RESUMO
BACKGROUND: Novel noninvasive predictors of disease severity and prognosis in primary sclerosing cholangitis (PSC) are needed. This study evaluated the ability of extracellular matrix remodeling markers to diagnose fibrosis stage and predict PSC-related fibrosis progression and clinical events. METHODS: Liver histology and serum markers of collagen formation (propeptide of type III collagen [Pro-C3], propeptide of type IV collagen, propeptide of type V collagen), collagen degradation (type III collagen matrix metalloproteinase degradation product and type IV collagen matrix metalloproteinase degradation product), and fibrosis (enhanced liver fibrosis [ELF] score and its components [metalloproteinase-1, type III procollagen, hyaluronic acid]) were assessed in samples from baseline to week 96 in patients with PSC enrolled in a study evaluating simtuzumab (NCT01672853). Diagnostic performance for advanced fibrosis (Ishak stages 3-6) and cirrhosis (Ishak stages 5-6) was evaluated by logistic regression and AUROC. Prognostic performance for PSC-related clinical events and fibrosis progression was assessed by AUROC and Wilcoxon rank-sum test. RESULTS: Among 234 patients, 51% had advanced fibrosis and 11% had cirrhosis at baseline. Baseline Pro-C3 and ELF score and its components provided moderate diagnostic ability for discrimination of advanced fibrosis (AUROC 0.73-0.78) and cirrhosis (AUROC 0.73-0.81). Baseline Pro-C3, ELF score, and type III procollagen provided a moderate prognosis for PSC-related clinical events (AUROC 0.70-0.71). Among patients without cirrhosis at baseline, median changes in Pro-C3 and ELF score to week 96 were higher in those with than without progression to cirrhosis (both p < 0.001). CONCLUSIONS: Pro-C3 correlated with fibrosis stage, and Pro-C3 and ELF score provided discrimination of advanced fibrosis and cirrhosis and predicted PSC-related events and fibrosis progression. The results support the clinical utility of Pro-C3 and ELF score for staging and as prognostic markers in PSC.
Assuntos
Anticorpos Monoclonais Humanizados , Biomarcadores , Colangite Esclerosante , Progressão da Doença , Matriz Extracelular , Cirrose Hepática , Humanos , Colangite Esclerosante/tratamento farmacológico , Colangite Esclerosante/sangue , Colangite Esclerosante/patologia , Masculino , Feminino , Biomarcadores/sangue , Prognóstico , Adulto , Cirrose Hepática/sangue , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/etiologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Pessoa de Meia-Idade , Matriz Extracelular/patologia , Índice de Gravidade de Doença , Ácido Hialurônico/sangue , Fígado/patologiaRESUMO
Invadosome is an umbrella term used to describe a family of cellular structures including podosomes and invadopodia. They serve as contact zones between the cell plasma membrane and extracellular matrix, contributing to matrix remodeling by locally enriched proteolytic enzymes. Invadosomes, which are actin-dependent, are implicated in cellular processes promoting adhesion, migration, and invasion. Invadosomes, which exist in various cell types, play crucial roles in physiological phenomena such as vascularization and bone resorption. Invadosomes are also implicated in pathological processes such as matrix tissue remodeling during metastatic tumor cell invasion. This review summarizes basic information and recent advances about mechanisms underlying podosome and invadopodia formation, their organization and function.
Title: Invadosomes - Entre mobilité et invasion, naviguer dans la dualité des fonctions cellulaires. Abstract: Le terme « invadosome ¼ désigne une famille de structures cellulaires, comprenant les podosomes et les invadopodes, qui constituent des zones de contact entre la membrane plasmique des cellules et la matrice extracellulaire. Ces structures contribuent au remodelage de la matrice grâce à un enrichissement local en enzymes protéolytiques qui dégradent ses constituants fibrillaires. Les invadosomes, présents dans des types cellulaires variés, contribuent à des processus physiologiques, tels que la vascularisation, ou pathologiques, comme l'invasion des tissus par les cellules métastatiques.
Assuntos
Movimento Celular , Matriz Extracelular , Invasividade Neoplásica , Neoplasias , Podossomos , Humanos , Podossomos/fisiologia , Podossomos/patologia , Movimento Celular/fisiologia , Animais , Neoplasias/patologia , Matriz Extracelular/fisiologia , Matriz Extracelular/patologiaRESUMO
BACKGROUND: Extracellular matrix (ECM) remodeling in skeletal muscle is a significant factor in the development of sarcopenia. This study aims to evaluate changes in ECM remodeling in the lumbar paravertebral muscles of sarcopenic rats using diffusion-tensor magnetic resonance imaging (DT-MRI) and compare them with histology. METHODS: Twenty 6-month-old female Sprague Dawley rats were randomly divided into the dexamethasone (DEX) group and the control (CON) group. Both groups underwent 3.0T MRI scanning, including Mensa, T2WI, and DT-MRI sequences. The changes in muscle fibers and extracellular matrix (ECM) of the erector spinal muscle were observed using hematoxylineosin and sirius red staining. The expressions of collagen I, III, and fibronectin in the erector spinae were detected by western blot. Pearson correlation analysis was employed to assess the correlation between MRI quantitative parameters and corresponding histopathology markers. RESULTS: The cross-sectional area and fractional anisotropy values of the erector spinae in the DEX group rats were significantly lower than those in the CON group (p < 0.05). Hematoxylin eosin staining revealed muscle fiber atrophy and disordered arrangement in the DEX group, while sirius red staining showed a significant increase in collagen volume fraction in the DEX group. The western blot results indicate a significant increase in the expression of collagen I, collagen III, and fibronectin in the DEX group (p < 0.001 for all). Correlation coefficients between fractional anisotropy values and collagen volume fraction, collagen I, collagen III, and fibronectin were - 0.71, -0.94, -0.85, and - 0.88, respectively (p < 0.05 for all). CONCLUSIONS: The fractional anisotropy value is strongly correlated with the pathological collagen volume fraction, collagen I, collagen III, and fibronectin. This indicates that DT-MRI can non-invasively evaluate the changes in extracellular matrix remodeling in the erector spinal muscle of sarcopenia. It provides a potential imaging biomarker for the diagnosis of sarcopenia.
Assuntos
Matriz Extracelular , Ratos Sprague-Dawley , Sarcopenia , Animais , Feminino , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Ratos , Sarcopenia/diagnóstico por imagem , Sarcopenia/metabolismo , Sarcopenia/patologia , Imagem de Tensor de Difusão/métodos , Músculos Paraespinais/diagnóstico por imagem , Músculos Paraespinais/patologia , Músculos Paraespinais/metabolismo , Fibronectinas/metabolismo , Modelos Animais de Doenças , DexametasonaRESUMO
BACKGROUND: Extracellular matrix (ECM) stiffness is closely related to the progress of diabetic cardiomyopathy (DCM) and the response of treatment of DCM to anti-diabetic drugs. Dapagliflozin (Dapa) has been proven to have cardio-protective efficacy for diabetes and listed as the first-line drug to treat heart failure. But the regulatory relationship between ECM stiffness and treatment efficacy of Dapa remains elusive. MATERIALS AND METHODS: This work investigated the effect of ECM stiffness on DCM progression and Dapa efficacy using both in vivo DCM rat model and in vitro myocardial cell model with high glucose injury. First, through DCM rat models with various levels of myocardial injury and administration with Dapa treatment for four weeks, the levels of myocardial injury, myocardial oxidative stress, expressions of AT1R (a mechanical signal protein) and the stiffness of myocardial tissues were obtained. Then for mimicking the stiffness of myocardial tissues at early and late stages of DCM, we constructed cell models through culturing H9c2 myocardial cells on the polyacrylamide gels with two stiffness and exposed to a high glucose level and without/with Dapa intervention. The cell viability, reactive oxygen species (ROS) levels and expressions of mechanical signal sensitive proteins were obtained. RESULTS: The DCM progression is accompanied by the increased myocardial tissue stiffness, which can synergistically exacerbate myocardial cell injury with high glucose. Dapa can improve the ECM stiffness-induced DCM progression and its efficacy on DCM is more pronounced on the soft ECM, which is related to the regulation pathway of AT1R-FAK-NOX2. Besides, Dapa can inhibit the expression of the ECM-induced integrin ß1, but without significant impact on piezo 1. CONCLUSIONS: Our study found the regulation and effect of biomechanics in the DCM progression and on the Dapa efficacy on DCM, providing the new insights for the DCM treatment. Additionally, our work showed the better clinical prognosis of DCM under early Dapa intervention.
Assuntos
Compostos Benzidrílicos , Cardiomiopatias Diabéticas , Matriz Extracelular , Glucosídeos , Miócitos Cardíacos , Estresse Oxidativo , Ratos Sprague-Dawley , Inibidores do Transportador 2 de Sódio-Glicose , Animais , Cardiomiopatias Diabéticas/fisiopatologia , Cardiomiopatias Diabéticas/metabolismo , Cardiomiopatias Diabéticas/tratamento farmacológico , Cardiomiopatias Diabéticas/etiologia , Cardiomiopatias Diabéticas/patologia , Glucosídeos/farmacologia , Matriz Extracelular/metabolismo , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/patologia , Compostos Benzidrílicos/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Miócitos Cardíacos/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Masculino , Estresse Oxidativo/efeitos dos fármacos , Linhagem Celular , Modelos Animais de Doenças , Espécies Reativas de Oxigênio/metabolismo , Ratos , Quinase 1 de Adesão Focal/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/complicaçõesRESUMO
Background: The standard of care for stage 1 NSCLC is upfront surgery followed by surveillance. However, 20-30% of stage 1 NSCLC recur. There is an unmet need to identify individuals likely to recur who would benefit from frequent monitoring and aggressive cancer treatments. Collagen 1 (Col1) fibers detected by second harmonic generation (SHG) microscopy are a major structural component of the extracellular matrix (ECM) of tumors that play a role in cancer progression. Method: We characterized Col1 fibers with SHG microscopy imaging of surgically resected stage 1 NSCLC. Gene expression from RNA sequencing data was used to validate the SHG microscopy findings. Results: We identified a significant (p ≤ 0.05) increase in the Col1 fiber volume in stage 1 NSCLC that recurred. The increase in Col1 fiber volume was supported by significant increases in the gene expression of Col1 in invasive, compared to noninvasive, lung adenocarcinoma. Significant differences were identified in the gene expression of other ECM proteins, as well as CAFs, immune checkpoint markers, immune cytokines, and T-cell markers. Conclusion: Col1 fiber analysis can provide a companion diagnostic test to evaluate the likelihood of tumor recurrence following stage 1 NSCLC. The studies expand our understanding of the role of the ECM in NSCLC recurrence.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Colágeno Tipo I , Neoplasias Pulmonares , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Humanos , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/diagnóstico por imagem , Recidiva Local de Neoplasia/patologia , Colágeno Tipo I/metabolismo , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Matriz Extracelular/metabolismo , Matriz Extracelular/patologiaRESUMO
Recent research has identified that miR-539-3p impedes chondrogenic differentiation, yet its specific role and underlying mechanisms in childhood-onset osteoarthritis (OA) remain unclear. This study found that miR-539-3p levels were considerably lower in cartilage samples derived from childhood-onset OA patients compared to the control group. Enhancing miR-539-3p expression or suppressing RUNX2 expression notably reduced apoptosis, inflammation, and extracellular matrix (ECM) degradation in OA chondrocytes. In contrast, reducing miR-539-3p or increasing RUNX2 had the opposite effects. RUNX2 was confirmed as a direct target of miR-539-3p. Further experiments demonstrated that miR-539-3p targeting RUNX2 effectively lessened apoptosis, inflammation, and ECM degradation in OA chondrocytes, accompanied by changes in key molecular markers like reduced caspase-3 and matrix etallopeptidase 13 (MMP-13) levels, and increased B-cell lymphoma 2 (Bcl-2) and collagen type X alpha 1 chain (COL2A1). This study underscores the pivotal role of miR-539-3p in alleviating inflammation and ECM degradation in childhood-onset OA through targeting RUNX2, offering new insights for potential therapeutic strategies against this disease.
Assuntos
Apoptose , Condrócitos , Subunidade alfa 1 de Fator de Ligação ao Core , Matriz Extracelular , MicroRNAs , Osteoartrite , Humanos , MicroRNAs/metabolismo , MicroRNAs/genética , Condrócitos/metabolismo , Condrócitos/patologia , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Osteoartrite/metabolismo , Osteoartrite/patologia , Osteoartrite/genética , Criança , Masculino , Feminino , Células Cultivadas , AdolescenteRESUMO
BACKGROUND: Although various anti-inflammatory medicines are widely recommended for osteoarthritis (OA) treatment, no significantly clinical effect has been observed. This study aims to examine the effects of vitamin B6, a component that has been reported to be capable of alleviating inflammation and cell death in various diseases, on cartilage degeneration in OA. METHODS: Collagen-induced arthritis (CIA) mice model were established and the severity of OA in cartilage was determined using the Osteoarthritis Research Society International (OARSI) scoring system. The mRNA and protein levels of indicators associated with extracellular matrix (ECM) metabolism, apoptosis and inflammation were detected. The effect of vitamin B6 (VB6) on the mice were assessed using HE staining and masson staining. The apoptosis rate of cells was assessed using TdT-mediated dUTP nick end labeling. RESULTS: Our results showed a trend of improved OARSI score in mice treated with VB6, which remarkably inhibited the hyaline cartilage thickness, chondrocyte disordering, and knees hypertrophy. Moreover, the VB6 supplementation reduced the protein expression of pro-apoptosis indicators, including Bax and cleaved caspase-3 and raised the expression level of anti-apoptosis marker Bcl-2. Importantly, VB6 improved ECM metabolism in both in vivo and in vitro experiments. CONCLUSIONS: This study demonstrated that VB6 alleviates OA through regulating ECM metabolism, inflammation and apoptosis in chondrocytes and CIA mice. The findings in this study provide a theoretical basis for targeted therapy of OA, and further lay the theoretical foundation for studies of mechanisms of VB6 in treating OA.
Assuntos
Apoptose , Artrite Experimental , Condrócitos , Inflamação , Osteoartrite , Vitamina B 6 , Animais , Apoptose/efeitos dos fármacos , Camundongos , Vitamina B 6/farmacologia , Vitamina B 6/uso terapêutico , Osteoartrite/tratamento farmacológico , Osteoartrite/patologia , Osteoartrite/metabolismo , Artrite Experimental/tratamento farmacológico , Artrite Experimental/patologia , Artrite Experimental/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Masculino , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Condrócitos/patologia , Camundongos Endogâmicos DBA , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Matriz Extracelular/metabolismo , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/patologia , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/patologia , Cartilagem Articular/metabolismoRESUMO
Ductal carcinoma in situ (DCIS) is a heterogeneous breast disease that remains challenging to treat due to its unpredictable progression to invasive breast cancer (IBC). Contemporary literature has become increasingly focused on extracellular matrix (ECM) alterations with breast cancer progression. However, the spatial regulation of the ECM proteome in DCIS has yet to be investigated in relation to IBC. We hypothesized that DCIS and IBC present distinct ECM proteomes that could discriminate between these pathologies. Tissue sections of pure DCIS, mixed DCIS-IBC, or pure IBC (n = 22) with detailed pathological annotations were investigated by multiplexed spatial proteomics. Across tissues, 1,005 ECM peptides were detected in pathologically annotated regions and their surrounding extracellular microenvironments. A comparison of DCIS to IBC pathologies demonstrated 43 significantly altered ECM peptides. Notably, eight fibrillar collagen peptides could distinguish with high specificity and sensitivity between DCIS and IBC. Lesion-targeted proteomic imaging revealed heterogeneity of the ECM proteome surrounding individual DCIS lesions. Multiplexed spatial proteomics reported an invasive cancer field effect, in which DCIS lesions in closer proximity to IBC shared a more similar ECM profile to IBC than distal counterparts. Defining the ECM proteomic microenvironment provides novel molecular insights relating to DCIS and IBC.
Assuntos
Neoplasias da Mama , Carcinoma Intraductal não Infiltrante , Matriz Extracelular , Proteômica , Microambiente Tumoral , Humanos , Feminino , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinoma Intraductal não Infiltrante/metabolismo , Carcinoma Intraductal não Infiltrante/patologia , Proteômica/métodos , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Proteoma/metabolismo , Proteoma/análise , Invasividade Neoplásica , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Pessoa de Meia-IdadeAssuntos
Carcinoma Basocelular , Matriz Extracelular , Neoplasias Cutâneas , Insuficiência Venosa , Humanos , Insuficiência Venosa/fisiopatologia , Insuficiência Venosa/patologia , Insuficiência Venosa/complicações , Neoplasias Cutâneas/patologia , Matriz Extracelular/patologia , Matriz Extracelular/metabolismo , Carcinoma Basocelular/patologia , Masculino , Feminino , Perna (Membro)/irrigação sanguínea , Doença Crônica , Idoso , Pessoa de Meia-IdadeRESUMO
We previously reported that extracellular matrix protein 1 isoform a (ECM1a) promotes epithelial ovarian cancer (EOC) through autocrine signaling by binding to cell surface receptors αXß2. However, the role of ECM1a as a secretory molecule in the tumor microenvironment is rarely reported. In this study, we constructed murine Ecm1-knockout mice and human ECM1a-knockin mice and further generated orthotopic or peritoneal xenograft tumor models to mimic the different metastatic stages of EOC. We show that ECM1a induces oncogenic metastasis of orthotopic xenograft tumors, but inhibits early-metastasis of peritoneal xenograft tumors. ECM1a remodels extracellular matrices (ECM) and promotes remote metastases by recruiting and transforming bone marrow mesenchymal stem cells (BMSCs) into platelet-derived growth factor receptor beta (PDGFRß+) cancer-associated fibroblasts (CAFs) and facilitating the secretion of angiopoietin-like protein 2 (ANGPTL2). Competing with ECM1a, ANGPTL2 also binds to integrin αX through the P1/P2 peptides, resulting in negative effects on BMSC differentiation. Collectively, this study reveals the dual functions of ECM1a in remodeling of TME during tumor progression, emphasizing the complexity of EOC phenotypic heterogeneity and metastasis.
Assuntos
Proteína 2 Semelhante a Angiopoietina , Fibroblastos Associados a Câncer , Proteínas da Matriz Extracelular , Camundongos Knockout , Neoplasias Ovarianas , Microambiente Tumoral , Animais , Feminino , Humanos , Camundongos , Proteínas Semelhantes a Angiopoietina/metabolismo , Proteínas Semelhantes a Angiopoietina/genética , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Carcinoma Epitelial do Ovário/patologia , Carcinoma Epitelial do Ovário/metabolismo , Carcinoma Epitelial do Ovário/genética , Linhagem Celular Tumoral , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Proteínas da Matriz Extracelular/metabolismo , Proteínas da Matriz Extracelular/genética , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/patologia , Metástase Neoplásica , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismoRESUMO
BACKGROUND: Glioblastoma (GBM) is a high-grade and heterogeneous subtype of glioma that presents a substantial challenge to human health, characterized by a poor prognosis and low survival rates. Despite its known involvement in regulating leukemia and melanoma, the function and mechanism of DNAJC1 in GBM remain poorly understood. METHODS: Utilizing data from the TCGA, CGGA, and GEO databases, we investigated the expression pattern of DNAJC1 and its correlation with clinical characteristics in GBM specimens. Loss-of-function experiments were conducted to explore the impact of DNAJC1 on GBM cell lines, with co-culture experiments assessing macrophage infiltration and functional marker expression. RESULTS: Our analysis demonstrated frequent overexpression of DNAJC1 in GBM, significantly associated with various clinical characteristics including WHO grade, IDH status, chromosome 1p/19q codeletion, and histological type. Moreover, KaplanâMeier and ROC analyses revealed DNAJC1 as a negative prognostic predictor and a promising diagnostic biomarker for GBM patients. Functional studies indicated that silencing DNAJC1 impeded cell proliferation and migration, induced cell cycle arrest, and enhanced apoptosis. Mechanistically, DNAJC1 was implicated in stimulating extracellular matrix reorganization, triggering the epithelial-mesenchymal transition (EMT) process, and initiating immunosuppressive macrophage infiltration. CONCLUSIONS: Our findings underscore the pivotal role of DNAJC1 in GBM pathogenesis, suggesting its potential as a diagnostic and therapeutic target for this challenging disease.
Assuntos
Neoplasias Encefálicas , Progressão da Doença , Matriz Extracelular , Glioblastoma , Macrófagos , Animais , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/imunologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Transição Epitelial-Mesenquimal/genética , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Regulação Neoplásica da Expressão Gênica , Glioblastoma/patologia , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/imunologia , Proteínas de Choque Térmico HSP40/genética , Proteínas de Choque Térmico HSP40/metabolismo , Macrófagos/metabolismo , Macrófagos/patologia , Macrófagos/imunologia , PrognósticoRESUMO
Background: The desmoplastic reaction is considered a promising prognostic parameter for colorectal cancer. However, intermediate desmoplastic reaction is characterized by sizeable stromal heterogeneity, including both small amounts of keloid-like collagen (KC) in the fibrotic stroma and thick tufts of KC circumferentially surrounding cancer nests and occupying most of the fields of view. The present study aimed to evaluate the diagnostic and prognostic significance of KC histophenotyping with a quantitative visual assessment of its presence in the stroma of the invasive margin of TNM (The "tumor-node-metastasis" classification) stage II/III colorectal cancer (CRC). Methods and results: 175 resected tumors from patients with TNM stage II/III CRC were examined. Keloid-like collagen was assessed according to Ueno H. criteria. KC was assessed at the primary tumor invasive margin using Hematoxylin & Eosin and Masson's trichrome staining. The cut-off point for KC was examined using "the best cutoff approach by log-rank test." Using a cutoff point of 30%, we histologically divided fibrous stroma in the invasive area into two groups: "type A"-KC ≤ 0.3 and "type B"-KC>0.3. Type A stroma was observed in 48% of patients, type B-in 52%. The association between collagen amount and 5-year recurrence-free survival (5-RFS) was assessed using Cox regression analysis. Kaplan-Meier analysis and log-rank tests were used to assess the significance of survival analysis. Analysis of categorical variables showed that increased KC in CRC stroma predicted adverse outcomes for 5-RFS (hazard ratio [HR] = 3.143, 95%, confidence interval [CI] = 1.643-6.012, p = 0.001). Moreover, in Kaplan-Meier analysis, the log-rank test showed that type B exhibited worse 5-RFS than type A (p = 0.000). Conclusion: KC is an independent predictor of 5-year overall and RFS in patients with TNM stage II/III CRC treated with surgery, with worse survival rates when the amount of KC increases by >30%.
Assuntos
Colágeno , Neoplasias Colorretais , Matriz Extracelular , Queloide , Humanos , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Masculino , Feminino , Prognóstico , Pessoa de Meia-Idade , Colágeno/metabolismo , Idoso , Matriz Extracelular/patologia , Matriz Extracelular/metabolismo , Queloide/patologia , Queloide/metabolismo , Adulto , Idoso de 80 Anos ou mais , Taxa de Sobrevida , SeguimentosRESUMO
OBJECTIVE: Perineuronal nets (PNN) are specialized extracellular matrix (ECM) components of the central nervous system, frequently accumulating at the surface of inhibitory GABAergic interneurons. While an altered distribution of PNN has been observed in neurological disorders including Alzheimer's disease, schizophrenia and epilepsy, their anatomical distribution also changes during physiological brain maturation and aging. Such an age-dependent shift was experimentally associated also with hippocampal engram formation during brain maturation. Our aim was to histopathologically assess PNN in the hippocampus of adult and pediatric patients with temporal lobe epilepsy (TLE) compared to age-matched post-mortem control subjects and to compare PNN-related changes with memory impairment observed in our patient cohort. METHODS: Sixty-six formalin-fixed and paraffin-embedded tissue specimens of the human hippocampus were retrieved from the European Epilepsy Brain Bank. Twenty-nine patients had histopathologically confirmed hippocampal sclerosis (HS), and eleven patients suffered from TLE without HS. PNN were immunohistochemically visualized using an antibody directed against aggrecan and manually counted from hippocampus subfields and the subiculum. RESULTS: PNN density increased with age in both human controls and TLE patients. However, their density was significantly higher in all HS patients compared to age-matched controls. Intriguingly, TLE patients presented presurgically with better memory when their hippocampal PNN density was higher (p < 0.05). SIGNIFICANCE: Our results were compatible with age-dependent ECM specialization in the human hippocampus and its precocious aging in the epileptic condition. These observations confirm recent experimental animal models and also support the notion that PNN play a role in memory formation in the human brain. PLAIN LANGUAGE SUMMARY: "Perineuronal nets" (PNN) are a specialized compartment of the extracellular matrix (ECM), especially surrounding highly active neurons of the mammalian brain. There is evidence that PNN play a role in memory formation, brain maturation, and in some pathologies like Alzheimer's disease, schizophrenia or epilepsy. In this study, we investigated the role of PNN in patients suffering from drug-resistant focal epilepsy compared to controls. We found that with increasing age, more neurons are surrounded by PNN. Similarly, all epilepsy patients but especially patients with better memory performance also had more PNN. This study raises further interest in studying ECM molecules in the human brain under physiological and pathophysiological conditions.
Assuntos
Envelhecimento , Epilepsia do Lobo Temporal , Matriz Extracelular , Hipocampo , Humanos , Hipocampo/patologia , Masculino , Feminino , Adulto , Matriz Extracelular/patologia , Epilepsia do Lobo Temporal/patologia , Envelhecimento/patologia , Pessoa de Meia-Idade , Adulto Jovem , Criança , Adolescente , Idoso , EscleroseRESUMO
Mechanical force exerted on cancer cells by their microenvironment have been reported to drive cells toward invasive phenotypes by altering cells' motility, proliferation, and apoptosis. These mechanical forces include compressive, tensile, hydrostatic, and shear forces. The importance of forces is then hypothesized to be an alteration of cancer cells' and their microenvironment's biophysical properties as the indicator of a tumor's malignancy state. Our objective is to investigate and quantify the correlation between a tumor's malignancy state and forces experienced by the cancer cells and components of the microenvironment. In this study, we have developed a multicomponent, three-dimensional model of tumor tissue consisting of a cancer cell surrounded by fibroblasts and extracellular matrix (ECM). Our results on three different organs including breast, kidney, and pancreas show that: A) the stresses within tumor tissue are impacted by the organ specific ECM's biophysical properties, B) more invasive cancer cells experience higher stresses, C) in pancreas which has a softer ECM (Young modulus of 1.0 kPa) and stiffer cancer cells (Young modulus of 2.4 kPa and 1.7 kPa) than breast and kidney, cancer cells experienced significantly higher stresses, D) cancer cells in contact with ECM experienced higher stresses compared to cells surrounded by fibroblasts but the area of tumor stroma experiencing high stresses has a maximum length of 40 µm when the cancer cell is surrounded by fibroblasts and 12 µm for when the cancer cell is in vicinity of ECM. This study serves as an important first step in understanding of how the stresses experienced by cancer cells, fibroblasts, and ECM are associated with malignancy states of cancer cells in different organs. The quantification of forces exerted on cancer cells by different organ-specific ECM and at different stages of malignancy will help, first to develop theranostic strategies, second to predict accurately which tumors will become highly malignant, and third to establish accurate criteria controlling the progression of cancer cells malignancy. Furthermore, our in silico model of tumor tissue can yield critical, useful information for guiding ex vivo or in vitro experiments, narrowing down variables to be investigated, understanding what factors could be impacting cancer treatments or even biomarkers to be looking for.
Assuntos
Matriz Extracelular , Modelos Biológicos , Células Estromais , Humanos , Células Estromais/patologia , Matriz Extracelular/patologia , Matriz Extracelular/metabolismo , Neoplasias/patologia , Neoplasias/fisiopatologia , Microambiente Tumoral , Estresse Mecânico , FemininoRESUMO
BACKGROUND: To evaluate the presence of myofibroblasts (MFs) in the development of lip carcinogenesis, through the correlation of clinical, histomorphometric and immunohistochemical parameters, in actinic cheilitis (ACs) and lower lip squamous cell carcinomas (LLSCCs). METHODS: Samples of ACs, LLSCCs, and control group (CG) were prepared by tissue microarray (TMA) for immunohistochemical TGF-ß, α-SMA, and Ki-67 and histochemical hematoxylin and eosin, picrosirius red, and verhoeff van gieson reactions. Clinical and microscopic data were associated using the Mann-Whitney, Kruskal-Wallis/Dunn, and Spearman correlation tests (SPSS, p < 0.05). RESULTS: ACs showed higher number of α-SMA+ MFs when compared to CG (p = 0.034), and these cells were associated with the vertical expansion of solar elastosis (SE) itself (p = 0.027). Areas of SE had lower deposits of collagen (p < 0.001), immunostaining for TGF-ß (p < 0.001), and higher density of elastic fibers (p < 0.05) when compared to areas without SE. A positive correlation was observed between high-risk epithelial dysplasia (ED) and the proximity of SE to the dysplastic epithelium (p = 0.027). LLSCCs showed a higher number of α-SMA+ MFs about CG (p = 0.034), as well as a reduction in the deposition of total collagen (p = 0.009) in relation to ACs and CG. There was also a negative correlation between the amount of α-SMA+ cells and the accumulation of total collagen (p = 0.041). Collagen and elastic density loss was higher in larger tumors (p = 0.045) with nodal invasion (p = 0.047). CONCLUSIONS: Our findings show the possible role of MFs, collagen fibers, and elastosis areas in the lip carcinogenesis process.
Assuntos
Carcinoma de Células Escamosas , Queilite , Matriz Extracelular , Neoplasias Labiais , Miofibroblastos , Humanos , Queilite/patologia , Queilite/metabolismo , Neoplasias Labiais/patologia , Neoplasias Labiais/metabolismo , Miofibroblastos/patologia , Carcinoma de Células Escamosas/patologia , Masculino , Feminino , Pessoa de Meia-Idade , Matriz Extracelular/patologia , Idoso , Fator de Crescimento Transformador beta , Adulto , Actinas , Imuno-Histoquímica , Antígeno Ki-67 , Colágeno , Tecido Elástico/patologiaRESUMO
Tumor evolution is driven by genetic variation; however, it is the tumor microenvironment (TME) that provides the selective pressure contributing to evolution in cancer. Despite high histopathological heterogeneity within glioblastoma (GBM), the most aggressive brain tumor, the interactions between the genetically distinct GBM cells and the surrounding TME are not fully understood. To address this, we analyzed matched primary and recurrent GBM archival tumor tissues with imaging-based techniques aimed to simultaneously evaluate tumor tissues for the presence of hypoxic, angiogenic, and inflammatory niches, extracellular matrix (ECM) organization, TERT promoter mutational status, and several oncogenic amplifications on the same slide and location. We found that the relationships between genetic and TME diversity are different in primary and matched recurrent tumors. Interestingly, the texture of the ECM, identified by label-free reflectance imaging, was predictive of single-cell genetic traits present in the tissue. Moreover, reflectance of ECM revealed structured organization of the perivascular niche in recurrent GBM, enriched in immunosuppressive macrophages. Single-cell spatial transcriptomics further confirmed the presence of the niche-specific macrophage populations and identified interactions between endothelial cells, perivascular fibroblasts, and immunosuppressive macrophages. Our results underscore the importance of GBM tissue organization in tumor evolution and highlight genetic and spatial dependencies.
Assuntos
Neoplasias Encefálicas , Matriz Extracelular , Glioblastoma , Recidiva Local de Neoplasia , Microambiente Tumoral , Glioblastoma/genética , Glioblastoma/patologia , Glioblastoma/diagnóstico por imagem , Humanos , Microambiente Tumoral/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/diagnóstico por imagem , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Matriz Extracelular/patologia , Matriz Extracelular/metabolismo , Matriz Extracelular/genética , Análise Espacial , Masculino , Macrófagos/patologia , Feminino , Telomerase/genética , Análise de Célula Única , Mutação , Pessoa de Meia-IdadeRESUMO
A vast ensemble of extracellular proteins influences the development and progression of cancer, shaped and reshaped by a complex network of extracellular proteases. These proteases, belonging to the distinct classes of metalloproteases, serine proteases, cysteine proteases, and aspartic proteases, play a critical role in cancer. They often become dysregulated in cancer, with increases in pathological protease activity frequently driven by the loss of normal latency controls, diminished regulation by endogenous protease inhibitors, and changes in localization. Dysregulated proteases accelerate tumor progression and metastasis by degrading protein barriers within the extracellular matrix (ECM), stimulating tumor growth, reactivating dormant tumor cells, facilitating tumor cell escape from immune surveillance, and shifting stromal cells toward cancer-promoting behaviors through the precise proteolysis of specific substrates to alter their functions. These crucial substrates include ECM proteins and proteoglycans, soluble proteins secreted by tumor and stromal cells, and extracellular domains of cell surface proteins, including membrane receptors and adhesion proteins. The complexity of the extracellular protease web presents a significant challenge to untangle. Nevertheless, technological strides in proteomics, chemical biology, and the development of new probes and reagents are enabling progress and advancing our understanding of the pivotal importance of extracellular proteolysis in cancer.
Assuntos
Metástase Neoplásica , Neoplasias , Peptídeo Hidrolases , Proteólise , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Neoplasias/enzimologia , Peptídeo Hidrolases/metabolismo , Animais , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Progressão da DoençaRESUMO
AIMS: Perineuronal nets (PNNs) are an extracellular matrix structure that encases excitable neurons. PNNs play a role in neuroprotection against oxidative stress. Oxidative stress within motor neurons can trigger neuronal death, which has been implicated in amyotrophic lateral sclerosis (ALS). We investigated the spatio-temporal timeline of PNN breakdown and the contributing cellular factors in the SOD1G93A strain, a fast-onset ALS mouse model. METHODS: This was conducted at the presymptomatic (P30), onset (P70), mid-stage (P130), and end-stage disease (P150) using immunofluorescent microscopy, as this characterisation has not been conducted in the SOD1G93A strain. RESULTS: We observed a significant breakdown of PNNs around α-motor neurons in the ventral horn of onset and mid-stage disease SOD1G93A mice compared with wild-type controls. This was observed with increased numbers of microglia expressing matrix metallopeptidase-9 (MMP-9), an endopeptidase that degrades PNNs. Microglia also engulfed PNN components in the SOD1G93A mouse. Further increases in microglia and astrocyte number, MMP-9 expression, and engulfment of PNN components by glia were observed in mid-stage SOD1G93A mice. This was observed with increased expression of fractalkine, a signal for microglia engulfment, within α-motor neurons of SOD1G93A mice. Following PNN breakdown, α-motor neurons of onset and mid-stage SOD1G93A mice showed increased expression of 3-nitrotyrosine, a marker for protein oxidation, which could render them vulnerable to death. CONCLUSIONS: Our observations suggest that increased numbers of MMP-9 expressing glia and their subsequent engulfment of PNNs around α-motor neurons render these neurons sensitive to oxidative damage and eventual death in the SOD1G93A ALS model mouse.
Assuntos
Esclerose Lateral Amiotrófica , Astrócitos , Metaloproteinase 9 da Matriz , Microglia , Fagocitose , Superóxido Dismutase-1 , Animais , Camundongos , Esclerose Lateral Amiotrófica/patologia , Esclerose Lateral Amiotrófica/metabolismo , Esclerose Lateral Amiotrófica/genética , Astrócitos/metabolismo , Astrócitos/patologia , Modelos Animais de Doenças , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Metaloproteinase 9 da Matriz/metabolismo , Camundongos Transgênicos , Microglia/metabolismo , Microglia/patologia , Neurônios Motores/patologia , Neurônios Motores/metabolismo , Fagocitose/fisiologia , Superóxido Dismutase-1/genética , Superóxido Dismutase-1/metabolismoRESUMO
Breast cancer (BC) is currently the most common malignant tumour in women and one of the leading causes of their death around the world. New and increasingly personalised diagnostic and therapeutic tools have been introduced over the last few decades, along with significant advances regarding the study and knowledge related to BC. The tumour microenvironment (TME) refers to the tumour cell-associated cellular and molecular environment which can influence conditions affecting tumour development and progression. The TME is composed of immune cells, stromal cells, extracellular matrix (ECM) and signalling molecules secreted by these different cell types. Ever deeper understanding of TME composition changes during tumour development and progression will enable new and more innovative therapeutic strategies to become developed for targeting tumours during specific stages of its evolution. This review summarises the role of BC-related TME components and their influence on tumour progression and the development of resistance to therapy. In addition, an account on the modifications in BC-related TME components associated with therapy is given, and the completed or ongoing clinical trials related to this topic are presented.
Assuntos
Neoplasias da Mama , Microambiente Tumoral , Humanos , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/terapia , Neoplasias da Mama/etiologia , Feminino , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Progressão da DoençaRESUMO
The extracellular matrix surrounding the tumor undergoes changes in its organization during the metastasis process. The present study aims to quantify total collagen, collagen I (Col I) and collagen III (Col III), analyze the alignment of collagen fibers and assess the basement membrane integrity in samples from patients with metastatic and non-metastatic prostate cancer. Tissue samples from 60 patients were classified into groups based on prognostic parameters: better prognosis (n = 20), worse prognosis without metastasis (n = 23) and metastatic (n = 17). Picrosirius red with further analysis under polarizing microscope was used to quantify (with validation using immunohistochemistry) and analyze collagen alignment, and Periodic Acid Schiff staining was used to analyze the basement membrane integrity. The Col I/Col III ratio was found to be higher in the metastatic group than in the groups with better prognosis (p = 0.012) and worse prognosis without metastasis (p = 0.018). Basement membrane integrity constitution in malignant tumor tissue differed from that of adjacent non-tumor tissue (p < 0.001). Moreover, the worsening in the tumor tissue integrity was positively correlated with worse prognostic parameters. All in all, absence of Col III and basement membrane integrity might be indicators of poor prognosis in prostate cancer.