Search Results (1,222)

While normal fibroblasts suppress tumor growth, during cancer initiation and progression, this capacity can be lost and even switched to tumor-promoting, for reasons that are not understood. In this study, we aimed to determine differences between patient-derived cancer-associated fibroblasts and fibroblasts from healthy breast tissue to identify if and how these changes stimulate Triple-negative breast cancer (TNBC). Two-dimensional and three-dimensional mono and co-cultures of TNBC cells with fibroblasts from healthy breast or TNBC were analyzed for cell contractility, migration, distribution, proliferation, and hyaluronan production by traction force microscopy, live cell imaging, flow cytometry, Western blot, and ELISA. In 3D spheroid co-culture, CAFs migrated into the tumor mass, mixing with tumor cells, whereas normal fibroblasts remained separate. In 2D, CAFs showed increased cell migration and contractile force, and, in both 2D and 3D co-culture, CAFs increased the proliferation of TNBC cells. CAFs showed increased production of hyaluronan, as compared to normal fibroblasts, and loss of hyaluronan synthase 2 reduced CAF-induced stimulation of TNBC proliferation. These findings suggest that increased production of hyaluronan by TNBC CAFs enhances their capacity to mix with and induce the proliferation of cancer cells, and that the production of hyaluronan by CAFs can be a future therapeutic target against TNBC. Full article

Background. The dense hyaluronan (HA)-rich stroma in solid tumors can prevent effective tumor growth inhibition by hindering drug delivery and immune cell infiltration. However, the degradation of HA alone by systemic delivery of hyaluronidase has not shown significant improvement of tumor growth inhibition. Objectives/Methods. In this study, we targeted hyaluronan degradation by using antibody–enzyme (AbEn) molecules by fusing antibodies to a recombinant human hyaluronidase (HYAL). Results. The AbEn molecules were stable, retained both antigen-binding and enzymatic activities, and demonstrated a prolonged serum half-life of 132 h in rodent models. In the HA-rich colorectal cancer model, the cancer-associated fibroblast (CAF)-directed AbEn, TAVO423 (FAP × LRRC15 × HYAL trispecific antibody) achieved greater intratumoral HA depletion resulting in superior tumor growth inhibition compared to untargeted HYAL. Furthermore, the combination of TAVO423 in combination with other solid tumor cell targeting modalities such as 5-fluorouracil (5-FU), anti-PD-L1 monoclonal antibody, a PD-L1 × CD3 bispecific T-cell engager (TCE), and a CD318-targeting antibody–drug conjugate (ADC) all demonstrated enhanced tumor growth inhibition (TGI) values of 49–67% as compared to the respective monotherapy TGI values of 1–28%. In addition, TAVO423 improved the antitumor response of a 5T4 × CD3 TCE with an increase in TGI from 73% to 92% in an in vivo HA-rich pancreatic cancer model. The CAF-targeted HA degradation mediated by TAVO423 also reversed immune exclusion by increasing the density of CD8⁺ tumor-infiltrating lymphocytes (TILs) by 6–9-fold and synergized with PD-1 blockade to enhance TGI from 33% to 51% in an in vivo immunocompetent EMT-6 breast cancer model. Conclusions. These findings demonstrated the broad potential of the modular AbEn platform for targeted HA degradation to overcome barrier entry in stromal HA-rich solid tumors. Full article

Background/Objectives: Cutaneous squamous cell carcinoma (cSCC) is a very common skin malignancy of the head and neck area, with a propensity to spread to local lymph nodes. Epithelial-to-mesenchymal transition (EMT) and cancer-associated fibroblasts (CAFs) play a well-documented role in the progression of the disease. In this study, we developed and characterised multicellular tumour spheroids (MCTS) composed of patient-derived metastatic cSCC cell lines—each exhibiting distinct phenotypes—combined with either dermal- or lymph node-derived fibroblasts. We aimed to investigate how these cellular combinations influence MCTS formation, spatial architecture, and invasive behaviour. We hypothesised that the interplay between different cSCC and fibroblast cell combinations would differentially influence spheroid formation and invasion. Methods: Using live-cell microscopy we assessed the spatial architectures specific to each cell line-fibroblast combination and evaluated the expression of EMT and CAF markers. Furthermore, we utilised MCTS in invasion models to investigate associations between the mode of invasion and the EMT phenotype of the cancer cell line. Results: We show that metastatic cSCC/fibroblast MCTS self-organise into distinct spatial architectures. They also invade through collagen in a manner influenced by fibroblasts but dominated by the EMT status of the originating cancer cells. Conclusions: These findings highlight the physiological relevance and utility of MCTS as models for investigating tumour–stroma interactions and invasion dynamics in metastatic cSCC. Full article

Accurate segmentation of colorectal polyps is crucial for the early screening and clinical diagnosis of colorectal cancer. However, the diverse morphology of polyps, significant variations in scale, and unstable quality of endoscopic imaging pose serious challenges for existing algorithms in achieving precise boundary segmentation. To address these issues, this study proposes a novel polyp segmentation algorithm, GDCA-Net, which is developed based on the You Only Look Once version 12 segmentation model (YOLOv12-seg). GDCA-Net introduces several architectural innovations. First, a Gather-and-Distribute (GD) mechanism is incorporated to optimize multi-scale feature fusion, while Alterable Kernel Convolution (AKConv) is integrated to enhance the modeling of complex geometric structures. Second, the Convolution and Attention Fusion Module (CAF) and Context-Mixing dynamic convolution (ContMix) modules are designed to strengthen long-range dependency modeling and multi-scale feature extraction for polyp boundary representation. Finally, a Wise Intersection over Union–based (Wise-IoU) loss function is introduced to accelerate model convergence and improve robustness to low-quality samples. Experiments conducted on the PolypDB, Kvasir-SEG, and CVC-ClinicDB datasets demonstrate the superior performance of GDCA-Net in polyp segmentation tasks. On the most challenging PolypDB dataset, GDCA-Net achieved a mean Average Precision at 50% IoU threshold (mAP50) of 85.9% and an F1-score (F1) of 85.5%, representing improvements of 2.2% and 0.7% over YOLOv12-seg, respectively. Moreover, on the Kvasir-SEG dataset, GDCA-Net achieved a leading F1 score of 94.9%. These results clearly demonstrate that GDCA-Net possesses strong performance and generalization capabilities in handling polyps of varying sizes, shapes, and imaging qualities. Full article

Background: Jawbone invasion is a common and prognostically unfavorable feature of oral squamous cell carcinoma (OSCC). Although cancer-associated fibroblasts (CAFs) are recognized for their role in tumor progression, their spatial dynamics at the tumor–bone interface remain poorly understood. Methods: We analyzed 14 OSCC specimens with confirmed jawbone invasion using histopathological and immunohistochemical techniques. Digital pathology combined with AI-assisted image analysis was employed to quantify and visualize the spatial distribution of OSCC cells (RANKL-positive), CAFs (α-SMA and FAP-positive), and osteoclasts (cathepsin K-positive) within defined regions of interest at the tumor–bone invasive front. Results: A consistent laminar stromal region enriched in CAFs was observed between the tumor nests and jawbone. CAFs were spatially clustered near OSCC cells and osteoclasts, with 81% and 74% residing within 50 μm, respectively. On average, 11.4 CAFs were present per OSCC cell and 23.2 per osteoclast. These spatial proximities were largely preserved irrespective of stromal thickness, suggesting active bidirectional cellular interactions. Conclusions: Our findings demonstrate that CAFs are strategically positioned to facilitate intercellular signaling between tumor cells and osteoclasts, potentially coordinating OSCC proliferation and bone resorption. This study highlights the utility of AI-assisted spatial histology in unraveling tumor microenvironmental dynamics and proposes CAFs as potential therapeutic targets in OSCC-induced osteolytic invasion. Full article

Background: Gingival recession (GR) is defined as the exposure of the root surface due to the gingival margin shifting apically from the cemento-enamel junction. Current effective management of defects related to GR relies on root coverage periodontal plastic surgery (RCPPS), using the Modified Coronally Advanced Flap (mCAF) with an envelope design. Recent literature also reported the association of different biomaterials to the mCAF procedure. In light of these considerations, a systematic review (SR) was conducted to determine and compare the efficacy of all mCAF adjunctive techniques for the treatment of multiple adjacent GR-type (MAGR) defects. Methods: An electronic search was conducted in 2025 on studies published between 2013 and 2025, using PubMed, Scopus, Web of Science, and Cinahl Complete, to address the focused question: “which is the efficacy of different mCAF adjunctive techniques for the treatment of multiple adjacent GR-type defects, in terms of root coverage (RC), esthetic outcomes, and keratinized tissue (KT) augmentation?”. Randomized controlled trials with a minimum follow-up of 6 months with ≥ 5 patients treated for coverage of MAGR were included. Risk of bias was assessed with RoB 2 Tool. A meta-analysis was performed using RevMan5.4 software and the level of evidence of included studies was analyzed with GRADEPro GDT. Results: A total of 17 studies were included in the SR, 9 of which evaluating mCAF + sCTG (subepithelial connective tissue graft) vs. mCAF adjunctive techniques [Collagen Matrix (CM), xenogeneic acellular dermal matrix (XADM), Platelet-Rich Fibrin (PRF), Enamel Matrix Derivatives (EMD), sCTG harvested double blade scalpel] were then included in the meta-analysis. The primary outcomes of complete root coverage (CRC) and keratinized tissue width variation (ΔKTW) were statistically significant ([CRC: Odds Ratio (OR) 1.70; 95% CI (confidence interval) 1.18, 2.44; p = 0.004]; [ΔKTW: SMD (standardized mean difference) 0.37; 95% CI 0.11, 0.63; p = 0.005]) in favor of mCAF + CTG. Meanwhile, no statistically significant difference was observed in terms of RES. The certainty assessment highlighted relevant results: despite the lack of evidence in the long-term, a high level of evidence showed that sCTG was more effective than XADM in terms of CRC (p = 0.002) and ΔKTW (p = 0.0001). A low level of evidence revealed that sCTG achieved a greater ΔKTW compared to CM (p = 0.0006). Although no significant differences were observed, a low level of evidence suggested that mCAF + EMD and mCAF + sCTG (DBS) may provide good results. To date, only one RCT showed long-term stable results of CTG in terms of RC. Conclusions: The association of sCTG to mCAF demonstrated better results in terms of RC and KTW augmentation in short- and medium-term follow-ups. Long-term studies are needed to confirm the efficacy of the other mCAF adjunctive techniques, considering limitations due to heterogeneity in follow-ups, distribution of techniques analyzed, and different study designs. Registration in PROSPERO (International prospective register of systematic reviews) was performed with ID CRD420251085823. Full article

Background: Esophageal cancer remains a highly aggressive malignant tumor with poor prognosis, despite advances in combination therapies and novel immunotherapies. Tertiary lymphoid structures (TLSs), characterized by densely packed CD20⁺ B cells in a germinal-center-like structure, have recently been recognized as immune-stimulating components within the tumor microenvironment. In contrast, cancer-associated fibroblasts (CAFs) are stromal cells expressing fibroblast-activating protein (FAP) involved in immunosuppression. Methods: In this retrospective study, 124 clinical samples from patients who underwent radical surgery for esophageal cancer at our institute were analyzed. We investigated whether TLSs could serve as a prognostic factor and examined their association with tumor microenvironment factors. Results: The presence of TLSs was an independent prognostic factor for overall and progression-free survival in multivariate analyses. A high level of TLS formation correlated with better nutritional status, fewer M2 macrophages, and greater plasma cell infiltration. Additionally, little TLS formation was observed in areas with abundant CAFs, and quantitative analyses revealed a significant negative correlation between TLSs and CAFs. Conclusions: TLSs enhance antitumor immunity via macrophages and plasma cells and can be a valuable prognostic indicator in patients undergoing surgery for esophageal cancer. Targeting CAFs may prove to be a promising therapeutic strategy to enhance tumor-immunity-related TLSs. Full article

To alleviate CaF₂ scaling on reverse osmosis membranes, polyepoxysuccinic acid (PESA) was modified with 2,5-dihydroxyterephthalic acid (DHTA) to obtain DHTA-PESA. Its structure and thermal stability were confirmed through characterization. Scale inhibition performance was evaluated using static and dynamic experiments. Results showed that in static tests, at a dosage of 200 mg/L, DHTA-PESA achieved a CaF₂ scale inhibition rate of nearly 100%, demonstrating Ca²⁺ chelation ability and the capacity to prolong crystallization induction time. In dynamic experiments, indicating superior CaF₂ dispersion performance and effective mitigation of membrane fouling. X-ray diffraction and scanning electron microscopy analysis revealed that DHTA-PESA induces irregular growth of CaF₂ crystals, disrupting their formation and altering crystal morphology. The primary scale inhibition mechanisms include dispersion, lattice distortion, and chelation. Full article

Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment (TME) that influence cancer progression via extracellular matrix (ECM) remodeling and secretion of growth factors and cytokines. Endothelial-to-mesenchymal transition (EndMT) is emerging as an important axis among the heterogeneous origins of CAFs. This review introduces the diverse methods used to induce EndMT in cancer—mouse tumor models, conditioned-medium treatment, co-culture, targeted gene perturbation, ligand stimulation, exosome exposure, irradiation, viral infection, and three-dimensional (3D) culture systems—and summarizes EndMT cell-type evidence uncovered using transcriptomic and proteomic technologies. Hallmark EndMT features include spindle-like morphology, increased motility, impaired angiogenesis and barrier function, decreased endothelial markers (CD31, VE-cadherin), and increased mesenchymal markers (α-SMA, FN1). Reported mechanisms include signaling via TGF-β, cytoskeletal/mechanical stress, reactive oxygen species, osteopontin, PAI-1, IL-1β, GSK-3β, HSP90α, Tie1, TNF-α, HSBP1, and NOTCH. Cancer-induced EndMT affects tumors and surrounding TME—promoting tumor growth and metastasis, expanding cancer stem cell-like cells, driving macrophage differentiation, and redistributing pericytes—and is closely associated with poor survival and therapy resistance. Finally, we indicate each study’s stance: some frame cancer-induced EndMT as a source of CAFs, whereas others, from an endothelial perspective, emphasize barrier weakening and promotion of metastasis. Full article

Hypopharyngeal carcinoma (HPC) represents the most prognostically unfavorable subtype among head and neck malignancies. Platinum-based neoadjuvant chemotherapy serves as a critical therapeutic approach for improving outcomes in hypopharyngeal carcinoma; however, its efficacy remains suboptimal due to the high incidence of chemoresistance. Current research on chemoresistance has primarily focused on head and neck squamous cell carcinoma (HNSCC), yet significant heterogeneity exists between hypopharyngeal carcinoma and other head and neck tumors, limiting the direct applicability of broader HNSCC research findings to hypopharyngeal carcinoma. This review systematically summarizes recent advances in understanding the mechanisms underlying chemoresistance in hypopharyngeal carcinoma, with emphasis on the comprehensive elucidation of key mechanisms, including apoptosis evasion, enhanced DNA damage repair, augmented autophagy, and increased drug efflux. Moreover, three noteworthy special scenarios involving cancer stem cells (CSCs), epithelial–mesenchymal transition (EMT), and cancer-associated fibroblasts (CAFs) are discussed. These entities not only intrinsically participate in multiple chemoresistance mechanisms but also interact synergistically, thereby further exacerbating chemoresistance in hypopharyngeal carcinoma. Full article

The tumor microenvironment (TME) comprises neoplastic and stromal cells, and extracellular matrix elements, all engaging in a complex interplay that ultimately dictates tumorigenesis, cancer progression, and therapeutic response. While extensive research on the TME has been conducted in human oncology, data on its veterinary counterpart, particularly in feline mammary tumors (FMTs), are still scarce. In this review, we explore current understanding of feline mammary carcinoma (FMC) microenvironment, focusing on tumor necrosis, fibrosis, angiogenesis, adipose tissue tumor-associated inflammation, extracellular vesicles, and epithelial–mesenchymal transition (EMT) and their prognostic implications. In FMC, remodeling of collagen fibers, cancer-associated fibroblasts (CAFs), regulatory T cells (Tregs) and elevated serum leptin have been associated with poor prognosis, whereas stromal cytotoxic T cells correlate with more favorable outcomes. By contrast, findings on necrosis and pro-angiogenic factors remain inconsistent, and research on extracellular vesicles (EVs) is still in its early stages. This review presents insights from human breast cancer (HBC) that further support and elucidate the potential relevance of these TME components. As FMCs are highly aggressive tumors, a deeper understanding of their microenvironment could not only improve prognostic accuracy but also uncover novel therapeutic targets. Furthermore, due to their similarities, FMCs offer a potential valuable spontaneous model for HBC, particularly for the aggressive triple-negative phenotypes. Full article

Cancer-associated fibroblasts (CAFs) are a key constituent of the tumor microenvironment. CAFs may affect the development of tumor cells. The critical role of CAFs in the tumor microenvironment is linked to their epigenetic modifications, as a stable yet reversible regulation of cellular phenotypes. Current evidence indicates that their formation and function are closely linked to epigenetic mechanisms. Existing research indicates that the epigenetic alteration abnormalities are triggered by metabolic cues and stabilize the acquired phenotype of CAFs. This process is associated with transcriptional changes and patient outcomes in various tumors, providing a biological rationale and translational potential for reprogramming CAFs. Understanding of epigenetic modifications in CAFs remain insufficient, while DNA methylation in CAFs can alter CAF states through multiple pathways and thereby influence tumor progression. It is necessary to investigate the unique, identifiable epigenetic signatures of CAF. As an epigenetic reader couple histone acetylation to high-output oncogenic transcription; meanwhile, noncoding RNAs modulate CAF formation and therapeutic responses via bidirectional crosstalk between tumor cells and stroma. The interactions between different epigenetic modifications and their underlying regulatory logic may play a crucial role in developing new therapeutic strategies. This review focuses on the roles of DNA methylation, histone acetylation, and enhancer reprogramming in CAFs. Full article

Head and neck cancer (HNC) is highly heterogeneous and difficult to treat, underscoring the need for rapid, patient-specific models. Standard three-dimensional (3D) cultures often lose stromal partners that influence therapy response. We developed a patient-derived system maintaining tumor cells, cancer-associated fibroblasts (CAFs), and cells undergoing partial epithelial–mesenchymal transition (pEMT) for drug sensitivity testing. Biopsies from four HNC patients were enzymatically dissociated. CAFs were directly cultured, and their conditioned medium (CAF-CM) was collected. Cryopreserved primary tumor cell suspensions were later revived, screened in five different growth media under 2D conditions, and the most heterogeneous cultures were re-embedded in 3D hydrogels with varied gel mixtures, media, and seeding geometries. Tumoroid morphology was quantified using a perimeter-based complexity index. Viability after treatment with cisplatin or Notch modulators (RIN-1, recombination signal-binding protein for immunoglobulin κ J region (RBPJ) inhibitor; FLI-06, inhibitor) was assessed by live imaging and the water-soluble tetrazolium-8 (WST-8) assay. Endothelial Cell Growth Medium 2 (ECM-2) medium alone produced compact CAF-free spheroids, whereas ECM-2 supplemented with CAF-CM generated invasive aggregates that deposited endogenous matrix. Matrigel with this medium and single-point seeding gave the highest complexity scores. Two of the three patient tumoroids were cisplatin-sensitive, and all showed significant growth inhibition with the FLI-06 Notch inhibitor, while the RBPJ inhibitor RIN-1 induced minimal change. The optimized scaffold retains tumor–stroma crosstalk and provides patient-specific drug response data within days after operation, supporting personalized treatment selection in HNC. Full article

Tamibarotene (Am80) is a promising anti-tumor drug that induces the expression of Meflin (a glycosylphosphatidyl inositol-anchored protein) in cancer-associated fibroblasts, thereby improving the tumor microenvironment. However, Am80, which is approved only for oral administration owing to its poor water solubility, has the challenge of poor tumor penetration. In this study, we developed poly(lactic-co-glycolic acid) nanoparticles loaded with Am80 (Am80–PLGA nanoparticles) as a potential intravenous drug for targeted Am80 delivery to the tumor site. The Am80–PLGA nanoparticles were fabricated using the single-emulsion method in the presence of cationic polyethyleneimine (PEI). The loading efficiency of Am80 in the nanoparticles was controlled by tuning the PEI concentration in the preparation mixture. Nanoparticles with the highest Am80-loading efficiency were dispersible and showed a hydrodynamic diameter of approximately 190 nm in phosphate-buffered saline for up to 2 weeks. The Am80 release from the nanoparticles started in a day and lasted for weeks. The nanoparticles upregulated Meflin expression in human fibroblasts (fHDF/TERT166 cells). These results suggest the potential of Am80–PLGA nanoparticles as a new intravenous anti-tumor drug that can improve the tumor microenvironment, thereby enhancing the efficacy of chemotherapy and immunotherapy. Full article

Background: The aim of this bibliometric study was to evaluate publication trends in the most frequently cited clinical trials on the treatment of gingival recession, taking into account the augmentation materials used. Methods: A Web of Science search was performed among articles published by 30 September 2024. Two independent reviewers evaluated year of publication, journal, authorship country of authors, collaborative relationship, keywords, and the main domains. Results: The top one hundred most-cited clinical trials were published in the span of 26 years from 1993 to 2019, and the total citation counts varied from 44 to 284 (83.69 citations per paper). There was correlation between the time of publication and the number of citations. The articles were authored by 333 researchers representing twenty-two countries. Italy contributed the highest number of articles (n = 36), followed by the USA (n = 28) and Brazil (n = 17). International collaborations were predominantly observed between Italy, the USA, and Switzerland. The type of graft was the most cited field of research (34), followed by guided tissue regeneration (17) and enamel matrix derivative (13). Conclusions: The country that produced the highest number publications among the 100 most-cited clinical trials on gingival recession treatment was Italy. The use of connective tissue graft (CTG) and coronally advanced flap (CAF) was the most prominent trend. Future work should combine bibliometric mapping with critical quality appraisal and explore whether citation trends align with best available evidence. Full article