Objectives:High-grade serous ovarian cancer(HGSOC),the most common subtype of epithelial ovarian cancer(EOC),exhibits a mesenchymal phenotype characterized by fibrotic stroma and poor prognosis.Human epididymis protei...Objectives:High-grade serous ovarian cancer(HGSOC),the most common subtype of epithelial ovarian cancer(EOC),exhibits a mesenchymal phenotype characterized by fibrotic stroma and poor prognosis.Human epididymis protein 4(HE4),a key diagnostic biomarker for ovarian cancer,is involved in fibrotic processes in several non-malignant diseases.Given the clinical significance of stromal fibrosis in HGSOC and the potential link between HE4 and fibrosis,this study aimed to investigate the role of HE4 in the formation of stromal fibrosis in HGSOC.Methods:A total of 126 patients with gynecological conditions were included and divided into normal,benign,and EOC groups.Tissue stiffness was quantitatively measured and analyzed for its correlation with clinicopathological features.We further investigated the correlation between tumor stiffness and the expression levels of HE4 and fibroblast activation markers(α-smooth muscle actin(α-SMA)and fibroblast activation protein(FAP))in tumor tissues from 22 HGSOC patients.In vitro,primary fibroblasts were treated with recombinant HE4(rHE4)or conditioned media from HE4-knockdown ovarian cancer cells to assess fibroblasts activation and matrix contractility(Collagen gel contraction assays).In vivo,a subcutaneous xenograft model using HE4-knockdown cells was established to evaluate the effects of HE4 suppression on tumor growth and extensive extracellular matrix(ECM)remodeling.Results:Ovarian cancer tissues showed significantly increased stiffness compared to benign/normal groups,showing positive correlation with serum HE4 levels.High-stiffness HGSOC tumors exhibited upregulated expression of HE4,α-SMA,FAP,and collagen I.rHE4 stimulated fibroblast activation and enhanced matrix contractility,whereas HE4 knockdown in cancer cells abrogated these pro-fibrotic effects.In vivo,HE4-silenced xenografts displayed restricted tumor growth accompanied by reduced stromal expression ofα-SMA,FAP,and collagen I.Conclusion:Our findings suggest that HE4 may facilitate ECM remodeling in HGSOC through promoting fibroblast activation and increasing collagen deposition.展开更多
Fibrosis is marked by the excessive accumulation of extracellular matrix(ECM)components,leading to tissue scarring and progressive loss of organ function.Myofibroblasts,which emerge during tissue repair,are specialize...Fibrosis is marked by the excessive accumulation of extracellular matrix(ECM)components,leading to tissue scarring and progressive loss of organ function.Myofibroblasts,which emerge during tissue repair,are specialized contractile cells exhibiting features of both fibroblasts and smooth muscle cells.Their expression ofα-smooth muscle actin facilitates contractile activity,while their persistent activation and overproduction of ECM components contribute significantly to pathological wound contraction and fibrotic progression.Beyond ECM production,myofibroblasts play a significant role in the tumor microenvironment(TME)of various solid tumors.The TME is a complex network of immune cells,blood vessels,ECM components,and stromal cells like fibroblasts and myofibroblasts that surrounds and interacts with cancer cells,thereby influencing tumor growth,progression,and therapy responsiveness.Through these interactions,myofibroblasts modulate inflammation,angiogenesis,and tissue remodeling.Maintaining myofibroblast homeostasis is therefore crucial,as its disruption can drive the onset of chronic fibrotic conditions and malignancies.This review explores preclinical and clinical developments in targeting myofibroblasts in fibrotic and TME across various disease models,including hypertrophic scar,idiopathic pulmonary fibrosis,oral submucous fibrosis,cardiac fibrosis,and the desmoplastic stroma of pancreatic and breast cancers.展开更多
Rheumatoid arthritis(RA)is a systemic autoimmune disease in which synovial fibroblasts(SFs)maintain chronic inflammation by secreting proinflammatory mediators,leading to joint destruction.While the role of proinflamm...Rheumatoid arthritis(RA)is a systemic autoimmune disease in which synovial fibroblasts(SFs)maintain chronic inflammation by secreting proinflammatory mediators,leading to joint destruction.While the role of proinflammatory mediators in this process is well-established,the contribution of non-inflammatory regulators in SFs to joint pathology remains poorly understood.In this study,we investigated the non-inflammatory role of SFs in RA using a co-culture model,and found that SFs from RA patients promote apoptosis of human chondrocytes.Mechanistic investigations reveal that SFs can secrete small extracellular vesicles(sEVs),which are taken up by chondrocytes and induce chondrocyte apoptosis in both normal chondrocytes and chondrocytes from patients with RA.sEV-derived miRNA 15-29148 are identified as key signaling molecules mediating the apoptosis effects of chondrocytes.Further studies reveal that SF-derived miRNA 15-29148 targeting CIAPIN1 results in increased chondrocyte apoptosis.We further demonstrate that SF-derived miRNA 15-29148 is transferred to chondrocytes,exacerbating cartilage damage in vivo.Moreover,chondrocyte-specific aptamer-modified polyamidoamine nanoparticles not only ameliorated RA but also prevented its onset.This study suggests that,in RA,the secretion of specific sEV-miRNAs from SFs plays a crucial role in promoting chondrocyte apoptosis,potentially through non-inflammatory regulation,and that sEV-miRNA inhibition in SFs may represent an early preventive treatment strategy for cartilage degradation in RA.展开更多
Fibroblast activation protein(FAP)is overexpressed in cancer-associated fibroblasts across various cancer types.Numerous radiolabeled FAP inhibitors(FAPIs)(Fig.S1A)currently under clinical investigation have shown rem...Fibroblast activation protein(FAP)is overexpressed in cancer-associated fibroblasts across various cancer types.Numerous radiolabeled FAP inhibitors(FAPIs)(Fig.S1A)currently under clinical investigation have shown remarkable potential in cancer theranostics.展开更多
Hepatocellular carcinoma(HCC)remains a leading cause of cancer-related mortality globally,with limited therapeutic progress for advanced stages.The aberrant fibroblast growth factor 19(FGF19)-fibroblast growth factor ...Hepatocellular carcinoma(HCC)remains a leading cause of cancer-related mortality globally,with limited therapeutic progress for advanced stages.The aberrant fibroblast growth factor 19(FGF19)-fibroblast growth factor receptor 4(FGFR4)axis promotes oncogenesis and is linked to targeted-immunotherapy of HCC.Multi-kinase inhibitors(MKIs)enhance anti-tumor effects by targeting this axis and FGF19 overexpression upregulates programmed cell death ligand 1 in tumor microenvironment.Clinical studies have demonstrated the efficacy of selective FGFR4 inhibitors in HCC treatment,with enhanced anti-tumor effects when combined with MKIs or immune checkpoint inhibitors.Phase I clinical trials of Irpagratinib(ABSK-011)demonstrated an objective response rate of 43.5%,which increased to 55.6%combined with atezolizumab.FGF19 also serves as a biomarker for HCC.This review systematically summarizes the literature retri-eved from PubMed and other databases using search terms“HCC”,“fibroblast growth factor 19”,“fibroblast growth factor receptor 4”,“FGFR4 inhibitor”,“targeted therapy”,“multi-kinase inhibitor”,“immunotherapy”,“immune checkpoint inhibitor”,and“biomarker”.It also firstly synthesizes combination strategies and underlying mechanisms between FGFR4 inhibitors and targeted-immunotherapy,addressing critical gaps in existing reviews.Additionally,we discuss the potential of FGF19 as a predictive biomarker,integrating mechanistic and clinical evidence to advance precision HCC therapeutics.展开更多
Fibroblast growth factor(FGF)signaling encompasses a multitude of functions,including regulation of cell proliferation,differentiation,morphogenesis,and patterning.FGFs and their receptors(FGFR)are crucial for adult t...Fibroblast growth factor(FGF)signaling encompasses a multitude of functions,including regulation of cell proliferation,differentiation,morphogenesis,and patterning.FGFs and their receptors(FGFR)are crucial for adult tissue repair processes.Aberrant FGF signal transduction is associated with various pathological conditions such as cartilage damage,bone loss,muscle reduction,and other core pathological changes observed in orthopedic degenerative diseases like osteoarthritis(OA),intervertebral disc degeneration(IVDD),osteoporosis(OP),and sarcopenia.In OA and IVDD pathologies specifically,FGF1,FGF2,FGF8,FGF9,FGF18,FGF21,and FGF23 regulate the synthesis,catabolism,and ossification of cartilage tissue.Additionally,the dysregulation of FGFR expression(FGFR1 and FGFR3)promotes the pathological process of cartilage degradation.In OP and sarcopenia,endocrine-derived FGFs(FGF19,FGF21,and FGF23)modulate bone mineral synthesis and decomposition as well as muscle tissues.FGF2 and other FGFs also exert regulatory roles.A growing body of research has focused on understanding the implications of FGF signaling in orthopedic degeneration.Moreover,an increasing number of potential targets within the FGF signaling have been identified,such as FGF9,FGF18,and FGF23.However,it should be noted that most of these discoveries are still in the experimental stage,and further studies are needed before clinical application can be considered.Presently,this review aims to document the association between the FGF signaling pathway and the development and progression of orthopedic diseases.Besides,current therapeutic strategies targeting the FGF signaling pathway to prevent and treat orthopedic degeneration will be evaluated.展开更多
Complement C3 plays a critical role in periodontitis.However,its source,role and underlying mechanisms remain unclear.In our study,by analyzing single-cell sequencing data from mouse model of periodontitis,we identifi...Complement C3 plays a critical role in periodontitis.However,its source,role and underlying mechanisms remain unclear.In our study,by analyzing single-cell sequencing data from mouse model of periodontitis,we identified that C3 is primarily derived from periodontal fibroblasts.Subsequently,we demonstrated that C3a has a detrimental effect in ligature-induced periodontitis.C3ar−/−mice exhibited significantly less destruction of periodontal support tissues compared to wild-type mice,characterized by mild gingival tissue damage and reduced alveolar bone loss.This reduction was associated with decreased production of proinflammatory mediators and reduced osteoclast infiltration in the periodontal tissues.Mechanistic studies suggested that C3a could promote macrophage polarization and osteoclast differentiation.Finally,by analyzing single-cell sequencing data from the periodontal tissues of patients with periodontitis,we found that the results observed in mice were consistent with human data.Therefore,our findings clearly demonstrate the destructive role of fibroblast-derived C3 in ligature-induced periodontitis,driven by macrophage M1 polarization and osteoclast differentiation.These data strongly support the feasibility of C3a-targeted interventions for the treatment of human periodontitis.展开更多
Background : To study the relationships among emodin, synovial fibroblasts (FLSs), and macrophages (STMs) to provide guidance for the use of emodin in rheumatoid arthritis (RA) treatment. Methods : RA clinical samples...Background : To study the relationships among emodin, synovial fibroblasts (FLSs), and macrophages (STMs) to provide guidance for the use of emodin in rheumatoid arthritis (RA) treatment. Methods : RA clinical samples from patients with different pathological processes were collected, and the correlations between the subsets of FLSs and STMs and pathological processes were analyzed via flow cytometry. In vitro experimental methods such as enzyme linked immunosorbent assay (ELISA), Western blotting, Transwell assays, CCK- 8 assays and cell coculture were used to assess cell proliferation, migration and secretion of inflammatory factors. A collagen- induced arthritis mouse model was constructed to investigate the therapeutic potential of emodin in RA by flow cytometry, micro- CT and staining. Results : Unique subsets of FLSs and STMs, namely, FAPα ^(+)THY1 − FLSs, FAPα ^(+)THY1 ^(+)FLSs, and MerTK ^(pos) TREM2 ^(high) STMs, were identified in synovial tissues from RA patients. The number of MerTK ^(pos) TREM2 ^(high) STMs was negatively correlated with the degree of damage in RA, while the number of FAPα ^(+)THY1 − FLSs was positively correlated with damage. On the one hand, emodin promoted the aggregation of MerTKposTREM2high STMs. Moreover, MerTK pos TREM2 high STM- mediated secretion of exosomes was promoted, which can inhibit the secretion of pro- inflammatory factors by FAPα ^(+)THY1 ^(+)FLSs and promote the secretion of anti- inflammatory factors by FAPα ^(+)THY1 ^(+)FLSs, thereby inhibiting FAPα ^(+)THY1 − FLS proliferation and migration, improving the local immune microenvironment, and inhibiting RA damage. Conclusion : Emodin was shown to regulate the aggregation of STM subsets and exosome secretion, affecting the secretion, proliferation and migration of inflammatory factors in FLS subsets, and ultimately achieving good therapeutic efficacy in RA patients, suggesting that it has important clinical value.展开更多
Osteosarcoma(OS)is a prevalent primary bone malignancy with limited treatment options.Therefore,it is imperative to investigate and understand the mechanisms underlying OS pathogenesis.Cancer-associated fibroblasts(CA...Osteosarcoma(OS)is a prevalent primary bone malignancy with limited treatment options.Therefore,it is imperative to investigate and understand the mechanisms underlying OS pathogenesis.Cancer-associated fibroblasts(CAFs)are markedly abundant in tumor stromal cells and are essentially involved in the modulation of tumor occurrence and development.In recent years,CAFs have become a hotspot as researchers aim to elucidate CAF mechanisms that regulate tumor progression.However,most studies on CAFs are limited to a few common cancers,and their association with OS remains elusive.This review describes the role and current knowledge of CAFs in OS,focusing on their potential cellular origin,classification,and diverse functionality.It was found that CAFs influenced OS tumor cell signaling,proliferation,invasion,metastasis,epithelial-mesenchymal transition,stemness maintenance,angiogenesis,and the ability to modify immune system components.Furthermore,findings on other common cancers indicated that effective therapeutic strategies included the manipulation of CAF activation,targeting CAF-derived components,and depletion of CAFs by biomarkers.This review provides new insights and a theoretical basis for OS research.展开更多
The presence of endogenous neural stem/progenitor cells in the adult mammalian brain suggests that the central nervous system can be repaired and regenerated after injury.However,whether it is possible to stimulate ne...The presence of endogenous neural stem/progenitor cells in the adult mammalian brain suggests that the central nervous system can be repaired and regenerated after injury.However,whether it is possible to stimulate neurogenesis and reconstruct cortical layers II to VI in non-neurogenic regions,such as the cortex,remains unknown.In this study,we implanted a hyaluronic acid collagen gel loaded with basic fibroblast growth factor into the motor cortex immediately following traumatic injury.Our findings reveal that this gel effectively stimulated the proliferation and migration of endogenous neural stem/progenitor cells,as well as their differentiation into mature and functionally integrated neurons.Importantly,these new neurons reconstructed the architecture of cortical layers II to VI,integrated into the existing neural circuitry,and ultimately led to improved brain function.These findings offer novel insight into potential clinical treatments for traumatic cerebral cortex injuries.展开更多
Fibroblasts support a broad range of essential organ functions via microarchitectural,biomechanical,and biochemical cues.Despite great advances in fluorescence,photoacoustic conversion,and Raman scattering over the pa...Fibroblasts support a broad range of essential organ functions via microarchitectural,biomechanical,and biochemical cues.Despite great advances in fluorescence,photoacoustic conversion,and Raman scattering over the past decades,their invasiveness and limited spatial resolution hinder the characterization of fibroblasts in a single cell.Here,taking mouse embryonic fibroblasts(MEFs)as an example,we propose a novel noninvasive approach to investigate the compositional distribution of MEFs at the single-cell scale via terahertz(THz)nanos⁃copy.Compared to the topological morphology,THz nano-imaging enables the component-based visualization of MEFs,such as the membrane,cytoplasm,nucleus,and extracellular vesicles(EVs).Notably,we demonstrate the real-space observation of the influence of rapamycin treatment on the increase of EVs in MEFs.Moreover,the line-cut and area-statistical analysis establishes the relationship between the topological morphology and the THz near-field amplitudes for different cellular components of MEFs.This work provides a new pathway to char⁃acterize the effects of pharmaceutical treatments,with potential applications in disease diagnosis and drug devel⁃opment.展开更多
Pancreatic ductal adenocarcinoma stands out as an exceptionally fatal cancer owing to the complexities associated with its treatment and diagnosis,leading to a notably low five-year survival rate.This study offers a d...Pancreatic ductal adenocarcinoma stands out as an exceptionally fatal cancer owing to the complexities associated with its treatment and diagnosis,leading to a notably low five-year survival rate.This study offers a detailed exploration of epidemiological trends in pancreatic cancer and key molecular drivers,such as mutations in CDKN2A,KRAS,SMAD4,and TP53,along with the influence of cancer-associated fibroblasts(CAFs)on disease progression.In particular,we focused on the pivotal roles of signaling pathways such as the transforming growth factor-βand Wnt/β-catenin pathways in the development of pancreatic cancer and investigated their application in emerging therapeutic strategies.This study provides new scientific perspectives on pancreatic cancer treatment,especially in the development of precision medicine and targeted therapeutic strategies,and demonstrates the importance of signaling pathway research in the development of effective therapeutic regimens.Future studies should explore the subtypes of CAFs and their specific roles in the tumor microenvironment to devise more effective therapeutic methods.展开更多
BACKGROUND Cancer-associated fibroblasts(CAFs),crucial components of the tumor microenvironment in primary and metastatic tumors,can impact the activity of cancer cells and contribute to their progression.Given their ...BACKGROUND Cancer-associated fibroblasts(CAFs),crucial components of the tumor microenvironment in primary and metastatic tumors,can impact the activity of cancer cells and contribute to their progression.Given their extensive interactions with cancer cells and other stromal cells,we aimed to evaluate the prognostic value of CAFs in patients with liver cancer(LC).AIM To investigate the association between CAF expression and clinicopathological characteristics as well as overall survival(OS)in patients with LC,including hepatocellular carcinoma(HCC)and intrahepatic cholangiocarcinoma(iCCA).METHODS We performed a meta-analysis of cohort studies with available data on the effects of CAF expression on both clinicopathological characteristics and OS via hazard ratios(HRs)and risk ratios with 95%confidence intervals(CIs).Studies were subgrouped on the basis of CAF markers and cancer type,and the subgroup effects of CAF expression on both HCC and iCCA were analyzed through meta-regression.The Newcastle-Ottawa Scale was used to evaluate the included studies to guarantee their quality and minimize the possibility of bias.RESULTS Nine trials were selected and included a total of 1518 patients.According to our primary meta-analysis,the expression of CAFs in LC patients was significantly associated with a decrease in OS(LC:HR:1.62;95%CI:1.34-1.97;P<0.001;HCC:HR:1.67;95%CI:1.34-2.07;P<0.001;iCCA:HR:1.47;95%CI:0.97-2.23;P=0.07);nevertheless,it was not significantly associated with almost all clinicopathologic characteristics,including tumor size,venous infiltration,alpha-fetoprotein level,and differentiation grade.According to the subgroup analysis of smooth muscle actin(SMA)markers in both HCC patients and iCCA patients,high CAF expression in HCC(HR:2.29;95%CI:1.01-5.22;P=0.048)and iCCA(HR:2.04;95%CI:1.09-3.81;P=0.025)patients was a significant indicator of poor OS.Moreover,the clinicopathological characteristics were also verified by the SMA marker,which had a nearly significant effect on the venous infiltration of iCCA(risk ratio:2.70;95%CI:0.97-7.49;P=0.057).CONCLUSION High CAF expression,evaluated by both mixed markers and SMAs,is significantly associated with poor OS in patients with LC,including both HCC patients and iCCA patients.However,further research is necessary since how CAF expression and clinicopathologic features are related is yet unknown.展开更多
Pancreatic cancer(PC)is a highly aggressive cancer characterized by a unique tumor microenvironment(TME)that confers resistance to traditional therapies.As the dominant stromal cells in the TME,cancer-associated fibro...Pancreatic cancer(PC)is a highly aggressive cancer characterized by a unique tumor microenvironment(TME)that confers resistance to traditional therapies.As the dominant stromal cells in the TME,cancer-associated fibroblasts(CAFs)promote PC progression by modulating the extracellular matrix and interacting with surrounding cells.Numerous PC treatment strategies targeting CAFs have been explored in the past decade.However,targeting different subtypes of CAFs leads to varying therapeutic outcomes,highlighting the intricate and multifaceted nature of CAFs.The heterogeneity and dynamism of CAFs increase the complexity and challenges associated with tumor therapeutics.Currently,combination therapies incorporating CAF-targeted approaches in PC treatment have shown encouraging outcomes in select clinical trials.A comprehensive understanding of CAFs is essential for developing individualized therapeutic approaches.This review outlines the current knowledge of CAF heterogeneity,crosstalk with surrounding cells,and strategies for targeting CAFs in PC,aiming to keep researchers and clinicians up-to-date with the latest information on CAFs in PC.展开更多
Pancreatic cancer is a highly aggressive malignancy with a poor prognosis and limited therapeutic options.The tumor microenvironment(TME),including cancer-associated fibroblasts(CAFs),plays a pivotal role in tumor pro...Pancreatic cancer is a highly aggressive malignancy with a poor prognosis and limited therapeutic options.The tumor microenvironment(TME),including cancer-associated fibroblasts(CAFs),plays a pivotal role in tumor progression and therapy resistance.Senescent CAFs,which exhibit a senescence-associated secretory phenotype(SASP),further exacerbate cancer growth through inflammatory cytokine secretion.This editorial highlights a study by Jiang et al,which investigates the potential of resveratrol,a natural polyphenolic compound,in targeting senescent CAFs to inhibit pancreatic cancer progression.The study demonstrates that resveratrol reduces senescent CAFs and downregulates SASP factors,thereby disrupting the pro-tumorigenic activities of these cells.Resveratrol’s ability to modulate the TME,induce apoptosis in pancreatic cancer cells,and inhibit metastasis underscores its potential as an adjunctive therapy.This research offers promising insights into novel strategies for improving therapeutic outcomes in pancreatic cancer by targeting the TME and senescent CAFs.展开更多
Breast cancer is one of the most common malignancies worldwide and is a major cause of cancer-related mortality among women.Beyond tumor cells,the tumor microenvironment(TME)also plays an important role in cancer prog...Breast cancer is one of the most common malignancies worldwide and is a major cause of cancer-related mortality among women.Beyond tumor cells,the tumor microenvironment(TME)also plays an important role in cancer progression,therapy resistance,and metastasis.The TME is a complex ecosystem consisting of stromal and immune cells,extracellular matrix(ECM),and various signaling molecules that dynamically interact with tumor cells.Cancer-associated fibro-blasts remodel the ECM and secrete growth factors that promote tumor growth and invasion.Immune cells,such as tumor-associated macrophages,regulatory T cells,and myeloid-derived suppressor cells,often contribute to an immunosup-pressive environment that hinders anti-tumor immune responses.The ECM pro-vides structural support and acts as a reservoir for signaling molecules that in-fluence cancer cell behavior.These components evolve together with tumor cells,facilitating immune evasion,therapy resistance,and epithelial-to-mesenchymal transition,which promotes metastasis.Understanding these interactions is nece-ssary to develop novel therapeutic strategies that target both tumor and micro-environmental components.This minireview highlights the key stromal and immune elements within the breast cancer microenvironment,discussing their individual and collective roles in tumor progression and clinical outcomes,while emphasizing emerging therapeutic approaches aiming to reprogram the TME to improve treatment efficacy.展开更多
Objectives:The present study investigated whether Tripartite Motif-Containing Protein 32(TRIM32)contributes to the aberrant activation of keloid fibroblasts(KFs)via glycolysis.Methods:The expression levels of TRIM32,p...Objectives:The present study investigated whether Tripartite Motif-Containing Protein 32(TRIM32)contributes to the aberrant activation of keloid fibroblasts(KFs)via glycolysis.Methods:The expression levels of TRIM32,pyruvate dehydrogenase kinase 1(PDK1),hexokinase 2(HK2),and glucose transporter 1(GLUT1)in normal human skin fibroblasts(NFs)and KFs were analyzed using RT-qPCR analyses and western blotting.Cellular proliferation,invasion,and migration were evaluated using Transwell,wound healing,5-ethynyl-2′-deoxyuridine(EdU),and cell counting kit-8(CCK-8)assays.The extracellular acidification rate(ECAR)was measured using the XF96 Extracellular Flux Analyzer.Glucose uptake and ATP production were measured using specific assay kits.The expression ofα-smooth muscle actin(α-SMA)was determined by immunofluorescence assays.The expression levels of collagen I,α-smooth muscle actin(α-SMA),fibronectin(FN),and components of the phosphoinositide-3-kinase/protein kinase B(PI3K/AKT)signaling pathway were quantified by western blotting.Results:The expression of TRIM32 and glycolysis-related proteins was significantly elevated in KFs compared to that in NFs.TRIM32 overex-pression enhanced the proliferation,invasion,and migration of KFs,as well as extracellular matrix(ECM)deposition,glucose uptake,and ATP production,while TRIM32 silencing produced the opposite effects.The glycolysis inhibitor,2-deoxy-glucose(2-DG),significantly suppressed the biological functions of KFs;however,TRIM32 overexpression effectively counteracted the inhibitory effects of 2-DG.TRIM32 activated the PI3K/AKT signaling pathway in KFs.The PI3K inhibitor LY294002 decreased cellular glycolysis,with TRIM32 overexpression mitigated these inhibitory effects.Conclusion:This study demonstrated that TRIM32 enhances the viability of KFs by regulating glycolytic activity,potentially mediated via the PI3K/AKT signaling pathway,thereby suggesting novel therapeutic approaches for the treatment of keloids.展开更多
The onset of pregnancy is marked by the formation of a zygote,while the culmination of gestation is manifested by the delivery of a fetus.Meanwhile,a successful pregnancy entails a meticulously coordinated sequence of...The onset of pregnancy is marked by the formation of a zygote,while the culmination of gestation is manifested by the delivery of a fetus.Meanwhile,a successful pregnancy entails a meticulously coordinated sequence of events from embryo implantation to sustained decidualization of the uterus to placental development and childbirth.The decidual reaction,a pivotal process occurring within the endometrium during pregnancy,is finely regulated by sex steroids and cytokines.Notably,fibroblast growth factors(FGFs),particularly FGF2,play a critical role in this physiological cascade.Dysregulated FGF expression may trigger inadequate decidualization,precipitating a spectrum of adverse pregnancy outcomes,including preeclampsia,recurrent implantation failure,and miscarriage.Furthermore,the human decidua,distinct from most mammalian species and similar to great apes,undergoes regular cycles of formation and shedding,independent of the presence of the embryo in the endometrium.This process is also tightly controlled by various FGFs.In this review,we comprehensively compare diverse research decidualization models,delineate the trend of endometrial FGFs during the menstrual cycle,and provide a synopsis of endometrial diseases triggered by FGF dysregulation.展开更多
Perineural invasion(PNI)by tumor cells is a key phenotype of highly-invasive oral squamous cell carcinoma(OSCC).Since Schwann cells(SCs)and fibroblasts maintain the physiological homeostasis of the peripheral nervous ...Perineural invasion(PNI)by tumor cells is a key phenotype of highly-invasive oral squamous cell carcinoma(OSCC).Since Schwann cells(SCs)and fibroblasts maintain the physiological homeostasis of the peripheral nervous system,and we have focused on cancer-associated fibroblasts(CAFs)for decades,it’s imperative to elucidate the impact of CAFs on SCs in PNI+OSCCs.We describe a disease progression-driven shift of PNI−towards PNI+during the progression of early-stage OSCC(31%,n=125)to late-stage OSCC(53%,n=97),characterized by abundant CAFs and nerve demyelination.CAFs inhibited SC proliferation/migration and reduced neurotrophic factors and myelin in vitro,and this involved up-regulated ER stress and decreased MAPK signals.Moreover,CAFs also aggravated the paralysis of the hind limb and PNI in vivo.Unexpectedly,leukemia inhibitory factor(LIF)was exclusively expressed on CAFs and up-regulated in metastatic OSCC.The LIF inhibitor EC330 restored CAF-induced SC inactivation.Thus,OSCC-derived CAFs inactivate SCs to aggravate nerve injury and PNI development.展开更多
Rheumatoid arthritis(RA)is a common chronic autoimmune disease characterized by joint pain,swelling and dysfunction[1].According to epidemiologic statistics,the incidence of RA is 1%–2%,and in severe cases,it can dev...Rheumatoid arthritis(RA)is a common chronic autoimmune disease characterized by joint pain,swelling and dysfunction[1].According to epidemiologic statistics,the incidence of RA is 1%–2%,and in severe cases,it can develop into joint deformity and disability,which brings a heavy burden to the family and society[2].However,the pathogenesis of RA is complex and involves multiple cellular interactions,which increases the difficulty of curing RA.Current therapeutic options,such as disease-modifying antirheumatic drugs,non-steroidal anti-inflammatory drugs,and biologics,still face the challenge of relapse after drug discontinuation[3,4].Therefore,the pathogenesis of RA needs to be analyzed in depth to break through the existing therapeutic bottlenecks and promote the iterative innovation of individualized diagnosis and treatment.展开更多
文摘Objectives:High-grade serous ovarian cancer(HGSOC),the most common subtype of epithelial ovarian cancer(EOC),exhibits a mesenchymal phenotype characterized by fibrotic stroma and poor prognosis.Human epididymis protein 4(HE4),a key diagnostic biomarker for ovarian cancer,is involved in fibrotic processes in several non-malignant diseases.Given the clinical significance of stromal fibrosis in HGSOC and the potential link between HE4 and fibrosis,this study aimed to investigate the role of HE4 in the formation of stromal fibrosis in HGSOC.Methods:A total of 126 patients with gynecological conditions were included and divided into normal,benign,and EOC groups.Tissue stiffness was quantitatively measured and analyzed for its correlation with clinicopathological features.We further investigated the correlation between tumor stiffness and the expression levels of HE4 and fibroblast activation markers(α-smooth muscle actin(α-SMA)and fibroblast activation protein(FAP))in tumor tissues from 22 HGSOC patients.In vitro,primary fibroblasts were treated with recombinant HE4(rHE4)or conditioned media from HE4-knockdown ovarian cancer cells to assess fibroblasts activation and matrix contractility(Collagen gel contraction assays).In vivo,a subcutaneous xenograft model using HE4-knockdown cells was established to evaluate the effects of HE4 suppression on tumor growth and extensive extracellular matrix(ECM)remodeling.Results:Ovarian cancer tissues showed significantly increased stiffness compared to benign/normal groups,showing positive correlation with serum HE4 levels.High-stiffness HGSOC tumors exhibited upregulated expression of HE4,α-SMA,FAP,and collagen I.rHE4 stimulated fibroblast activation and enhanced matrix contractility,whereas HE4 knockdown in cancer cells abrogated these pro-fibrotic effects.In vivo,HE4-silenced xenografts displayed restricted tumor growth accompanied by reduced stromal expression ofα-SMA,FAP,and collagen I.Conclusion:Our findings suggest that HE4 may facilitate ECM remodeling in HGSOC through promoting fibroblast activation and increasing collagen deposition.
文摘Fibrosis is marked by the excessive accumulation of extracellular matrix(ECM)components,leading to tissue scarring and progressive loss of organ function.Myofibroblasts,which emerge during tissue repair,are specialized contractile cells exhibiting features of both fibroblasts and smooth muscle cells.Their expression ofα-smooth muscle actin facilitates contractile activity,while their persistent activation and overproduction of ECM components contribute significantly to pathological wound contraction and fibrotic progression.Beyond ECM production,myofibroblasts play a significant role in the tumor microenvironment(TME)of various solid tumors.The TME is a complex network of immune cells,blood vessels,ECM components,and stromal cells like fibroblasts and myofibroblasts that surrounds and interacts with cancer cells,thereby influencing tumor growth,progression,and therapy responsiveness.Through these interactions,myofibroblasts modulate inflammation,angiogenesis,and tissue remodeling.Maintaining myofibroblast homeostasis is therefore crucial,as its disruption can drive the onset of chronic fibrotic conditions and malignancies.This review explores preclinical and clinical developments in targeting myofibroblasts in fibrotic and TME across various disease models,including hypertrophic scar,idiopathic pulmonary fibrosis,oral submucous fibrosis,cardiac fibrosis,and the desmoplastic stroma of pancreatic and breast cancers.
基金the National Natural Science Foundation of China(82372412)the Social Development Project of Jiangsu Province(BE2022701)+4 种基金the Top Talent Support Program for Young and Middle-aged People of the Wuxi Health Committee(BJ2020044,BJ2020057,HB2020043)the Fundamental Research Funds of the Health and Family Planning Commission of Wuxi(M202024)the Special Program for Translational Medicine Research of the Wuxi Translational Medicine Center(2020DHYB07,2020DHYB03)the Key Special Project of Precision Medicine of the Wuxi Health Commission(J202101)peking union medical college hospital talent cultivation program(UHB50192).
文摘Rheumatoid arthritis(RA)is a systemic autoimmune disease in which synovial fibroblasts(SFs)maintain chronic inflammation by secreting proinflammatory mediators,leading to joint destruction.While the role of proinflammatory mediators in this process is well-established,the contribution of non-inflammatory regulators in SFs to joint pathology remains poorly understood.In this study,we investigated the non-inflammatory role of SFs in RA using a co-culture model,and found that SFs from RA patients promote apoptosis of human chondrocytes.Mechanistic investigations reveal that SFs can secrete small extracellular vesicles(sEVs),which are taken up by chondrocytes and induce chondrocyte apoptosis in both normal chondrocytes and chondrocytes from patients with RA.sEV-derived miRNA 15-29148 are identified as key signaling molecules mediating the apoptosis effects of chondrocytes.Further studies reveal that SF-derived miRNA 15-29148 targeting CIAPIN1 results in increased chondrocyte apoptosis.We further demonstrate that SF-derived miRNA 15-29148 is transferred to chondrocytes,exacerbating cartilage damage in vivo.Moreover,chondrocyte-specific aptamer-modified polyamidoamine nanoparticles not only ameliorated RA but also prevented its onset.This study suggests that,in RA,the secretion of specific sEV-miRNAs from SFs plays a crucial role in promoting chondrocyte apoptosis,potentially through non-inflammatory regulation,and that sEV-miRNA inhibition in SFs may represent an early preventive treatment strategy for cartilage degradation in RA.
基金supported by the grants provided by Zhuhai People's Hospital,China(Grant No.:2021KYQD-03)the National Natural Science Foundation of China(Grant No.:22176016).
文摘Fibroblast activation protein(FAP)is overexpressed in cancer-associated fibroblasts across various cancer types.Numerous radiolabeled FAP inhibitors(FAPIs)(Fig.S1A)currently under clinical investigation have shown remarkable potential in cancer theranostics.
基金Supported by Chen Xiao-Ping Foundation for the Development of Science and Technology of Hubei Province,No.CXPJJH124001-2406National Natural Science Foundation of China,No.U23A20483.
文摘Hepatocellular carcinoma(HCC)remains a leading cause of cancer-related mortality globally,with limited therapeutic progress for advanced stages.The aberrant fibroblast growth factor 19(FGF19)-fibroblast growth factor receptor 4(FGFR4)axis promotes oncogenesis and is linked to targeted-immunotherapy of HCC.Multi-kinase inhibitors(MKIs)enhance anti-tumor effects by targeting this axis and FGF19 overexpression upregulates programmed cell death ligand 1 in tumor microenvironment.Clinical studies have demonstrated the efficacy of selective FGFR4 inhibitors in HCC treatment,with enhanced anti-tumor effects when combined with MKIs or immune checkpoint inhibitors.Phase I clinical trials of Irpagratinib(ABSK-011)demonstrated an objective response rate of 43.5%,which increased to 55.6%combined with atezolizumab.FGF19 also serves as a biomarker for HCC.This review systematically summarizes the literature retri-eved from PubMed and other databases using search terms“HCC”,“fibroblast growth factor 19”,“fibroblast growth factor receptor 4”,“FGFR4 inhibitor”,“targeted therapy”,“multi-kinase inhibitor”,“immunotherapy”,“immune checkpoint inhibitor”,and“biomarker”.It also firstly synthesizes combination strategies and underlying mechanisms between FGFR4 inhibitors and targeted-immunotherapy,addressing critical gaps in existing reviews.Additionally,we discuss the potential of FGF19 as a predictive biomarker,integrating mechanistic and clinical evidence to advance precision HCC therapeutics.
基金supported by the National Key R&D Program of China(2023YFC3603400)the National Natural Science Foundation of China(82072506,92268115)+2 种基金the Hunan Provincial Science Fund for Distinguished Young Scholars(2024JJ2089)the Science and Technology Innovation Program of Hunan Province(2021RC3025)the National Clinical Research Center for Geriatric Disorders(Xiangya Hospital,2021KF02).
文摘Fibroblast growth factor(FGF)signaling encompasses a multitude of functions,including regulation of cell proliferation,differentiation,morphogenesis,and patterning.FGFs and their receptors(FGFR)are crucial for adult tissue repair processes.Aberrant FGF signal transduction is associated with various pathological conditions such as cartilage damage,bone loss,muscle reduction,and other core pathological changes observed in orthopedic degenerative diseases like osteoarthritis(OA),intervertebral disc degeneration(IVDD),osteoporosis(OP),and sarcopenia.In OA and IVDD pathologies specifically,FGF1,FGF2,FGF8,FGF9,FGF18,FGF21,and FGF23 regulate the synthesis,catabolism,and ossification of cartilage tissue.Additionally,the dysregulation of FGFR expression(FGFR1 and FGFR3)promotes the pathological process of cartilage degradation.In OP and sarcopenia,endocrine-derived FGFs(FGF19,FGF21,and FGF23)modulate bone mineral synthesis and decomposition as well as muscle tissues.FGF2 and other FGFs also exert regulatory roles.A growing body of research has focused on understanding the implications of FGF signaling in orthopedic degeneration.Moreover,an increasing number of potential targets within the FGF signaling have been identified,such as FGF9,FGF18,and FGF23.However,it should be noted that most of these discoveries are still in the experimental stage,and further studies are needed before clinical application can be considered.Presently,this review aims to document the association between the FGF signaling pathway and the development and progression of orthopedic diseases.Besides,current therapeutic strategies targeting the FGF signaling pathway to prevent and treat orthopedic degeneration will be evaluated.
基金supported by the National Key R&D Program of China(No.2022YFC2504200)the National Natural Science Foundation of China(Nos.82370936,81920108012,82471032).
文摘Complement C3 plays a critical role in periodontitis.However,its source,role and underlying mechanisms remain unclear.In our study,by analyzing single-cell sequencing data from mouse model of periodontitis,we identified that C3 is primarily derived from periodontal fibroblasts.Subsequently,we demonstrated that C3a has a detrimental effect in ligature-induced periodontitis.C3ar−/−mice exhibited significantly less destruction of periodontal support tissues compared to wild-type mice,characterized by mild gingival tissue damage and reduced alveolar bone loss.This reduction was associated with decreased production of proinflammatory mediators and reduced osteoclast infiltration in the periodontal tissues.Mechanistic studies suggested that C3a could promote macrophage polarization and osteoclast differentiation.Finally,by analyzing single-cell sequencing data from the periodontal tissues of patients with periodontitis,we found that the results observed in mice were consistent with human data.Therefore,our findings clearly demonstrate the destructive role of fibroblast-derived C3 in ligature-induced periodontitis,driven by macrophage M1 polarization and osteoclast differentiation.These data strongly support the feasibility of C3a-targeted interventions for the treatment of human periodontitis.
文摘Background : To study the relationships among emodin, synovial fibroblasts (FLSs), and macrophages (STMs) to provide guidance for the use of emodin in rheumatoid arthritis (RA) treatment. Methods : RA clinical samples from patients with different pathological processes were collected, and the correlations between the subsets of FLSs and STMs and pathological processes were analyzed via flow cytometry. In vitro experimental methods such as enzyme linked immunosorbent assay (ELISA), Western blotting, Transwell assays, CCK- 8 assays and cell coculture were used to assess cell proliferation, migration and secretion of inflammatory factors. A collagen- induced arthritis mouse model was constructed to investigate the therapeutic potential of emodin in RA by flow cytometry, micro- CT and staining. Results : Unique subsets of FLSs and STMs, namely, FAPα ^(+)THY1 − FLSs, FAPα ^(+)THY1 ^(+)FLSs, and MerTK ^(pos) TREM2 ^(high) STMs, were identified in synovial tissues from RA patients. The number of MerTK ^(pos) TREM2 ^(high) STMs was negatively correlated with the degree of damage in RA, while the number of FAPα ^(+)THY1 − FLSs was positively correlated with damage. On the one hand, emodin promoted the aggregation of MerTKposTREM2high STMs. Moreover, MerTK pos TREM2 high STM- mediated secretion of exosomes was promoted, which can inhibit the secretion of pro- inflammatory factors by FAPα ^(+)THY1 ^(+)FLSs and promote the secretion of anti- inflammatory factors by FAPα ^(+)THY1 ^(+)FLSs, thereby inhibiting FAPα ^(+)THY1 − FLS proliferation and migration, improving the local immune microenvironment, and inhibiting RA damage. Conclusion : Emodin was shown to regulate the aggregation of STM subsets and exosome secretion, affecting the secretion, proliferation and migration of inflammatory factors in FLS subsets, and ultimately achieving good therapeutic efficacy in RA patients, suggesting that it has important clinical value.
基金supported by the National Natural Science Foundation of China(grant number 81773285)Beijing Chao-Yang Hospital Golden Seeds Foundation(grant number CYJZ202341).
文摘Osteosarcoma(OS)is a prevalent primary bone malignancy with limited treatment options.Therefore,it is imperative to investigate and understand the mechanisms underlying OS pathogenesis.Cancer-associated fibroblasts(CAFs)are markedly abundant in tumor stromal cells and are essentially involved in the modulation of tumor occurrence and development.In recent years,CAFs have become a hotspot as researchers aim to elucidate CAF mechanisms that regulate tumor progression.However,most studies on CAFs are limited to a few common cancers,and their association with OS remains elusive.This review describes the role and current knowledge of CAFs in OS,focusing on their potential cellular origin,classification,and diverse functionality.It was found that CAFs influenced OS tumor cell signaling,proliferation,invasion,metastasis,epithelial-mesenchymal transition,stemness maintenance,angiogenesis,and the ability to modify immune system components.Furthermore,findings on other common cancers indicated that effective therapeutic strategies included the manipulation of CAF activation,targeting CAF-derived components,and depletion of CAFs by biomarkers.This review provides new insights and a theoretical basis for OS research.
基金supported by the National Natural Science Foundation of China,Nos.82272171(to ZY),82271403(to XL),81941011(to XL),31971279(to ZY),31730030(to XL)the Natural Science Foundation of Beijing,No.7222004(to HD).
文摘The presence of endogenous neural stem/progenitor cells in the adult mammalian brain suggests that the central nervous system can be repaired and regenerated after injury.However,whether it is possible to stimulate neurogenesis and reconstruct cortical layers II to VI in non-neurogenic regions,such as the cortex,remains unknown.In this study,we implanted a hyaluronic acid collagen gel loaded with basic fibroblast growth factor into the motor cortex immediately following traumatic injury.Our findings reveal that this gel effectively stimulated the proliferation and migration of endogenous neural stem/progenitor cells,as well as their differentiation into mature and functionally integrated neurons.Importantly,these new neurons reconstructed the architecture of cortical layers II to VI,integrated into the existing neural circuitry,and ultimately led to improved brain function.These findings offer novel insight into potential clinical treatments for traumatic cerebral cortex injuries.
基金Supported by the National Natural Science Foundation of China(61988102,62401113,92463308)the National Safety Academic Fund(U2130113)+2 种基金the Sichuan Science and Technology Program(2022JDJQ0065)the Chengdu Science and Technology Program(2024-YF05-01803-SN)the Sichuan Provincial Administration of Traditional Chinese Medicine(2024MS512)and the from Key Laboratory of THz Technology,Ministry of Education.
文摘Fibroblasts support a broad range of essential organ functions via microarchitectural,biomechanical,and biochemical cues.Despite great advances in fluorescence,photoacoustic conversion,and Raman scattering over the past decades,their invasiveness and limited spatial resolution hinder the characterization of fibroblasts in a single cell.Here,taking mouse embryonic fibroblasts(MEFs)as an example,we propose a novel noninvasive approach to investigate the compositional distribution of MEFs at the single-cell scale via terahertz(THz)nanos⁃copy.Compared to the topological morphology,THz nano-imaging enables the component-based visualization of MEFs,such as the membrane,cytoplasm,nucleus,and extracellular vesicles(EVs).Notably,we demonstrate the real-space observation of the influence of rapamycin treatment on the increase of EVs in MEFs.Moreover,the line-cut and area-statistical analysis establishes the relationship between the topological morphology and the THz near-field amplitudes for different cellular components of MEFs.This work provides a new pathway to char⁃acterize the effects of pharmaceutical treatments,with potential applications in disease diagnosis and drug devel⁃opment.
基金Supported by National Key Research and Development Program Project,No.2017YFC1700601Shaanxi Provincial Key Research and Development Program Project,No.2018SF-350Leading Talents in Scientific and Technological Innovation of the Shaanxi Province Special Support Plan,No.00518。
文摘Pancreatic ductal adenocarcinoma stands out as an exceptionally fatal cancer owing to the complexities associated with its treatment and diagnosis,leading to a notably low five-year survival rate.This study offers a detailed exploration of epidemiological trends in pancreatic cancer and key molecular drivers,such as mutations in CDKN2A,KRAS,SMAD4,and TP53,along with the influence of cancer-associated fibroblasts(CAFs)on disease progression.In particular,we focused on the pivotal roles of signaling pathways such as the transforming growth factor-βand Wnt/β-catenin pathways in the development of pancreatic cancer and investigated their application in emerging therapeutic strategies.This study provides new scientific perspectives on pancreatic cancer treatment,especially in the development of precision medicine and targeted therapeutic strategies,and demonstrates the importance of signaling pathway research in the development of effective therapeutic regimens.Future studies should explore the subtypes of CAFs and their specific roles in the tumor microenvironment to devise more effective therapeutic methods.
基金Supported by the Sichuan Science and Technology Program,No.2024NSFSC1936.
文摘BACKGROUND Cancer-associated fibroblasts(CAFs),crucial components of the tumor microenvironment in primary and metastatic tumors,can impact the activity of cancer cells and contribute to their progression.Given their extensive interactions with cancer cells and other stromal cells,we aimed to evaluate the prognostic value of CAFs in patients with liver cancer(LC).AIM To investigate the association between CAF expression and clinicopathological characteristics as well as overall survival(OS)in patients with LC,including hepatocellular carcinoma(HCC)and intrahepatic cholangiocarcinoma(iCCA).METHODS We performed a meta-analysis of cohort studies with available data on the effects of CAF expression on both clinicopathological characteristics and OS via hazard ratios(HRs)and risk ratios with 95%confidence intervals(CIs).Studies were subgrouped on the basis of CAF markers and cancer type,and the subgroup effects of CAF expression on both HCC and iCCA were analyzed through meta-regression.The Newcastle-Ottawa Scale was used to evaluate the included studies to guarantee their quality and minimize the possibility of bias.RESULTS Nine trials were selected and included a total of 1518 patients.According to our primary meta-analysis,the expression of CAFs in LC patients was significantly associated with a decrease in OS(LC:HR:1.62;95%CI:1.34-1.97;P<0.001;HCC:HR:1.67;95%CI:1.34-2.07;P<0.001;iCCA:HR:1.47;95%CI:0.97-2.23;P=0.07);nevertheless,it was not significantly associated with almost all clinicopathologic characteristics,including tumor size,venous infiltration,alpha-fetoprotein level,and differentiation grade.According to the subgroup analysis of smooth muscle actin(SMA)markers in both HCC patients and iCCA patients,high CAF expression in HCC(HR:2.29;95%CI:1.01-5.22;P=0.048)and iCCA(HR:2.04;95%CI:1.09-3.81;P=0.025)patients was a significant indicator of poor OS.Moreover,the clinicopathological characteristics were also verified by the SMA marker,which had a nearly significant effect on the venous infiltration of iCCA(risk ratio:2.70;95%CI:0.97-7.49;P=0.057).CONCLUSION High CAF expression,evaluated by both mixed markers and SMAs,is significantly associated with poor OS in patients with LC,including both HCC patients and iCCA patients.However,further research is necessary since how CAF expression and clinicopathologic features are related is yet unknown.
基金supported by the Natural Science Foundation of Hubei Province(Grant No.2025AFB849).
文摘Pancreatic cancer(PC)is a highly aggressive cancer characterized by a unique tumor microenvironment(TME)that confers resistance to traditional therapies.As the dominant stromal cells in the TME,cancer-associated fibroblasts(CAFs)promote PC progression by modulating the extracellular matrix and interacting with surrounding cells.Numerous PC treatment strategies targeting CAFs have been explored in the past decade.However,targeting different subtypes of CAFs leads to varying therapeutic outcomes,highlighting the intricate and multifaceted nature of CAFs.The heterogeneity and dynamism of CAFs increase the complexity and challenges associated with tumor therapeutics.Currently,combination therapies incorporating CAF-targeted approaches in PC treatment have shown encouraging outcomes in select clinical trials.A comprehensive understanding of CAFs is essential for developing individualized therapeutic approaches.This review outlines the current knowledge of CAF heterogeneity,crosstalk with surrounding cells,and strategies for targeting CAFs in PC,aiming to keep researchers and clinicians up-to-date with the latest information on CAFs in PC.
基金Supported by National Natural Science Foundation of China,No.82304151.
文摘Pancreatic cancer is a highly aggressive malignancy with a poor prognosis and limited therapeutic options.The tumor microenvironment(TME),including cancer-associated fibroblasts(CAFs),plays a pivotal role in tumor progression and therapy resistance.Senescent CAFs,which exhibit a senescence-associated secretory phenotype(SASP),further exacerbate cancer growth through inflammatory cytokine secretion.This editorial highlights a study by Jiang et al,which investigates the potential of resveratrol,a natural polyphenolic compound,in targeting senescent CAFs to inhibit pancreatic cancer progression.The study demonstrates that resveratrol reduces senescent CAFs and downregulates SASP factors,thereby disrupting the pro-tumorigenic activities of these cells.Resveratrol’s ability to modulate the TME,induce apoptosis in pancreatic cancer cells,and inhibit metastasis underscores its potential as an adjunctive therapy.This research offers promising insights into novel strategies for improving therapeutic outcomes in pancreatic cancer by targeting the TME and senescent CAFs.
文摘Breast cancer is one of the most common malignancies worldwide and is a major cause of cancer-related mortality among women.Beyond tumor cells,the tumor microenvironment(TME)also plays an important role in cancer progression,therapy resistance,and metastasis.The TME is a complex ecosystem consisting of stromal and immune cells,extracellular matrix(ECM),and various signaling molecules that dynamically interact with tumor cells.Cancer-associated fibro-blasts remodel the ECM and secrete growth factors that promote tumor growth and invasion.Immune cells,such as tumor-associated macrophages,regulatory T cells,and myeloid-derived suppressor cells,often contribute to an immunosup-pressive environment that hinders anti-tumor immune responses.The ECM pro-vides structural support and acts as a reservoir for signaling molecules that in-fluence cancer cell behavior.These components evolve together with tumor cells,facilitating immune evasion,therapy resistance,and epithelial-to-mesenchymal transition,which promotes metastasis.Understanding these interactions is nece-ssary to develop novel therapeutic strategies that target both tumor and micro-environmental components.This minireview highlights the key stromal and immune elements within the breast cancer microenvironment,discussing their individual and collective roles in tumor progression and clinical outcomes,while emphasizing emerging therapeutic approaches aiming to reprogram the TME to improve treatment efficacy.
文摘Objectives:The present study investigated whether Tripartite Motif-Containing Protein 32(TRIM32)contributes to the aberrant activation of keloid fibroblasts(KFs)via glycolysis.Methods:The expression levels of TRIM32,pyruvate dehydrogenase kinase 1(PDK1),hexokinase 2(HK2),and glucose transporter 1(GLUT1)in normal human skin fibroblasts(NFs)and KFs were analyzed using RT-qPCR analyses and western blotting.Cellular proliferation,invasion,and migration were evaluated using Transwell,wound healing,5-ethynyl-2′-deoxyuridine(EdU),and cell counting kit-8(CCK-8)assays.The extracellular acidification rate(ECAR)was measured using the XF96 Extracellular Flux Analyzer.Glucose uptake and ATP production were measured using specific assay kits.The expression ofα-smooth muscle actin(α-SMA)was determined by immunofluorescence assays.The expression levels of collagen I,α-smooth muscle actin(α-SMA),fibronectin(FN),and components of the phosphoinositide-3-kinase/protein kinase B(PI3K/AKT)signaling pathway were quantified by western blotting.Results:The expression of TRIM32 and glycolysis-related proteins was significantly elevated in KFs compared to that in NFs.TRIM32 overex-pression enhanced the proliferation,invasion,and migration of KFs,as well as extracellular matrix(ECM)deposition,glucose uptake,and ATP production,while TRIM32 silencing produced the opposite effects.The glycolysis inhibitor,2-deoxy-glucose(2-DG),significantly suppressed the biological functions of KFs;however,TRIM32 overexpression effectively counteracted the inhibitory effects of 2-DG.TRIM32 activated the PI3K/AKT signaling pathway in KFs.The PI3K inhibitor LY294002 decreased cellular glycolysis,with TRIM32 overexpression mitigated these inhibitory effects.Conclusion:This study demonstrated that TRIM32 enhances the viability of KFs by regulating glycolytic activity,potentially mediated via the PI3K/AKT signaling pathway,thereby suggesting novel therapeutic approaches for the treatment of keloids.
基金supported by the National Natural Science Foundation of China(Nos.91949123 and 81871155).
文摘The onset of pregnancy is marked by the formation of a zygote,while the culmination of gestation is manifested by the delivery of a fetus.Meanwhile,a successful pregnancy entails a meticulously coordinated sequence of events from embryo implantation to sustained decidualization of the uterus to placental development and childbirth.The decidual reaction,a pivotal process occurring within the endometrium during pregnancy,is finely regulated by sex steroids and cytokines.Notably,fibroblast growth factors(FGFs),particularly FGF2,play a critical role in this physiological cascade.Dysregulated FGF expression may trigger inadequate decidualization,precipitating a spectrum of adverse pregnancy outcomes,including preeclampsia,recurrent implantation failure,and miscarriage.Furthermore,the human decidua,distinct from most mammalian species and similar to great apes,undergoes regular cycles of formation and shedding,independent of the presence of the embryo in the endometrium.This process is also tightly controlled by various FGFs.In this review,we comprehensively compare diverse research decidualization models,delineate the trend of endometrial FGFs during the menstrual cycle,and provide a synopsis of endometrial diseases triggered by FGF dysregulation.
基金supported by the National Natural Science Foundation of China(82373037 and 82403486)the Natural Science Foundation of Jiangsu Province(BK20230054 and BK20230161)+1 种基金the China Postdoctoral Science Foundation(2023M741766)the Nanjing Medical Science and Technology Development Foundation,Nanjing Department of Health(YKK21182 and JQX23010).
文摘Perineural invasion(PNI)by tumor cells is a key phenotype of highly-invasive oral squamous cell carcinoma(OSCC).Since Schwann cells(SCs)and fibroblasts maintain the physiological homeostasis of the peripheral nervous system,and we have focused on cancer-associated fibroblasts(CAFs)for decades,it’s imperative to elucidate the impact of CAFs on SCs in PNI+OSCCs.We describe a disease progression-driven shift of PNI−towards PNI+during the progression of early-stage OSCC(31%,n=125)to late-stage OSCC(53%,n=97),characterized by abundant CAFs and nerve demyelination.CAFs inhibited SC proliferation/migration and reduced neurotrophic factors and myelin in vitro,and this involved up-regulated ER stress and decreased MAPK signals.Moreover,CAFs also aggravated the paralysis of the hind limb and PNI in vivo.Unexpectedly,leukemia inhibitory factor(LIF)was exclusively expressed on CAFs and up-regulated in metastatic OSCC.The LIF inhibitor EC330 restored CAF-induced SC inactivation.Thus,OSCC-derived CAFs inactivate SCs to aggravate nerve injury and PNI development.
文摘Rheumatoid arthritis(RA)is a common chronic autoimmune disease characterized by joint pain,swelling and dysfunction[1].According to epidemiologic statistics,the incidence of RA is 1%–2%,and in severe cases,it can develop into joint deformity and disability,which brings a heavy burden to the family and society[2].However,the pathogenesis of RA is complex and involves multiple cellular interactions,which increases the difficulty of curing RA.Current therapeutic options,such as disease-modifying antirheumatic drugs,non-steroidal anti-inflammatory drugs,and biologics,still face the challenge of relapse after drug discontinuation[3,4].Therefore,the pathogenesis of RA needs to be analyzed in depth to break through the existing therapeutic bottlenecks and promote the iterative innovation of individualized diagnosis and treatment.
