Matrix stiffness affects tumor-associated macrophage functional polarization and its potential in tumor therapy

Journal of Translational Medicine, Год журнала: 2024, Номер 22(1)

Опубликована: Янв. 21, 2024

The extracellular matrix (ECM) plays critical roles in cytoskeletal support, biomechanical transduction and biochemical signal transformation. Tumor-associated macrophage (TAM) function is regulated by stiffness solid tumors often associated with poor prognosis. ECM stiffness-induced mechanical cues can activate cell membrane mechanoreceptors corresponding mechanotransducers the cytoplasm, modulating phenotype of TAMs. Currently, tuning TAM polarization through stimulation has received increasing attention, whereas its effect on fate rarely been summarized. A better understanding relationship between will contribute to development new strategies for cancer therapy. In this review, we first introduced overall stiffness, analyzed changes mediated tumor progression, finally summarized effects targeting prognosis provide insight into field.

Язык: Английский

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Extracellular matrix stiffness regulates colorectal cancer progression via HSF4

Journal of Experimental & Clinical Cancer Research, Год журнала: 2025, Номер 44(1)

Опубликована: Янв. 30, 2025

Abstract Background Colorectal cancer (CRC) has high incidence and mortality rates, with severe prognoses during invasion metastasis stages. Despite advancements in diagnostic therapeutic technologies, the impact of tumour microenvironment, particularly extracellular matrix (ECM) stiffness, on CRC progression is not fully understood. Methods This study included 107 patients. Tumour stiffness was assessed using magnetic resonance elastography (MRE), collagen ratio analysed Masson staining. cell lines were cultured matrices varying followed by transcriptome sequencing to identify stiffness-related genes. An HSF4 knockout model different ECM evaluate effects proliferation, migration, vitro vivo. Results significantly higher than normal tissue positively correlated content TNM staging. High-stiffness regulated functions signalling pathways. High (heat shock transcriptional factor 4) expression strongly associated poor prognosis. increased stages, its inhibited invasion, especially high-stiffness matrices. In vivo experiments confirmed that promoted growth metastasis, independent protein increase. Conclusions reveals promotes proliferation regulating EMT-related pathways through HSF4. could be valuable targets for prognostic assessment intervention CRC.

Язык: Английский

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LOX-induced tubulointerstitial fibrosis via the TGF-β/LOX/Snail axis in diabetic mice

Journal of Translational Medicine, Год журнала: 2025, Номер 23(1)

Опубликована: Янв. 9, 2025

The partial epithelial-mesenchymal transition (EMT) is emerging as a significant mechanism in diabetic nephropathy (DN). LOX copper amine oxidase conventionally thought to act by crosslinking collagen. However, the role of EMT and fibrotic progression has not been investigated experimentally. bulk RNA sequencing single-nuclei (snRNA-seq) analysis were explored find nephropathy. We then possible signaling pathway LOX, both vivo vitro inhibition experiments mice HK-2 cells. Besides, we further assessed kidney fibrosis renal function. expression was elevated kidneys mice. Additionally, snRNA-seq results indicated that higher proximal tubular (PemtPT) epithelial Moreover, found increased prompted cells (RTECs) modulating transcription factor Snail vitro. Remarkably, effectively mitigated RTECs mice, thereby attenuating enhancing identified TGF-β an upstream regulator inhibiting partially reversed program induced pathway. Hyperglycemia induces via TGF-β/LOX/Snail axis, contributing fibrosis. Inhibiting can reverse RTECs, diminish fibrosis, improve

Язык: Английский

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Lysyl Oxidase (LOX): Functional Contributions to Signaling Pathways

Biomolecules, Год журнала: 2020, Номер 10(8), С. 1093 - 1093

Опубликована: Июль 22, 2020

Cu-dependent lysyl oxidase (LOX) plays a catalytic activity-related, primary role in the assembly of extracellular matrix (ECM), dynamic structural and regulatory framework which is essential for cell fate, differentiation communication during development, tissue maintenance repair. LOX, additionally, both activity-dependent independent extracellular, intracellular nuclear roles that fulfill significant functions normal tissues, contribute to vascular, cardiac, pulmonary, dermal, placenta, diaphragm, kidney pelvic floor disorders. LOX activities have also been recognized glioblastoma, diabetic neovascularization, osteogenic differentiation, bone formation, ligament remodeling, polycystic ovary syndrome, fetal membrane rupture tumor progression metastasis. In an inflammatory context, diminishing pluripotent mesenchymal pools are relevant pathology diabetes, osteoporosis rheumatoid arthritis. Most these conditions involve mechanisms with complex type-specific interactions signaling pathways, not only as target, but active player, including LOX-mediated alterations surface receptor mutual within loops. this review, we aim provide insight into diverse ways participates events, explore mechanistic details functional significance cross-regulatory EGFR, PDGF, VEGF, TGF-β, mechano-transduction, steroid pathways.

Язык: Английский

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Lysyl Oxidase‐Like 4 Fosters an Immunosuppressive Microenvironment During Hepatocarcinogenesis

Hepatology, Год журнала: 2020, Номер 73(6), С. 2326 - 2341

Опубликована: Окт. 17, 2020

Lysyl oxidase-like 4 (LOXL4) is an amine oxidase that primarily involved in extracellular matrix remodeling and highly expressed HCC tissues, but its functional role mediating liver carcinogenesis poorly understood. Therefore, we aimed to investigate the of LOXL4 hepatocarcinogenesis.Here, demonstrate hepatic expression was increased during mice concomitantly fed a choline-deficient, l-amino acid-defined diet. secreted by neoplastic cells localized within macrophages through exosome internalization. Supplementation had minimal effect on cells. In vitro exposure invoked immunosuppressive phenotype activated programmed death ligand 1 (PD-L1) expression, which further suppressed function CD8+ T Injection promoted infiltration into accelerated tumor growth, abolished adoptive T-cell transfer or PD-L1 neutralization. Label-free proteomics analysis revealed relied interferon (IFN)-mediated signal transducer activator transcription-dependent activation. Hydrogen peroxide scavenger copper chelation IFN-mediated presentation LOXL4. human tissue, CD68+ positively correlated with level. High low CD8A tissue cooperatively predict poor survival patients HCC.LOXL4 facilitates immune evasion leads hepatocarcinogenesis. Our study unveils fostering microenvironment

Язык: Английский

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Three Decades of Research on Recombinant Collagens: Reinventing the Wheel or Developing New Biomedical Products?

Bioengineering, Год журнала: 2020, Номер 7(4), С. 155 - 155

Опубликована: Дек. 2, 2020

Collagens provide the building blocks for diverse tissues and organs. Furthermore, these proteins act as signaling molecules that control cell behavior during organ development, growth, repair. Their long half-life, mechanical strength, ability to assemble into fibrils networks, biocompatibility, abundance from readily available discarded animal make collagens an attractive material in biomedicine, drug food industries, cosmetic products. About three decades ago, pioneering experiments led recombinant human collagens’ expression, thereby initiating studies on potential use of substitutes animal-derived collagens. Since then, scientists have utilized various systems produce native-like their fragments. They also tested materials repair tissues, deliver drugs, serve therapeutics. Although many tests demonstrated perform well native counterparts, collagen technology has not yet been adopted by biomedical, pharmaceutical, or industry. This paper highlights recent technologies utilize collagens, it contemplates prospects limitations.

Язык: Английский

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Lysyl Oxidase Family Enzymes and Their Role in Tumor Progression

International Journal of Molecular Sciences, Год журнала: 2022, Номер 23(11), С. 6249 - 6249

Опубликована: Июнь 2, 2022

The five genes of the lysyl oxidase family encode enzymes that covalently cross-link components extracellular matrix, such as various types collagen and elastin, and, thus, promote stabilization matrixes. Several these genes, in particular (LOX) like-2 (LOXL2) were identified are upregulated by hypoxia, tumor cells invasion metastasis. Here, we focus on description diverse molecular mechanisms which oxidases affect progression. We also describe attempts have been made, still on-going, development efficient inhibitors for treatment forms cancer, diseases associated with abnormal fibrosis.

Язык: Английский

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Treatment of liver fibrosis: Past, current, and future

World Journal of Hepatology, Год журнала: 2023, Номер 15(6), С. 755 - 774

Опубликована: Июнь 25, 2023

Liver fibrosis accompanies the progression of chronic liver diseases independent etiologies, such as hepatitis viral infection, alcohol consumption, and metabolic-associated fatty disease. It is commonly associated with injury, inflammation, cell death. characterized by abnormal accumulation extracellular matrix components that are expressed myofibroblasts collagens alpha-smooth actin proteins. Activated hepatic stellate cells contribute to major population myofibroblasts. Many treatments for have been investigated in clinical trials, including dietary supplementation (e.g., vitamin C), biological treatment simtuzumab), drug pegbelfermin natural herbs), genetic regulation non-coding RNAs), transplantation stem hematopoietic cells). However, none these has approved Food Drug Administration. The efficacy can be evaluated histological staining methods, imaging serum biomarkers, well scoring systems, fibrosis-4 index, aspartate aminotransferase platelet ratio, non-alcoholic disease score. Furthermore, reverse slowly frequently impossible advanced or cirrhosis. To avoid life-threatening stage fibrosis, anti-fibrotic treatments, especially combined behavior prevention, treatment, drugs herb medicines, needed. This review summarizes past studies current future fibrosis.

Язык: Английский

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Matrix stiffness mediates pancreatic cancer chemoresistance through induction of exosome hypersecretion in a cancer associated fibroblasts-tumor organoid biomimetic model

Matrix Biology Plus, Год журнала: 2022, Номер 14, С. 100111 - 100111

Опубликована: Май 16, 2022

In pancreatic ductal adenocarcinoma (PDAC), the abundant stromal cells which comprise tumor microenvironment constitute more than 90% of primary bulk. Moreover, this desmoplastic environment has been found to be three times stiffer normal pancreas tissue. Despite importance studying PDAC, there is still a lack models designed adequately recapitulate complex stiff microenvironment, critical hallmark disease that shown induce chemoresistance. Here, we present bio-mimetic, 3-dimensional co-culture system integrates organoids and host-matching cancer associated-fibroblasts (CAFs) recapitulates complex, fibrotic matrix PDAC using advanced biomaterials. With model, show matrix-activated CAFs are able "re-engineer" into significantly through lysyl-oxidase dependent crosslinking. culture in model leads an increase exosomes; extracellular vesicles known promote Finally, previously identified exosome inhibitors, climbazole imipramine, demonstrate how abrogation hypersecretion can reduce stiffness-induced These data highlight development new not only cellular composition tumors, but also biophysical stresses, like stiffness, exposed order identify therapies overcome feature contribute chemoresistance observed patients. We believe 3D bio-mimetic have developed will valuable tool for development, testing, optimization "mechano-medicines" target forces lead growth

Язык: Английский

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Research progress on drugs targeting the TGF-β signaling pathway in fibrotic diseases

Immunologic Research, Год журнала: 2022, Номер 70(3), С. 276 - 288

Опубликована: Фев. 11, 2022

Abstract Tissue fibrosis is a key factor leading to disability and death worldwide; however, thus far, there are no approved treatments for fibrosis. Transforming growth (TGF)-β major pro-fibrotic cytokine, which expected become target in the treatment of fibrosis; since TGF-β has wide range biological functions involving variety processes body, slight change may have systematic effect. Indiscriminate inhibition can lead adverse reactions, affect efficacy treatment. Therefore, it very important explore how both signaling pathway inhibited safe efficient small molecule inhibitors or neutralizing antibodies designed fibrotic diseases. In this review, we mainly discuss role diseases, as well development drugs recent years, potential targets diseases order guide subsequent drug development.

Язык: Английский

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