupting the pathological crosstalk between tumor cells and the bone microenvironment. This review synthesizes current mechanistic understanding, evaluates the therapeutic landscape, and outlines the translational challenges ahead in leveraging epigenetic science to prevent and treat bone metastases. Full article

Natural compounds, particularly flavonoids, have emerged as promising anticancer agents due to their various biological activities and no or negligible toxicity towards healthy tissues. Among these, isorhamnetin, a methylated flavonoid, has gained significant attention for its potential to target multiple cancer hallmarks. This review comprehensively explores the mechanisms by which isorhamnetin exerts its anticancer effects, including cell cycle regulation, apoptosis, suppression of metastasis and angiogenesis, and modulation of oxidative stress and inflammation. Notably, isorhamnetin arrests cancer cell proliferation by regulating cyclins, and CDKs induce apoptosis via caspase activation and mitochondrial dysfunction. It inhibits metastatic progression by downregulating MMPs, VEGF, and epithelial–mesenchymal transition (EMT) markers. Furthermore, its antioxidant and anti-inflammatory properties mitigate reactive oxygen species (ROS) and pro-inflammatory cytokines, restricting cancer progression and modulating tumor microenvironments. Combining isorhamnetin with other treatments was also discussed to overcome multidrug resistance. Importantly, this review integrates the recent literature (2022–2024) and highlights isorhamnetin’s roles in modulating cancer-specific signaling pathways, immune evasion, tumor microenvironment dynamics, and combination therapies. We also discuss nanoformulation-based strategies that significantly enhance isorhamnetin’s delivery and bioavailability. This positions isorhamnetin as a promising adjunct in modern oncology, capable of improving therapeutic outcomes when used alone or in synergy with conventional treatments. The future perspectives and potential research directions were also summarized. By consolidating current knowledge and identifying critical research gaps, this review positions Isorhamnetin as a potent and versatile candidate in modern oncology, offering a pathway toward safer and more effective cancer treatment strategies. Full article

Transforming growth factor-β (TGF-β) is a key protein family member that includes activins, inhibins, and bone morphogenetic proteins (BMPs). It is essential in numerous biological processes, such as chemotaxis, apoptosis, differentiation, growth, and cell migration. TGF-β receptors initiate signaling through two primary pathways: the canonical pathway involving Smad proteins and non-canonical pathways that utilize alternative signaling mechanisms. When TGF-β signaling is disrupted, it has been shown to contribute to the development of various diseases, including cancer. Initially, TGF-β effectively inhibits the cell cycle and promotes apoptosis. However, its role can transition to facilitating tumor growth and metastasis as the disease progresses. Moreover, TGF-β drives cancer progression through epithelial–mesenchymal transition (EMT), modulation of factor expression, and evasion of immune responses. This complexity establishes the need for further research, particularly into pharmacological agents targeting TGF-β, which are emerging as promising therapeutic options. Current clinical and preclinical studies are making significant strides toward mitigating the adverse effects of TGF-β. This underscores the critical importance of understanding its underlying mechanisms to enhance treatment effectiveness and improve survival rates for cancer patients. Full article

The B-cell lymphoma 2 (Bcl-2)-related ovarian killer (BOK), a member of the Bcl-2 protein family, shares a similar domain structure and amino acid sequence homology with the pro-apoptotic family members BAX and BAK. Although BOK is involved in the development of various types of cancer, its mechanism of action in breast cancer remains unclear. This study found that BOK was involved in the process of MG132, inhibiting the migration and epithelial–mesenchymal transition (EMT) of breast cancer cells induced by transforming growth factor-β. Furthermore, interfering BOK reversed the inhibition of breast cancer cell migration and the EMT process by MG132. Additional studies revealed that BOK silencing promoted the expression of EMT-related markers in breast cancer cells, while BOK overexpression inhibited EMT and migration. Using RNA-seq sequencing and Western blotting, we confirmed that the Wnt signaling pathway is involved in BOK regulating the EMT process in breast cancer cells. Therefore, we conclude that low BOK expression promotes breast cancer EMT and migration by activating the Wnt signaling pathway. This study enhances our understanding of breast cancer pathogenesis and suggests that BOK may serve as a potential prognostic marker and therapeutic target for breast cancer. Full article

Military personnel deployed to Iraq and Afghanistan were exposed to emissions from open-air burn pits, where plastics, metals, and medical waste were incinerated. These exposures have been linked to deployment-related respiratory diseases (DRRD) and may also impact neurological health via the lung–brain axis. To investigate molecular mechanisms, adult male rats were exposed to filtered air, naphthalene (a representative volatile organic compound), or a combination of naphthalene and carbon black (surrogate for particulate matter; CBN) via whole-body inhalation (six hours/day, three consecutive days). Lung, brain, and plasma samples were collected 24 h after the final exposure. Pro-inflammatory biomarkers were assessed using multiplex electrochemiluminescence and western blot. Differentially expressed genes (DEGs) were identified by RNA sequencing, and elastic net modeling was used to define exposure-predictive gene signatures. CBN exposure altered inflammatory biomarkers across tissues, with activation of nuclear factor kappa B (NF-κB) signaling. In the lung, gene set enrichment revealed activated pathways related to proliferation and inflammation, while epithelial–mesenchymal transition (EMT) and oxidative phosphorylation were suppressed. In the brain, EMT, inflammation, and senescence pathways were activated, while ribosomal function and oxidative metabolism were downregulated. Elastic net modeling identified a lung gene signature predictive of CBN exposure, including Kcnq3, Tgfbr1, and Tm4sf19. These findings demonstrate that inhalation of a surrogate burn pit mixture induces inflammatory and metabolic gene expression changes in both lung and brain tissues, supporting the utility of this animal model for understanding systemic effects of airborne military toxicants and for identifying potential biomarkers relevant to DRRD and Veteran health. Full article

The retinal pigment epithelium (RPE), a monolayer of pigmented cells, is critical for visual function through its interaction with the neural retina. In healthy eyes, RPE cells exhibit a uniform hexagonal arrangement, but under stress or disease, such as age-related macular degeneration (AMD), dysmorphic traits like cell enlargement and apparent multinucleation emerge. Multinucleation has been hypothesized to result from cellular fusion, a compensatory mechanism to maintain cell-to-cell contact and barrier function, as well as conserve resources in unhealthy tissue. However, traditional two-dimensional (2D) imaging using apical border markers alone may misrepresent multinucleation due to the lack of lateral markers. We present high-resolution confocal images enabling three-dimensional (3D) visualization of apical (ZO-1) and lateral (α-catenin) markers alongside nuclei. In two RPE damage models, we find that seemingly multinucleated cells are often single cells with displaced neighboring nuclei and lateral membranes. This emphasizes the need for 3D analyses to avoid misidentifying multinucleation and underlying fusion mechanisms. Lastly, images from the NaIO₃ oxidative damage model reveal variability in RPE damage, with elongated, dysmorphic cells showing increased ZsGreen reporter protein expression driven by EMT-linked CAG promoter activity, while more regular RPE cells displayed somewhat reduced green signal more typical of epithelial phenotypes. Full article

This study aimed to investigate the tyrosine kinase inhibitor Nintedanib and its potential role in reversing epithelial–mesenchymal transition (EMT) induced by transforming growth factor beta 2 (TGF-β2) in retinal pigment epithelial (RPE) cells, along with its therapeutic potential using a mouse model of subretinal fibrosis. We hypothesized that the blockade of angiogenesis promoting and fibrosis inducing signaling using the receptor tyrosine kinase inhibitor Nintedanib (OfevTM) can prevent or reverse EMT both in vitro and in our in vivo model of subretinal fibrosis. Primary human retinal pigment epithelial cells (phRPE) and adult retinal pigment epithelial cell line (ARPE-19) cells were treated with TGF-β210 ng/mL for two days followed by four days of Nintedanib (1 µM) incubation. Epithelial and mesenchymal phenotypes were assessed by morphological examination, quantitative real-time polymerase chain reaction(qPCR) (ZO-1, Acta2, FN, and Vim), and immunocytochemistry (ZO-1, vimentin, fibronectin, and αSMA). Metabolites were measured using luciferase-based assays. Extracellular acidification and oxygen consumption rates were measured using the Seahorse XF system. Metabolic-related genes (GLUT1, HK2, PFKFB3, CS, LDHA, LDHB) were evaluated by qPCR. A model of subretinal fibrosis using the two-stage laser-induced method in C57BL/6J mice assessed Nintedanib’s therapeutic potential. Fibro-vascular lesions were examined 10 days later via fluorescence angiography and immunohistochemistry. Both primary and ARPE-19 RPE stimulated with TGF-β2 upregulated expression of fibronectin, αSMA, and vimentin, and downregulation of ZO-1, consistent with morphological changes (i.e., elongation). Glucose consumption, lactate production, and glycolytic reserve were significantly increased in TGF-β2-treated cells, with upregulation of glycolysis-related genes (GLUT1, HK2, PFKFB3, CS). Nintedanib treatment reversed TGF-β2-induced EMT signatures, down-regulated glycolytic-related genes, and normalized glycolysis. Nintedanib intravitreal injection significantly reduced collagen-1+ fibrotic lesion size and Isolectin B4+ neovascularization and reduced vascular leakage in the two-stage laser-induced model of subretinal fibrosis. Nintedanib can induce Mesenchymal-to-Epithelial Transition (MET) in RPE cells and reduce subretinal fibrosis through metabolic reprogramming. Nintedanib can therefore potentially be repurposed to treat retinal fibrosis. Full article

Docetaxel is a chemotherapeutic agent widely used for breast cancer treatment; however, its efficacy is often limited by drug resistance and associated toxicity. This review examines the molecular mechanisms of docetaxel resistance in breast cancer and discusses research advances and future directions for overcoming this challenge. Key resistance mechanisms include alterations in drug targets (microtubules), increased drug efflux, suppression of apoptosis, activation of survival signalling pathways, epithelial-to-mesenchymal transition (EMT), and cancer stem cell enrichment. An evolutionary perspective distinguishes between intrinsic and acquired resistance, emphasising the need for adaptive therapeutic strategies. Recent advances in genomic profiling, non-coding RNA research, novel drug combinations, and biomarker-guided therapies have also been reviewed. Emerging approaches, such as targeting the tumour microenvironment, harnessing immunotherapy, and implementing adaptive dosing schedules, have been discussed. This review emphasises the understanding of resistance as a multifactorial phenomenon that requires multipronged interventions. Research has aimed to identify predictive biomarkers, develop targeted agents to reverse resistance, and design rational combination strategies to improve patient outcomes. Progress in deciphering and targeting docetaxel resistance mechanisms holds promise for enhancing treatment responses and extending survival in patients with breast cancer. Full article

Growth hormone (GH) signaling has been implicated in tumor progression and therapy resistance across multiple cancer types, yet its role in bladder cancer remains largely unexplored. In this study, we investigated the impact of GH and its receptor (GHR) on therapy resistance and disease progression in urothelial carcinoma (UC) through integrated transcriptomic and in vitro analyses. Transcriptomic profiling of The Cancer Genome Atlas bladder cancer cohort revealed that high tumoral GHR expression was associated with differential upregulation of genes involved in drug efflux, epithelial-to-mesenchymal transition (EMT), and extracellular matrix (ECM) remodeling. Notably, elevated GHR levels correlated with significantly reduced overall survival in patients with UC. In parallel, in vitro experiments demonstrated that GH promotes chemoresistance in UC cell lines via upregulation of ATP-binding cassette-containing (ABC) transporters and activation of EMT. GH also modulated ECM-remodeling-associated genes in a chemotherapy-dependent manner, including matrix metalloproteinases and tissue inhibitors of metalloproteinases. Importantly, these effects were abrogated by Pegvisomant, a GHR antagonist, indicating the functional relevance of GH/GHR signaling in the mediation of these phenotypes. Collectively, our findings support a mechanistic role for GH signaling in driving therapy resistance and tumor aggressiveness in bladder cancer and suggest GHR antagonism as a potential therapeutic strategy to improve treatment outcomes. Full article

Non-small cell lung cancer (NSCLC) is a predominant form of lung cancer that is often diagnosed at an advanced metastatic stage. The processes of cancer cell migration and invasion involve epithelial-to-mesenchymal transition (EMT), which is crucial for metastasis. Targeting cancer aggressiveness with effective plant compounds has gained attention as a potential adjuvant therapy. Eurycomanone (ECN), a bioactive quassinoid found in the root of Eurycoma longifolia Jack, has demonstrated anti-cancer activity against various carcinoma cell lines, including human NSCLC cells. This study aimed to investigate the in vitro effects of ECN on the migration and invasion of human NSCLC cells and to elucidate the mechanisms by which ECN modulates the EMT in these cells. Non-toxic doses (≤IC20) of ECN were determined using the MTT assay on two human NSCLC cell lines: A549 and Calu-1. The results from wound healing and transwell migration assays indicated that ECN significantly suppressed the migration of both TGF-β1-induced A549 and Calu-1 cells. ECN exhibited a strong anti-invasive effect, as its non-toxic doses significantly suppressed the TGF-β1-induced invasion of NSCLC cells through Matrigel and decreased the secretion of MMP-2 from these cancer cells. Furthermore, ECN could affect the TGF-β1-induced EMT process in various ways in NSCLC cells. In TGF-β1-induced A549 cells, ECN significantly restored the expression of E-cadherin by inhibiting the Akt signaling pathway. Conversely, in Calu-1, ECN reduced the aggressive phenotype by decreasing the expression of the mesenchymal protein N-cadherin and inhibiting the TGF-β1/Smad pathway. In conclusion, this study demonstrated the anti-invasive activity of eurycomanone from E. longifolia Jack in human NSCLC cells and provided insights into its mechanism of action by suppressing the effects of TGF-β1 signaling on the EMT program. These findings offer scientific evidence to support the potential of ECN as an alternative therapy for metastatic NSCLC. Full article

Background/Objectives: Cisplatin remains a cornerstone chemotherapeutic agent for non-small-cell lung cancer (NSCLC) treatment, yet its clinical utility is substantially limited by acquired resistance and the inadequate suppression of tumor metastasis. Emerging evidence implicates interleukin 6 (IL-6) as a critical mediator of chemoresistance through cancer stem cell (CSC) enrichment and metastasis promotion via epithelial–mesenchymal transition (EMT) induction, ultimately contributing to cisplatin therapy failure. This study sought to address these challenges by designing a nanoplatform with two innovative aims: (1) to achieve active tumor targeting through binding to the IL-6 receptor (IL-6R), and (2) to concurrently inhibit IL-6-mediated chemoresistance signaling pathways. Methods: A lipid–polymer hybrid nanoparticle (LPC) encapsulating cisplatin was synthesized and subsequently surface-functionalized with tocilizumab (TCZ), a monoclonal antibody that targets IL-6R. The therapeutic efficacy of this TCZ-modified nanoparticle (LPC-TCZ) was assessed through a series of in vitro and in vivo experiments, focusing on the inhibition of EMT, expression of CSC markers, tumor growth, and metastasis. Results: Systematic in vitro and in vivo evaluations revealed that LPC-TCZ synergistically attenuated both EMT progression and CSC marker expression through the targeted blockade of IL-6/STAT3 signaling. This multimodal therapeutic strategy demonstrated superior tumor growth inhibition and metastatic suppression compared to conventional cisplatin monotherapy. Conclusions: Our findings establish a nanotechnology-enabled approach to potentiate cisplatin efficacy by simultaneously countering chemoresistance mechanisms and metastatic pathways in NSCLC management. Full article

Crohn’s disease (CD), characterized by chronic gastrointestinal inflammation, is complicated by intestinal stenosis resulting from dysregulated fibrogenesis and is marked by excessive extracellular matrix (ECM) deposition, fibroblast activation, and luminal obstruction. While biologics control inflammation, their failure to halt fibrosis underscores a critical therapeutic void. Emerging evidence highlights the multifactorial nature of stenosis-associated fibrosis, driven by profibrotic mediators and dysregulated crosstalk among immune, epithelial, and mesenchymal cells. Key pathways, including transforming growth factor (TGF-β), drosophila mothers against decapentaplegic protein (Smad) signaling, Wnt/β-catenin activation, epithelial–mesenchymal transition (EMT), and matrix metalloproteinase (MMP) and tissue inhibitors of metalloproteinase (TIMP)-mediated ECM remodeling, orchestrate fibrotic progression. Despite the current pharmacological, endoscopic, and surgical interventions for fibrostenotic CD, their palliative nature and inability to reverse fibrosis highlight an unmet need for disease-modifying therapies. This review synthesizes mechanistic insights, critiques therapeutic limitations with original perspectives, and proposes a translational roadmap prioritizing biomarker-driven stratification, combinatorial biologics, and mechanistically targeted antifibrotics. Full article