AIM:To identify metastasis-associated prognostic genes and construct a robust molecular signature for survival prediction in uveal melanoma(UVM)patients.METHODS:Transcriptomic data and clinical information from 80 UVM...AIM:To identify metastasis-associated prognostic genes and construct a robust molecular signature for survival prediction in uveal melanoma(UVM)patients.METHODS:Transcriptomic data and clinical information from 80 UVM patients in the Cancer Genome Atlas(TCGA)-UVM cohort and an external Gene Expression Omnibus(GEO)microarray dataset(GSE73652;8 non-metastatic vs 5 metastatic cases)were analyzed to identify differentially expressed genes(DEGs).Functional enrichment,proteinprotein interaction(PPI)network construction,and survival analyses identified seven metastasis-and prognosisrelated genes.Their expression was further examined using public single-cell RNA-seq data(GSE139829;11 tumors).Experimental validation was performed in UVM cell lines(92.1,OMM1,MEL270)and adult retinal pigment epithelial(ARPE-19)cells using quantitative real-time polymerase chain reaction(qRT-PCR)and Western blotting to confirm transcriptomic trends.A LASSO Cox model was applied to construct a metastasis-related risk Score signature.Tumor immune microenvironment characteristics were evaluated via single-sample gene set enrichment analysis(ssGSEA)and ESTIMATE.Somatic mutation and copy number variation(CNV)profiles were also examined.RESULTS:Seven key genes(UBE2T,KIF20A,DLGAP5,KLC3,TPX2,UBE2C,AURKA)were significantly associated with overall survival and used to construct a metastasisrelated riskScore signature,which effectively stratified patients into high-and low-risk groups and served as an independent prognostic factor.qRT-PCR and Western blot results confirmed that the expression levels of selected key genes in UVM cell lines showed significant differences compared to ARPE-19 cells,which were largely consistent with the transcriptomic findings.The high-risk group exhibited reduced immune infiltration and stromal activity.Single-cell analysis revealed these genes were predominantly expressed in a tumor cell cluster characterized by BAP1 loss and high metastatic potential.Mutation and CNV analyses further supported the relevance of these genes to UVM progression.CONCLUSION:This study establishes and validates a seven-gene signature associated with metastasis and prognosis in UVM.The findings provide a framework for understanding molecular determinants of tumor progression and immune microenvironment alterations,and may offer guidance for future mechanistic studies and therapeutic exploration.展开更多
Skin cutaneous melanoma(SKCM),a highly invasive malignant tumor originating from skin melanocytes,poses a significant threat to public health[1,2].Its development is closely associated with multiple factors,such as ul...Skin cutaneous melanoma(SKCM),a highly invasive malignant tumor originating from skin melanocytes,poses a significant threat to public health[1,2].Its development is closely associated with multiple factors,such as ultraviolet radiation,gene mutations,and immune escape.Among these,imbalance in the immune surveillance and clearance of tumor cells is a crucial link to disease progression[3,4].Tripartite motif-containing 27,which belongs to the TRIM protein family and is encoded by the TRIM27 gene,contains the RING,B-box,and coiled-coil domains.It participates in biological processes such as cell-cycle regulation,signal transduction,and immune response mainly by modifying target proteins through ubiquitination.Notably,increasing evidence indicates that TRIM27 is closely associated with the tumor immune microenvironment and contributes to cancer immune escape via multiple mechanisms,thereby promoting tumor development[5].However,the role of TRIM27 in SKCM remains unclear,thus prompting our investigation to elucidate this.展开更多
Objective:Acral melanoma(AM),a unique subtype prevalent in China,develops on the palms,soles,and nail beds.Despite its distinct clinical and pathological features compared to cutaneous melanoma(CM),the molecular basis...Objective:Acral melanoma(AM),a unique subtype prevalent in China,develops on the palms,soles,and nail beds.Despite its distinct clinical and pathological features compared to cutaneous melanoma(CM),the molecular basis underlying these differences remains poorly understood.This study aims to perform a comprehensive comparative transcriptomic analysis of AM and CM at the single-cell level to uncover key molecular distinctions.Methods:We analyzed single-cell RNA sequencing(scRNA-seq)data from 39 AM patients and 18 CM cases.Single-cell transcriptomic profiling was used to compare tumor cell subpopulations and microenvironmental differences.Bioinformatics tools were employed for cell clustering,differential gene expression analysis,cell-cell communication network inferences,and survival analysis.Results:AM exhibited a significantly higher proportion of MPZ^(+)melanoma cells,a subpopulation with Schwann cell-like properties associated with poor prognosis.These MPZ^(+)melanoma cells established extensive communication networks with AM-specific immune and stromal components,prompting an immunosuppressive microenvironment and enhancing angiogenic potential.Survival analysis further indicated that the presence of MPZ^(+)melanoma cells is closely linked to worse clinical outcomes in AM patients.Conclusions:This study provides novel insights into the molecular distinctions between AM and CM,highlighting the critical role of MPZ^(+)melanoma cells in AM progression.These findings enhance our understanding of AM pathophysiology and may contribute to the development of more targeted therapeutic strategies.展开更多
BACKGROUND Cutaneous melanoma is an aggressive skin cancer with high metastatic potential.Accurate staging is critical to guide therapeutic strategies and improve prognosis.Whole-body magnetic resonance imaging(WB-MRI...BACKGROUND Cutaneous melanoma is an aggressive skin cancer with high metastatic potential.Accurate staging is critical to guide therapeutic strategies and improve prognosis.Whole-body magnetic resonance imaging(WB-MRI),particularly when combined with diffusion-weighted imaging(DWI),has emerged as promising tool for comprehensive,radiation-free assessment of metastatic spread.AIM To systematically review the diagnostic performance and clinical utility of WBMRI in the staging and restaging of cutaneous melanoma,with comparison to conventional imaging modalities such as computed tomography(CT)and positron emission tomography/CT(PET/CT).METHODS A systematic literature review was conducted using PubMed,Embase,Scopus and Web of Science databases for studies published in the last 10 years.Inclusion criteria focused on comparative diagnostic accuracy studies of WB-MRI vs CT and PET/CT for melanoma staging.The methodological quality of the studies was appraised using the QUADAS-2 tool.RESULTS Sixteen studies involving over 700 patients met the inclusion criteria.WB-MRI showed high sensitivity(73%-90%)and specificity(up to 98%)in detecting metastases,particularly in bone,liver and soft tissue.DWI enhanced lesion detection,and WB-MRI often influenced clinical management decisions.However,CT outperformed WB-MRI in identifying small pulmonary nodules.AI-assisted analysis and contrastenhanced sequences further improved diagnostic confidence.CONCLUSION WB-MRI represents a robust imaging modality for staging cutaneous melanoma,offering superior soft-tissue contrast and functional imaging without ionizing radiation.Its strengths lie in detecting bone,liver and brain metastases.Challenges include limited lung lesion detection,cost,and availability.Advances in artificial intelligence,Hybrid PET/MRY systems,and radiomics are poised to expand WB-MRI’s role in personalized melanoma management.展开更多
Angiogenesis,the expansion of pre-existing vascular networks,is crucial for normal organ growth and tissue repair,but is also involved in various pathologies,including inflammation,ischemia,diabetes,and cancer.In soli...Angiogenesis,the expansion of pre-existing vascular networks,is crucial for normal organ growth and tissue repair,but is also involved in various pathologies,including inflammation,ischemia,diabetes,and cancer.In solid tumors,angiogenesis supports growth,nutrient delivery,waste removal,and metastasis.Tumors can induce angiogenesis through proangiogenic factors including VEGF,FGF-2,PDGF,angiopoietins,HGF,TNF,IL-6,SCF,tryptase,and chymase.This balance is disrupted in tumors,and extracellular vesicles(EVs)contribute to this by transferring proangiogenic factors and increasing their expression in endothelial cells(ECs).Malignant melanoma,a particular type of skin cancer,accounts for only 1%of skin cancer cases but more than 75%of deaths.Its incidence has risen significantly,with a 40%increase between 2012 and 2022,especially in fair-skinned populations.Advanced metastatic stages have a high mortality due to delayed diagnosis.This review examines the molecular basis of angiogenesis in melanoma,focusing on melanoma-derived EVs and their possible use in new antiangiogenic therapies.展开更多
Anorectal melanoma is a rare tumor representing less than 1% of anorectal cancers and around 0.3% of malignant melanomas. Its prognosis is particularly poor due to the early occurrence of metastases. We report the cas...Anorectal melanoma is a rare tumor representing less than 1% of anorectal cancers and around 0.3% of malignant melanomas. Its prognosis is particularly poor due to the early occurrence of metastases. We report the case of a 65-year-old man presenting with rectorrhagia and anal pain, initially diagnosed as hemorrhoidal disease. Subsequent proctological examination revealed an ulcerating-bourging tumor, confirmed histologically as an anorectal melanoma. After a normal extension workup, an abdominoperineal amputation was performed. Anorectal melanoma is a pathology with a poor prognosis, requiring early diagnosis to improve chances of survival.展开更多
Programmed cell death protein 1/programmed cell death 1 ligand 1(PD-1/PD-L1)protein-protein interaction represents an appealing target for cancer therapy.Several antibody drugs have been developed to target this inter...Programmed cell death protein 1/programmed cell death 1 ligand 1(PD-1/PD-L1)protein-protein interaction represents an appealing target for cancer therapy.Several antibody drugs have been developed to target this interaction,but they are less effective in the treatment of melanoma.To overcome the limitations,the first proteolysis-targeting chimeric(PROTAC)small molecules simultaneously targeting PD-L1and Src homology phosphotyrosyl phosphatase 2(SHP2)were designed.By employment of PD-1/PD-L1inhibitors BMS01 or BMS-37,SHP2 inhibitor SHP099 and E3 ligase ligands,a series of potent PD-L1 and SHP2 dual PROTACs were synthesized.The most promising compounds BS-7C-V2 and BS327V2 efficiently induced PD-L1 and SHP2 degradation and demonstrated significantly improved immune potency in B16-F10 and A375 cell lines.More importantly,the efficacy of BS-7C-V2 and BS327V2 in a B16-F10 transplanted mouse model was further evaluated based on their degradation ability in vivo.Taken together,our work qualifies the new dual PROTACs as a potent degrader of PD-L1 and SHP2.The biological and mechanism investigations with BS-7C-V2 and BS327V2 prove that dual PROTACs can play an anti-tumor role in vivo and in vitro,and can provide a new therapeutic strategy for melanoma.展开更多
Melanoma is an aggressive type of skin cancer notorious for its resistance to chemotherapy,radiotherapy and immunotherapy,which greatly impacts its lethality.The hedgehog(HH)signaling cascade,originally known for its ...Melanoma is an aggressive type of skin cancer notorious for its resistance to chemotherapy,radiotherapy and immunotherapy,which greatly impacts its lethality.The hedgehog(HH)signaling cascade,originally known for its roles in embryonic development,regulates growth,proliferation and cancer stem cell(CSC)self-renewal.The glioma-associated oncogene homolog(GLI)transcription factors play crucial roles in melanoma.However,oncogenic B-Raf proto-oncogene,serine/threonine kinase(BRAF)steals the spotlight by driving the aberrant activation of HH-GLI1/2 signaling.Oncogenic BRAF-driven HH-GLI1/2 signaling imparts invasive phenotype to melanoma cells and sustains CSC self-renewal.Interestingly,the transcriptional activities of GLI1 and GLI2 are suppressed by acetylation,a process that is counteracted by the deacetylating actions of histone deacetylase(HDAC)1/2.Therefore,inhibiting HDAC1/2 might keep GLI proteins in inactive acetylated form,thus representing an attractive druggable target.Notably,both HDAC1 and HDAC2 are induced by HH signaling,creating a positive feedback loop where HH signaling upregulates the expression of both HDAC1 and HDAC2.Selective inhibition of BRAF/HH/HDAC/GLI signaling axis is likely to unravel new therapeutic opportunities in melanoma.However,the precise contribution of oncogenic BRAF-driven HH signaling to therapy resistance and CSC renewal remains unclear and requires thorough investigation.In this article,we endeavored to explore the crosstalk between oncogenic BRAF and HH signaling,and the pivotal role this interaction plays in the self-renewal of melanoma stem cells.A better understanding of the molecular mechanisms governing these interactions is essential for improving melanoma treatment strategies and identifying new therapeutic targets.展开更多
BACKGROUND Melanoma is a highly malignant tumor that has an extremely poor prognosis.It is the primary cause of death among cutaneous malignancies,accounting for 75%of such fatalities;approximately 325000 new cases an...BACKGROUND Melanoma is a highly malignant tumor that has an extremely poor prognosis.It is the primary cause of death among cutaneous malignancies,accounting for 75%of such fatalities;approximately 325000 new cases and 57000 deaths were reported worldwide in 2020.The main modalities for melanoma treatment include surgery,immunotherapy,targeted therapy,high-dose interferon,antitumor angiogenesis,chemotherapy,and radiotherapy.Due to China's special national conditions,the main pathological types and therapeutic effects are greatly different from those in Europe and the United States,so more studies are needed to determine the curative effects of such treatments in the Chinese population.AIM To explore their clinical characteristics,prognostic influencing factors and realworld data to provide a reference basis for further diagnosis and treatment.METHODS We collected pathological data from patients diagnosed with malignant melanoma in our hospital in recent years.Univariate analysis was conducted using the log-rank test,while multivariate analysis was performed with the Cox proportional hazard regression model.The survival rate was calculated using the Kaplan-Meier method.RESULTS The male-to-female patient ratio was 1.04:1.Among the clinical classifications,melanoma of the limb accounted for 47.56%of cases,followed by melanoma of the skin(18.18%)and mucosal melanoma(18.05%).The 5-year survival rates for stage I-II,stage III,and stage IV patients were 54.65%,37.88%,and 28.58%,respectively.Univariate analysis revealed that age,tumor stage,treatment mode,platelet count at the first visit,and lactate dehydrogenase(LDH)level were significantly related to patient survival.Patients with high LDH and high platelet counts exhibited significantly lower survival rates at 1 year,3 years,and 5 years.Multivariate analysis demonstrated that tumor stage,chemotherapy,interferon therapy,and LDH level were independent risk factors affecting patient survival and prognosis.Compared to the mortality rates of patients who did not receive chemotherapy or interferon therapy,those of patients who received chemotherapy and interferon therapy were 30.0%and 44.5%lower,respectively.Additionally,patients with elevated LDH levels were 2.27 times more likely to die than patients with normal LDH levels.CONCLUSION Melanoma is highly malignant,and its prognosis is influenced by numerous factors,resulting in an overall poor prognosis.This study identified several factors that impact patient prognosis,providing a foundation for individualized comprehensive treatment.展开更多
The increasing incidence of melanoma poses significant challenges for conventional treatment approaches,plagued by drug resistance and adverse side effects.Natural marine-derived compounds have gained prominence in me...The increasing incidence of melanoma poses significant challenges for conventional treatment approaches,plagued by drug resistance and adverse side effects.Natural marine-derived compounds have gained prominence in melanoma research for their unique bioactivities and diversity.This review delves into the therapeutic potential of these compounds in melanoma treatment,emphasizing their distinctive advantages such as multi-target mechanisms and immune modulation,which distinguish them from traditional therapies.Additionally,we discuss the challenges in translating these agents into clinical applications,including formulation stability,bioavailability,and regulatory hurdles.Recent advancements in preclinical models such as organoids and completed clinical trials further support the exploration of marine-derived compounds in melanoma management.By consolidating current research,this review underscores the potential of these agents to enhance treatment efficacy and foster new therapeutic strategies.展开更多
AIM:To explore the relationship between matrix metalloproteinases(MMPs)expression levels in the tumor and the prognosis of uveal melanoma(UM)and to construct prognostic prediction models.METHODS:Transcriptome sequenci...AIM:To explore the relationship between matrix metalloproteinases(MMPs)expression levels in the tumor and the prognosis of uveal melanoma(UM)and to construct prognostic prediction models.METHODS:Transcriptome sequencing data from 17 normal choroid tissues and 53 UM tumor tissues were collected.Based on the differential gene expression levels and their function,MMPs family was selected for establishing risk-score system and prognostic prediction model with machine learning.Tumor microenvironment(TME)analysis was also applied for the impact of immune cell infiltration on prognosis of the disease.RESULTS:Eight MMPs were significantly different expression levels between normal and the tumor tissues.MMP-2 and MMP-28 were selected to construct a risk-score system and divided patients accordingly into high-and low-risk groups.The prediction model based on the risk-score achieved an accuracy of approximately 80%at 1-,3-,and 5-year after diagnosis.Besides,a Nomogram prognostic prediction model which based on risk-score and pathological type(independent prognostic factors after Cox regression analysis)demonstrated good consistency between the predicted outcomes at 1-,3-,and 5-year after diagnosis and the actual prognosis of patients.TME analysis revealed that the high-risk group exhibited higher immune and stromal scores and increased infiltration of tumor-associated macrophages(TAMs)and regulatory T cells compared to the low-risk group.CONCLUSION:Based on MMP-2 and MMP-28 expression levels,our prediction model demonstrates accurate long-term prognosis prediction for UM patients.The aggregation of TAMs and regulatory T cells in the TME of UM may be associated with an unfavorable prognosis.展开更多
Melanoma,the most aggressive form of skin cancer,remains a significant clinical challenge due to the high metastatic potential and drug resistance.This review explores the pivotal roles of angiogenesis and vasculogeni...Melanoma,the most aggressive form of skin cancer,remains a significant clinical challenge due to the high metastatic potential and drug resistance.This review explores the pivotal roles of angiogenesis and vasculogenic mimicry in melanoma progression and treatment resistance.Angiogenesis,driven primarily by VEGF/VEGFR signaling,is critical for tumor sustenance but is often insufficient under hypoxic conditions,prompting melanoma cells to adapt by forming vascular-like structures(i.e.,vasculogenic mimicry).These structures enable melanoma cells to mimic endothelial functions and are linked to increased metastasis and poor prognosis.Molecular drivers,including VE-cadherin,EphA2,and hypoxia-inducible factors,have been identified as key regulators of these processes.Current anti-angiogenic agents have limited efficacy in advanced/metastatic melanoma due to tumor plasticity and the interplay between angiogenesis and vasculogenic mimicry.The review highlights the need for therapeutic strategies targeting both mechanisms,emphasizing the importance of combination treatments to overcome resistance.Future research should aim to elucidate the molecular underpinnings of angiogenesis and vasculogenic mimicry to improve melanoma management and patient outcomes.展开更多
BACKGROUND Acute liver failure(ALF)due to diffuse hepatic infiltration by metastatic mela-noma is extremely rare and often misdiagnosed.In the absence of prior malig-nancy,this presentation can mimic other hepatic eme...BACKGROUND Acute liver failure(ALF)due to diffuse hepatic infiltration by metastatic mela-noma is extremely rare and often misdiagnosed.In the absence of prior malig-nancy,this presentation can mimic other hepatic emergencies such as Budd-Chiari syndrome.Early identification is crucial,especially in transplant candidates,to prevent inappropriate management.CASE SUMMARY A 61-year-old male presented with jaundice,abdominal distension,and enceph-alopathy.Liver imaging suggested acute Budd-Chiari syndrome,and liver trans-plantation was considered.However,biopsy revealed extensive hepatic infilt-ration by human melanoma black-positive melanoma cells.There was no known can-cer history,although retrospective symptoms suggested uveal localization as a possi-ble primary site.The patient rapidly deteriorated and died.A review of 12 simi-lar cases revealed shared diagnostic challenges,frequent misdiagnoses,and poor outcomes.CONCLUSION Infiltrative melanoma should be considered in unexplained ALF,even without previously known malignancy.展开更多
Background:To investigate the effects of Astragalus polysaccharides(APS)on melanoma-bearing mice via the Janus kinase 2(JAK2)/signal transducer and activator of transcription 3(STAT3)signaling pathway.Methods:Fifty ma...Background:To investigate the effects of Astragalus polysaccharides(APS)on melanoma-bearing mice via the Janus kinase 2(JAK2)/signal transducer and activator of transcription 3(STAT3)signaling pathway.Methods:Fifty male C57BL/6 mice were randomly divided into five groups:model group,positive control group,APS low-dose group,APS middle-dose group,and APS high-dose group(10 mice per group).B16 cell-bearing melanoma mouse models were established in all groups.The low,middle,and high-dose APS groups received daily injections of APS solution at 20,40,and 80 mg/kg,respectively.Spleen and thymus indices were measured,tumor volumes were observed,and tumor inhibition rates were calculated.Tumor histopathological changes were examined via H&E staining.Ki67 and PCNA expression in tumor tissues were assessed via immunofluorescence staining and Western blot analysis RT-qPCR.Western blot was used to examine the expression of JAK2/STAT3 signaling pathway-related factors in tumor tissues.Results:APS significantly increased the spleen and thymus indices in melanoma mice and inhibited tumor growth.H&E staining revealed that APS significantly reduced the number of tumor cells in melanoma mice.Immunofluorescence results indicated that APS significantly decreased Ki67-positive expression in tumor tissues,while Western blot results showed that APS significantly reduced PCNA protein expression in tumor tissues.RT-qPCR and Western blot results indicated that APS significantly suppressed the expression of JAK2/STAT3 signaling pathway-related genes and proteins.Conclusion:APS may inhibit tumor growth in a melanoma mouse model by enhancing immune function through suppression of the JAK2/STAT3 signaling pathway.展开更多
Objectives:Among cutaneous malignancies,melanoma stands out for its particularly aggressive nature,with therapeutic interventions becoming notably limited once the disease progresses.In this research,we investigate th...Objectives:Among cutaneous malignancies,melanoma stands out for its particularly aggressive nature,with therapeutic interventions becoming notably limited once the disease progresses.In this research,we investigate the tumor-suppressing capabilities of water-extracted Korean mistletoe(Viscum album var.coloratum)and its purified lectin component(V.album var.coloratum agglutinin,VCA)using two distinct mouse melanoma models:B16BL6 and B16F10 cell lines.Methods:The impact of water extract and VCA treatments on melanoma cells was assessed through multiple experimental approaches,examining cellular survival rates,programmed cell death pathways,multicaspase activity,and cell cycle distribution patterns.To elucidate the interconnections among various cellular responses,we employed a suite of statistical techniques encompassing correlation studies,principal component analysis(PCA)-based dimensionality reduction,and dendrogram-based clusteringmethodologies.Results:Thewater extract exhibited dosedependent cytotoxicity with IC50 values of 372.3±8.7μg/mL and 202.5±8.4μg/mL for B16BL6 and B16F10 cells,respectively.VCA showed more significant effects,with IC50 values of 0.1992±0.0041 and 0.1981±0.0098μg/mL for B16BL6 and B16F10 cells,respectively.Both agents induced substantial apoptosis with a significant progression from early to late apoptotic stages,reaching up to 59.4%total apoptotic cells for VCA treatment.This was confirmed by strong multicaspase activation,particularly in VCA-treated cells(up to 88.4%caspase-positive cells).The water extract showed modest effects on cell cycle distribution,with increases in G0/G1 phase(74.6%)in B16BL6 cells and S phase(19.2%)in B16F10 cells,while VCA treatment resulted in G2/M phase reduction(10.0%)in B16F10 cells.Correlation analysis revealed strong negative associations between cell viability and caspase activity(r=−0.843 to−0.878),while hierarchical clustering demonstrated distinct response patterns between low and high concentrations of both agents.Effect size analysis confirmed strong treatment impacts on cell viability(d=−5.89 to−6.12)and caspase activation(d=3.45 to 5.23).Conclusion:These findings suggest that Korean mistletoe water extract and its isolated lectin may affect both primary and metastatic melanoma cells through distinct mechanisms,demonstrating particular potency in caspase-dependent apoptosis induction.Our findings establish a robust foundation for developing novel therapeutic interventions derived from natural compounds to combat malignant melanoma with high metastatic potential.展开更多
Malignant melanoma,characterized by its high metastatic potential and resistance to conventional therapies,presents a major challenge in oncology.This review explores the current status and advancements in tumor vacci...Malignant melanoma,characterized by its high metastatic potential and resistance to conventional therapies,presents a major challenge in oncology.This review explores the current status and advancements in tumor vaccines for melanoma,focusing on peptide,DNA/RNA,dendritic cell,tumor cell,and neoantigen-based vaccines.Despite promising results,significant challenges remain,including the immunosuppressive tumor microenvironment,patient heterogeneity,and the need for more effective antigen presentation.Recent strategies,such as combining vaccines with immune checkpoint inhibitors(ICIs),aim to counteract immune evasion and enhance T cell responses.Emerging approaches,including personalized neoantigen vaccines and the use of self-amplifying RNA platforms,hold promise for overcoming tumor heterogeneity and improving vaccine efficacy.Additionally,optimizing vaccine delivery systems through nanotechnology and genetic modifications is essential for increasing stability and scalability.This review highlights the potential of these innovative strategies to address current limitations,with a focus on how future research can refine and combine these approaches to improve melanoma treatment outcomes.展开更多
Immunotherapy with interleukin-2(IL-2)in treating cancers is subject to several limitations such as systemic side effects and reduced efficacy against tumors with low immune cell infiltration despite its promise.To ad...Immunotherapy with interleukin-2(IL-2)in treating cancers is subject to several limitations such as systemic side effects and reduced efficacy against tumors with low immune cell infiltration despite its promise.To address these challenges,IL-2-So-Lipo,a novel liposomal formulation combining IL-2 with sorafenib derivative,was developed as an anti-angiogenic drug that inhibits the growth of new blood vessels which play crucial roles in tumor growth.Sorafenib derivatives could target at melanoma-specific receptors,further enhancing liposomal specificity at the tumor site.Our results demonstrated that the prepared IL-2-So-Lipo significantly enhanced anti-tumor activity compared to IL-2 or sorafenib monotherapies,as well as their combination.In a B16F10 melanoma model,IL-2-So-Lipo was found to significantly inhibit tumor progression(tumor volume of 108.01±62.99 mm^(3))compared to the control group(tumor volume of 1,397.13±75.55 mm^(3)),improving the therapeutic efficacy.This enhanced efficacy is attributed to the targeted delivery of IL-2 which promoted the infiltration and activation of cytotoxic T lymphocytes.Additionally,liposomal encapsulation of sorafenib derivatives enhanced its delivery efficiency,promoting tumor cell apoptosis and suppressing angiogenesis.Mechanistically,IL-2-So-Lipo could kill tumors by inducing a shift towards an anti-tumor immune response via facilitating the polarization of macrophages towards the M1 phenotype.Furthermore,IL-2-So-Lipo downregulated several key proteins in the MAPK signaling pathway,exerting a significant role in mediating tumor resistance to sorafenib.These findings underscore the potential of IL-2-So-Lipo as a promising strategy to improve the therapeutic efficacy of immunotherapy and targeted therapy in cancers.Moreover,the combination of IL-2 and sorafenib in a liposomal delivery system overcame the limitations of conventional IL-2 therapy,offering a synergistic approach to improve therapeutic outcomes for solid tumors.展开更多
BACKGROUND Mesenchymal stromal cells(MSCs)are renowned for their immunosuppressive properties,which make them widely used in managing excessive inflammation.Although CD146+and CD146-MSCs exhibit similar morphological ...BACKGROUND Mesenchymal stromal cells(MSCs)are renowned for their immunosuppressive properties,which make them widely used in managing excessive inflammation.Although CD146+and CD146-MSCs exhibit similar morphological traits and surface marker expression levels,the specific characteristics and differential regulatory mechanisms of these two subtypes remain poorly understood.This knowledge gap has limited the precise application of MSCs in targeted thera-peutic strategies.AIM To compare the functional differences between CD146+and CD146-MSCs and investigate the underlying mechanisms.METHODS In this study,magnetic beads were used to sort umbilical cord-derived MSCs into CD146+and CD146-subsets.The pro-angiogenic factors(hepatocyte growth factor,prostaglandin E2,vascular endothelial growth factor,angiopoietin-1)production and immunomodulatory effects on T lymphocyte subsets were evaluated in vitro.The therapeutic efficacy was assessed in an acute respiratory distress syndrome(ARDS)mouse model via tail vein injection.RESULTS Cytokine secretion and angiogenesis:CD146+MSCs significantly increased the production of hepatocyte growth factor,prostaglandin E2,vascular endothelial growth factor,and angiopoietin-1 and exhibited increased pro-angiogenic activity in vitro.Immunomodulatory effects:CD146+MSCs potently inhibited the differentiation and proliferation of pro-inflammatory T helper type 1/T helper type 17 cells while promoting the expansion of regulatory T cells during T lymphocyte activation.ARDS therapy:In a mouse ARDS model,compared with CD146-MSCs,CD146+MSCs demonstrated superior therapeutic efficacy,as evidenced by improved clinical scores.Mechanistically,CD146+MSCs activated the nuclear factor kappa B pathway,upregulated cyclooxygenase 2 expression,and facilitated damaged epithelial cell repair.CONCLUSION CD146+MSCs show stronger ARDS therapeutic potential than CD146-MSCs via pro-angiogenic/immunomodulatory traits.Nuclear factor kappa B/cyclooxygenase 2 activation aids epithelial repair,highlighting CD146+MSCs as promising targets.展开更多
AIM:To investigate the role of Forkhead box protein P3(FOXP3)in choroidal melanoma(CM)metastases and elucidate its underlying mechanisms.METHODS:FOXP3 protein expression was analyzed in CM clinical specimens and cell ...AIM:To investigate the role of Forkhead box protein P3(FOXP3)in choroidal melanoma(CM)metastases and elucidate its underlying mechanisms.METHODS:FOXP3 protein expression was analyzed in CM clinical specimens and cell lines.A stable FOXP3 knockout cell line and a transient FOXP3-overexpressing cell line were established,with transfection efficiencies confirmed by Western blotting(WB).Functional assays,including monoclonal formation,cell counting kit-8(CCK-8)proliferation,migration,invasion,and in vivo tumorigenesis assays in nude mice,were performed to assess the biological effects of FOXP3.Additionally,WB was employed to evaluate epithelial-mesenchymal transition(EMT)markers and the activation of the Wnt5a/CaMKII signaling pathway.RESULTS:FOXP3 expression was significantly elevated in both CM clinical specimens and cell lines.Functional analyses revealed that FOXP3 enhanced CM cell proliferation,migration,and invasion in vitro and promoted tumorigenesis in vivo.Mechanistically,FOXP3 upregulated EMT-related proteins and activated the Wnt5a/CaMKII signaling pathway.Rescue experiments further confirmed that the oncogenic effects of FOXP3 were mediated via modulation of the Wnt5a/CaMKII axis.CONCLUSION:This study identifies FOXP3 as an oncogenic driver in CM,promoting tumor progression through the Wnt5a/CaMKII signaling pathway.These findings provide new insights into the molecular mechanisms of CM pathogenesis and highlight FOXP3 as a potential therapeutic target.展开更多
Introduction:Acral melanoma(AM)is the predominant subtype of cutaneous melanoma in Asian populations,characterized by more aggressive clinical features and limited neoadjuvant therapy response.Centrosomal protein 55 k...Introduction:Acral melanoma(AM)is the predominant subtype of cutaneous melanoma in Asian populations,characterized by more aggressive clinical features and limited neoadjuvant therapy response.Centrosomal protein 55 kDa(CEP55)has been implicated in the pathogenesis of various malignancies,but its role in AM remains undefined.Methods:CEP55 expression in melanoma tissues and cell lines was analyzed by RT-qPCR,Western blotting,and immunohistochemistry(IHC).Databases(GEPIA,Sangerbox,Kaplan-Meier plotter,and TIMER)were used to analyze the expression of CEP55 and its correlation with clinical data of melanoma patients.Functional assays were conducted in vitro and in vivo.RNA sequencing(RNA-seq)and rescue experiments were used to explore underlying mechanisms.Tissue microarrays were used to verify the relationship between CEP55 and immune checkpoints.Results:CEP55 overexpression is associated with Breslow thickness and TNM stage in melanoma tissues and cell lines.CEP55 knockdown inhibited melanoma cell proliferation,migration,and invasion.And CEP55 activated mitogen-activated protein kinase(MAPK)signaling,leading to BRAF inhibitor resistance.Besides,CEP55 overexpression was associated with more favorable responses to immunotherapy in melanoma patients.Conclusions:CEP55 plays a critical role in AM progression and immunotherapy.Targeting CEP55 may be a promising therapeutic strategy for AM.展开更多
基金Supported by the National Natural Science Foundation of China(No.82460215)National Natural Science Foundation of China Pre-experimental Project(No.2025GZRYSY006)+4 种基金2025 Youth Training Project of the Xi’an Municipal Health Commission(No.2025qn05)Xi’an Medical Research-Discipline Capacity Building Project(No.23YXYJ0002)Key R&D Plan of Shaanxi Province:Key Industrial Innovation Chain(Cluster)-Social Development Field(No.2022ZDLSF03-10)Research Incubation Fund of Xi’an People’s Hospital(Xi’an Fourth HospitalNo.LH-13).
文摘AIM:To identify metastasis-associated prognostic genes and construct a robust molecular signature for survival prediction in uveal melanoma(UVM)patients.METHODS:Transcriptomic data and clinical information from 80 UVM patients in the Cancer Genome Atlas(TCGA)-UVM cohort and an external Gene Expression Omnibus(GEO)microarray dataset(GSE73652;8 non-metastatic vs 5 metastatic cases)were analyzed to identify differentially expressed genes(DEGs).Functional enrichment,proteinprotein interaction(PPI)network construction,and survival analyses identified seven metastasis-and prognosisrelated genes.Their expression was further examined using public single-cell RNA-seq data(GSE139829;11 tumors).Experimental validation was performed in UVM cell lines(92.1,OMM1,MEL270)and adult retinal pigment epithelial(ARPE-19)cells using quantitative real-time polymerase chain reaction(qRT-PCR)and Western blotting to confirm transcriptomic trends.A LASSO Cox model was applied to construct a metastasis-related risk Score signature.Tumor immune microenvironment characteristics were evaluated via single-sample gene set enrichment analysis(ssGSEA)and ESTIMATE.Somatic mutation and copy number variation(CNV)profiles were also examined.RESULTS:Seven key genes(UBE2T,KIF20A,DLGAP5,KLC3,TPX2,UBE2C,AURKA)were significantly associated with overall survival and used to construct a metastasisrelated riskScore signature,which effectively stratified patients into high-and low-risk groups and served as an independent prognostic factor.qRT-PCR and Western blot results confirmed that the expression levels of selected key genes in UVM cell lines showed significant differences compared to ARPE-19 cells,which were largely consistent with the transcriptomic findings.The high-risk group exhibited reduced immune infiltration and stromal activity.Single-cell analysis revealed these genes were predominantly expressed in a tumor cell cluster characterized by BAP1 loss and high metastatic potential.Mutation and CNV analyses further supported the relevance of these genes to UVM progression.CONCLUSION:This study establishes and validates a seven-gene signature associated with metastasis and prognosis in UVM.The findings provide a framework for understanding molecular determinants of tumor progression and immune microenvironment alterations,and may offer guidance for future mechanistic studies and therapeutic exploration.
基金supported by the Natural Science Foundation of Hebei Province(Grant number:C2025405060).
文摘Skin cutaneous melanoma(SKCM),a highly invasive malignant tumor originating from skin melanocytes,poses a significant threat to public health[1,2].Its development is closely associated with multiple factors,such as ultraviolet radiation,gene mutations,and immune escape.Among these,imbalance in the immune surveillance and clearance of tumor cells is a crucial link to disease progression[3,4].Tripartite motif-containing 27,which belongs to the TRIM protein family and is encoded by the TRIM27 gene,contains the RING,B-box,and coiled-coil domains.It participates in biological processes such as cell-cycle regulation,signal transduction,and immune response mainly by modifying target proteins through ubiquitination.Notably,increasing evidence indicates that TRIM27 is closely associated with the tumor immune microenvironment and contributes to cancer immune escape via multiple mechanisms,thereby promoting tumor development[5].However,the role of TRIM27 in SKCM remains unclear,thus prompting our investigation to elucidate this.
基金supported by the National Key Research and Development Project(No.2023YFC3404400)。
文摘Objective:Acral melanoma(AM),a unique subtype prevalent in China,develops on the palms,soles,and nail beds.Despite its distinct clinical and pathological features compared to cutaneous melanoma(CM),the molecular basis underlying these differences remains poorly understood.This study aims to perform a comprehensive comparative transcriptomic analysis of AM and CM at the single-cell level to uncover key molecular distinctions.Methods:We analyzed single-cell RNA sequencing(scRNA-seq)data from 39 AM patients and 18 CM cases.Single-cell transcriptomic profiling was used to compare tumor cell subpopulations and microenvironmental differences.Bioinformatics tools were employed for cell clustering,differential gene expression analysis,cell-cell communication network inferences,and survival analysis.Results:AM exhibited a significantly higher proportion of MPZ^(+)melanoma cells,a subpopulation with Schwann cell-like properties associated with poor prognosis.These MPZ^(+)melanoma cells established extensive communication networks with AM-specific immune and stromal components,prompting an immunosuppressive microenvironment and enhancing angiogenic potential.Survival analysis further indicated that the presence of MPZ^(+)melanoma cells is closely linked to worse clinical outcomes in AM patients.Conclusions:This study provides novel insights into the molecular distinctions between AM and CM,highlighting the critical role of MPZ^(+)melanoma cells in AM progression.These findings enhance our understanding of AM pathophysiology and may contribute to the development of more targeted therapeutic strategies.
文摘BACKGROUND Cutaneous melanoma is an aggressive skin cancer with high metastatic potential.Accurate staging is critical to guide therapeutic strategies and improve prognosis.Whole-body magnetic resonance imaging(WB-MRI),particularly when combined with diffusion-weighted imaging(DWI),has emerged as promising tool for comprehensive,radiation-free assessment of metastatic spread.AIM To systematically review the diagnostic performance and clinical utility of WBMRI in the staging and restaging of cutaneous melanoma,with comparison to conventional imaging modalities such as computed tomography(CT)and positron emission tomography/CT(PET/CT).METHODS A systematic literature review was conducted using PubMed,Embase,Scopus and Web of Science databases for studies published in the last 10 years.Inclusion criteria focused on comparative diagnostic accuracy studies of WB-MRI vs CT and PET/CT for melanoma staging.The methodological quality of the studies was appraised using the QUADAS-2 tool.RESULTS Sixteen studies involving over 700 patients met the inclusion criteria.WB-MRI showed high sensitivity(73%-90%)and specificity(up to 98%)in detecting metastases,particularly in bone,liver and soft tissue.DWI enhanced lesion detection,and WB-MRI often influenced clinical management decisions.However,CT outperformed WB-MRI in identifying small pulmonary nodules.AI-assisted analysis and contrastenhanced sequences further improved diagnostic confidence.CONCLUSION WB-MRI represents a robust imaging modality for staging cutaneous melanoma,offering superior soft-tissue contrast and functional imaging without ionizing radiation.Its strengths lie in detecting bone,liver and brain metastases.Challenges include limited lung lesion detection,cost,and availability.Advances in artificial intelligence,Hybrid PET/MRY systems,and radiomics are poised to expand WB-MRI’s role in personalized melanoma management.
基金supported by grants from the Jagiellonian University,Poland(N18/DBS/000007)the Polish National Science Centre(2018/31/N/NZ4/03787).
文摘Angiogenesis,the expansion of pre-existing vascular networks,is crucial for normal organ growth and tissue repair,but is also involved in various pathologies,including inflammation,ischemia,diabetes,and cancer.In solid tumors,angiogenesis supports growth,nutrient delivery,waste removal,and metastasis.Tumors can induce angiogenesis through proangiogenic factors including VEGF,FGF-2,PDGF,angiopoietins,HGF,TNF,IL-6,SCF,tryptase,and chymase.This balance is disrupted in tumors,and extracellular vesicles(EVs)contribute to this by transferring proangiogenic factors and increasing their expression in endothelial cells(ECs).Malignant melanoma,a particular type of skin cancer,accounts for only 1%of skin cancer cases but more than 75%of deaths.Its incidence has risen significantly,with a 40%increase between 2012 and 2022,especially in fair-skinned populations.Advanced metastatic stages have a high mortality due to delayed diagnosis.This review examines the molecular basis of angiogenesis in melanoma,focusing on melanoma-derived EVs and their possible use in new antiangiogenic therapies.
文摘Anorectal melanoma is a rare tumor representing less than 1% of anorectal cancers and around 0.3% of malignant melanomas. Its prognosis is particularly poor due to the early occurrence of metastases. We report the case of a 65-year-old man presenting with rectorrhagia and anal pain, initially diagnosed as hemorrhoidal disease. Subsequent proctological examination revealed an ulcerating-bourging tumor, confirmed histologically as an anorectal melanoma. After a normal extension workup, an abdominoperineal amputation was performed. Anorectal melanoma is a pathology with a poor prognosis, requiring early diagnosis to improve chances of survival.
基金the National Natural Science Foundation of China(NSFC,No.82141216)Chunhui Program-Cooperative Research Project of the Ministry of Education+2 种基金Project of Frontier Technology Platform for Research Projects of Liaoning Provincial Department of Education in 2024Shenyang Young and Middle-aged Innovative Talents Support Program(No.RC210446)for financial supportsthe support from National-Local Joint Engineering Research Center for Molecular Biotechnology of Fujian&Taiwan TCM at Fujian University of Traditional Chinese Medicine。
文摘Programmed cell death protein 1/programmed cell death 1 ligand 1(PD-1/PD-L1)protein-protein interaction represents an appealing target for cancer therapy.Several antibody drugs have been developed to target this interaction,but they are less effective in the treatment of melanoma.To overcome the limitations,the first proteolysis-targeting chimeric(PROTAC)small molecules simultaneously targeting PD-L1and Src homology phosphotyrosyl phosphatase 2(SHP2)were designed.By employment of PD-1/PD-L1inhibitors BMS01 or BMS-37,SHP2 inhibitor SHP099 and E3 ligase ligands,a series of potent PD-L1 and SHP2 dual PROTACs were synthesized.The most promising compounds BS-7C-V2 and BS327V2 efficiently induced PD-L1 and SHP2 degradation and demonstrated significantly improved immune potency in B16-F10 and A375 cell lines.More importantly,the efficacy of BS-7C-V2 and BS327V2 in a B16-F10 transplanted mouse model was further evaluated based on their degradation ability in vivo.Taken together,our work qualifies the new dual PROTACs as a potent degrader of PD-L1 and SHP2.The biological and mechanism investigations with BS-7C-V2 and BS327V2 prove that dual PROTACs can play an anti-tumor role in vivo and in vitro,and can provide a new therapeutic strategy for melanoma.
基金Supported by the Science and Engineering Research Board,No.PDF/2016/002730.
文摘Melanoma is an aggressive type of skin cancer notorious for its resistance to chemotherapy,radiotherapy and immunotherapy,which greatly impacts its lethality.The hedgehog(HH)signaling cascade,originally known for its roles in embryonic development,regulates growth,proliferation and cancer stem cell(CSC)self-renewal.The glioma-associated oncogene homolog(GLI)transcription factors play crucial roles in melanoma.However,oncogenic B-Raf proto-oncogene,serine/threonine kinase(BRAF)steals the spotlight by driving the aberrant activation of HH-GLI1/2 signaling.Oncogenic BRAF-driven HH-GLI1/2 signaling imparts invasive phenotype to melanoma cells and sustains CSC self-renewal.Interestingly,the transcriptional activities of GLI1 and GLI2 are suppressed by acetylation,a process that is counteracted by the deacetylating actions of histone deacetylase(HDAC)1/2.Therefore,inhibiting HDAC1/2 might keep GLI proteins in inactive acetylated form,thus representing an attractive druggable target.Notably,both HDAC1 and HDAC2 are induced by HH signaling,creating a positive feedback loop where HH signaling upregulates the expression of both HDAC1 and HDAC2.Selective inhibition of BRAF/HH/HDAC/GLI signaling axis is likely to unravel new therapeutic opportunities in melanoma.However,the precise contribution of oncogenic BRAF-driven HH signaling to therapy resistance and CSC renewal remains unclear and requires thorough investigation.In this article,we endeavored to explore the crosstalk between oncogenic BRAF and HH signaling,and the pivotal role this interaction plays in the self-renewal of melanoma stem cells.A better understanding of the molecular mechanisms governing these interactions is essential for improving melanoma treatment strategies and identifying new therapeutic targets.
基金Supported by Natural Science Foundation of Chongqing,No.CSTB2023NSCQ-MSX0829.
文摘BACKGROUND Melanoma is a highly malignant tumor that has an extremely poor prognosis.It is the primary cause of death among cutaneous malignancies,accounting for 75%of such fatalities;approximately 325000 new cases and 57000 deaths were reported worldwide in 2020.The main modalities for melanoma treatment include surgery,immunotherapy,targeted therapy,high-dose interferon,antitumor angiogenesis,chemotherapy,and radiotherapy.Due to China's special national conditions,the main pathological types and therapeutic effects are greatly different from those in Europe and the United States,so more studies are needed to determine the curative effects of such treatments in the Chinese population.AIM To explore their clinical characteristics,prognostic influencing factors and realworld data to provide a reference basis for further diagnosis and treatment.METHODS We collected pathological data from patients diagnosed with malignant melanoma in our hospital in recent years.Univariate analysis was conducted using the log-rank test,while multivariate analysis was performed with the Cox proportional hazard regression model.The survival rate was calculated using the Kaplan-Meier method.RESULTS The male-to-female patient ratio was 1.04:1.Among the clinical classifications,melanoma of the limb accounted for 47.56%of cases,followed by melanoma of the skin(18.18%)and mucosal melanoma(18.05%).The 5-year survival rates for stage I-II,stage III,and stage IV patients were 54.65%,37.88%,and 28.58%,respectively.Univariate analysis revealed that age,tumor stage,treatment mode,platelet count at the first visit,and lactate dehydrogenase(LDH)level were significantly related to patient survival.Patients with high LDH and high platelet counts exhibited significantly lower survival rates at 1 year,3 years,and 5 years.Multivariate analysis demonstrated that tumor stage,chemotherapy,interferon therapy,and LDH level were independent risk factors affecting patient survival and prognosis.Compared to the mortality rates of patients who did not receive chemotherapy or interferon therapy,those of patients who received chemotherapy and interferon therapy were 30.0%and 44.5%lower,respectively.Additionally,patients with elevated LDH levels were 2.27 times more likely to die than patients with normal LDH levels.CONCLUSION Melanoma is highly malignant,and its prognosis is influenced by numerous factors,resulting in an overall poor prognosis.This study identified several factors that impact patient prognosis,providing a foundation for individualized comprehensive treatment.
文摘The increasing incidence of melanoma poses significant challenges for conventional treatment approaches,plagued by drug resistance and adverse side effects.Natural marine-derived compounds have gained prominence in melanoma research for their unique bioactivities and diversity.This review delves into the therapeutic potential of these compounds in melanoma treatment,emphasizing their distinctive advantages such as multi-target mechanisms and immune modulation,which distinguish them from traditional therapies.Additionally,we discuss the challenges in translating these agents into clinical applications,including formulation stability,bioavailability,and regulatory hurdles.Recent advancements in preclinical models such as organoids and completed clinical trials further support the exploration of marine-derived compounds in melanoma management.By consolidating current research,this review underscores the potential of these agents to enhance treatment efficacy and foster new therapeutic strategies.
基金Supported by the National Natural Science Foundation of China(No.82220108017,No.82141128,No.82101180)Beijing Natural Science Foundation(No.Z220012)+3 种基金The Capital Health Research and Development of Special(No.2020-1-2052)Science&Technology Project of Beijing Municipal Science&Technology Commission(No.Z201100005520045)Sanming Project of Medicine in Shenzhen(No.SZSM202311018)Beijing Science&Technology Development of TCM(No.BJZYYB-2023-17).
文摘AIM:To explore the relationship between matrix metalloproteinases(MMPs)expression levels in the tumor and the prognosis of uveal melanoma(UM)and to construct prognostic prediction models.METHODS:Transcriptome sequencing data from 17 normal choroid tissues and 53 UM tumor tissues were collected.Based on the differential gene expression levels and their function,MMPs family was selected for establishing risk-score system and prognostic prediction model with machine learning.Tumor microenvironment(TME)analysis was also applied for the impact of immune cell infiltration on prognosis of the disease.RESULTS:Eight MMPs were significantly different expression levels between normal and the tumor tissues.MMP-2 and MMP-28 were selected to construct a risk-score system and divided patients accordingly into high-and low-risk groups.The prediction model based on the risk-score achieved an accuracy of approximately 80%at 1-,3-,and 5-year after diagnosis.Besides,a Nomogram prognostic prediction model which based on risk-score and pathological type(independent prognostic factors after Cox regression analysis)demonstrated good consistency between the predicted outcomes at 1-,3-,and 5-year after diagnosis and the actual prognosis of patients.TME analysis revealed that the high-risk group exhibited higher immune and stromal scores and increased infiltration of tumor-associated macrophages(TAMs)and regulatory T cells compared to the low-risk group.CONCLUSION:Based on MMP-2 and MMP-28 expression levels,our prediction model demonstrates accurate long-term prognosis prediction for UM patients.The aggregation of TAMs and regulatory T cells in the TME of UM may be associated with an unfavorable prognosis.
基金supported by the European Union-Next Generation EU-PNRR M6C2-Investment 2.1 Enhancement and Strengthening of Biomedical Research in the NHS-Project:PNRR-MCNT2-2023-12377670(Grant No.CUP F93C24000250007).
文摘Melanoma,the most aggressive form of skin cancer,remains a significant clinical challenge due to the high metastatic potential and drug resistance.This review explores the pivotal roles of angiogenesis and vasculogenic mimicry in melanoma progression and treatment resistance.Angiogenesis,driven primarily by VEGF/VEGFR signaling,is critical for tumor sustenance but is often insufficient under hypoxic conditions,prompting melanoma cells to adapt by forming vascular-like structures(i.e.,vasculogenic mimicry).These structures enable melanoma cells to mimic endothelial functions and are linked to increased metastasis and poor prognosis.Molecular drivers,including VE-cadherin,EphA2,and hypoxia-inducible factors,have been identified as key regulators of these processes.Current anti-angiogenic agents have limited efficacy in advanced/metastatic melanoma due to tumor plasticity and the interplay between angiogenesis and vasculogenic mimicry.The review highlights the need for therapeutic strategies targeting both mechanisms,emphasizing the importance of combination treatments to overcome resistance.Future research should aim to elucidate the molecular underpinnings of angiogenesis and vasculogenic mimicry to improve melanoma management and patient outcomes.
文摘BACKGROUND Acute liver failure(ALF)due to diffuse hepatic infiltration by metastatic mela-noma is extremely rare and often misdiagnosed.In the absence of prior malig-nancy,this presentation can mimic other hepatic emergencies such as Budd-Chiari syndrome.Early identification is crucial,especially in transplant candidates,to prevent inappropriate management.CASE SUMMARY A 61-year-old male presented with jaundice,abdominal distension,and enceph-alopathy.Liver imaging suggested acute Budd-Chiari syndrome,and liver trans-plantation was considered.However,biopsy revealed extensive hepatic infilt-ration by human melanoma black-positive melanoma cells.There was no known can-cer history,although retrospective symptoms suggested uveal localization as a possi-ble primary site.The patient rapidly deteriorated and died.A review of 12 simi-lar cases revealed shared diagnostic challenges,frequent misdiagnoses,and poor outcomes.CONCLUSION Infiltrative melanoma should be considered in unexplained ALF,even without previously known malignancy.
基金supported by the Natural Science Foundation Project of Fujian Province(2021J011307).
文摘Background:To investigate the effects of Astragalus polysaccharides(APS)on melanoma-bearing mice via the Janus kinase 2(JAK2)/signal transducer and activator of transcription 3(STAT3)signaling pathway.Methods:Fifty male C57BL/6 mice were randomly divided into five groups:model group,positive control group,APS low-dose group,APS middle-dose group,and APS high-dose group(10 mice per group).B16 cell-bearing melanoma mouse models were established in all groups.The low,middle,and high-dose APS groups received daily injections of APS solution at 20,40,and 80 mg/kg,respectively.Spleen and thymus indices were measured,tumor volumes were observed,and tumor inhibition rates were calculated.Tumor histopathological changes were examined via H&E staining.Ki67 and PCNA expression in tumor tissues were assessed via immunofluorescence staining and Western blot analysis RT-qPCR.Western blot was used to examine the expression of JAK2/STAT3 signaling pathway-related factors in tumor tissues.Results:APS significantly increased the spleen and thymus indices in melanoma mice and inhibited tumor growth.H&E staining revealed that APS significantly reduced the number of tumor cells in melanoma mice.Immunofluorescence results indicated that APS significantly decreased Ki67-positive expression in tumor tissues,while Western blot results showed that APS significantly reduced PCNA protein expression in tumor tissues.RT-qPCR and Western blot results indicated that APS significantly suppressed the expression of JAK2/STAT3 signaling pathway-related genes and proteins.Conclusion:APS may inhibit tumor growth in a melanoma mouse model by enhancing immune function through suppression of the JAK2/STAT3 signaling pathway.
文摘Objectives:Among cutaneous malignancies,melanoma stands out for its particularly aggressive nature,with therapeutic interventions becoming notably limited once the disease progresses.In this research,we investigate the tumor-suppressing capabilities of water-extracted Korean mistletoe(Viscum album var.coloratum)and its purified lectin component(V.album var.coloratum agglutinin,VCA)using two distinct mouse melanoma models:B16BL6 and B16F10 cell lines.Methods:The impact of water extract and VCA treatments on melanoma cells was assessed through multiple experimental approaches,examining cellular survival rates,programmed cell death pathways,multicaspase activity,and cell cycle distribution patterns.To elucidate the interconnections among various cellular responses,we employed a suite of statistical techniques encompassing correlation studies,principal component analysis(PCA)-based dimensionality reduction,and dendrogram-based clusteringmethodologies.Results:Thewater extract exhibited dosedependent cytotoxicity with IC50 values of 372.3±8.7μg/mL and 202.5±8.4μg/mL for B16BL6 and B16F10 cells,respectively.VCA showed more significant effects,with IC50 values of 0.1992±0.0041 and 0.1981±0.0098μg/mL for B16BL6 and B16F10 cells,respectively.Both agents induced substantial apoptosis with a significant progression from early to late apoptotic stages,reaching up to 59.4%total apoptotic cells for VCA treatment.This was confirmed by strong multicaspase activation,particularly in VCA-treated cells(up to 88.4%caspase-positive cells).The water extract showed modest effects on cell cycle distribution,with increases in G0/G1 phase(74.6%)in B16BL6 cells and S phase(19.2%)in B16F10 cells,while VCA treatment resulted in G2/M phase reduction(10.0%)in B16F10 cells.Correlation analysis revealed strong negative associations between cell viability and caspase activity(r=−0.843 to−0.878),while hierarchical clustering demonstrated distinct response patterns between low and high concentrations of both agents.Effect size analysis confirmed strong treatment impacts on cell viability(d=−5.89 to−6.12)and caspase activation(d=3.45 to 5.23).Conclusion:These findings suggest that Korean mistletoe water extract and its isolated lectin may affect both primary and metastatic melanoma cells through distinct mechanisms,demonstrating particular potency in caspase-dependent apoptosis induction.Our findings establish a robust foundation for developing novel therapeutic interventions derived from natural compounds to combat malignant melanoma with high metastatic potential.
文摘Malignant melanoma,characterized by its high metastatic potential and resistance to conventional therapies,presents a major challenge in oncology.This review explores the current status and advancements in tumor vaccines for melanoma,focusing on peptide,DNA/RNA,dendritic cell,tumor cell,and neoantigen-based vaccines.Despite promising results,significant challenges remain,including the immunosuppressive tumor microenvironment,patient heterogeneity,and the need for more effective antigen presentation.Recent strategies,such as combining vaccines with immune checkpoint inhibitors(ICIs),aim to counteract immune evasion and enhance T cell responses.Emerging approaches,including personalized neoantigen vaccines and the use of self-amplifying RNA platforms,hold promise for overcoming tumor heterogeneity and improving vaccine efficacy.Additionally,optimizing vaccine delivery systems through nanotechnology and genetic modifications is essential for increasing stability and scalability.This review highlights the potential of these innovative strategies to address current limitations,with a focus on how future research can refine and combine these approaches to improve melanoma treatment outcomes.
基金supported by the Macao Science and Technology Development Fund (FDCT 0148/2022/A3 and 0019/2024/RIA1)the National Natural Science Foundation of China (No. 81572979)
文摘Immunotherapy with interleukin-2(IL-2)in treating cancers is subject to several limitations such as systemic side effects and reduced efficacy against tumors with low immune cell infiltration despite its promise.To address these challenges,IL-2-So-Lipo,a novel liposomal formulation combining IL-2 with sorafenib derivative,was developed as an anti-angiogenic drug that inhibits the growth of new blood vessels which play crucial roles in tumor growth.Sorafenib derivatives could target at melanoma-specific receptors,further enhancing liposomal specificity at the tumor site.Our results demonstrated that the prepared IL-2-So-Lipo significantly enhanced anti-tumor activity compared to IL-2 or sorafenib monotherapies,as well as their combination.In a B16F10 melanoma model,IL-2-So-Lipo was found to significantly inhibit tumor progression(tumor volume of 108.01±62.99 mm^(3))compared to the control group(tumor volume of 1,397.13±75.55 mm^(3)),improving the therapeutic efficacy.This enhanced efficacy is attributed to the targeted delivery of IL-2 which promoted the infiltration and activation of cytotoxic T lymphocytes.Additionally,liposomal encapsulation of sorafenib derivatives enhanced its delivery efficiency,promoting tumor cell apoptosis and suppressing angiogenesis.Mechanistically,IL-2-So-Lipo could kill tumors by inducing a shift towards an anti-tumor immune response via facilitating the polarization of macrophages towards the M1 phenotype.Furthermore,IL-2-So-Lipo downregulated several key proteins in the MAPK signaling pathway,exerting a significant role in mediating tumor resistance to sorafenib.These findings underscore the potential of IL-2-So-Lipo as a promising strategy to improve the therapeutic efficacy of immunotherapy and targeted therapy in cancers.Moreover,the combination of IL-2 and sorafenib in a liposomal delivery system overcame the limitations of conventional IL-2 therapy,offering a synergistic approach to improve therapeutic outcomes for solid tumors.
基金Supported by the Science and Technology SMEs Innovation Capacity Improvement Project of Shandong Province,No.2022TSGC1004National Key R&D Program of China,No.2021YFA1101502。
文摘BACKGROUND Mesenchymal stromal cells(MSCs)are renowned for their immunosuppressive properties,which make them widely used in managing excessive inflammation.Although CD146+and CD146-MSCs exhibit similar morphological traits and surface marker expression levels,the specific characteristics and differential regulatory mechanisms of these two subtypes remain poorly understood.This knowledge gap has limited the precise application of MSCs in targeted thera-peutic strategies.AIM To compare the functional differences between CD146+and CD146-MSCs and investigate the underlying mechanisms.METHODS In this study,magnetic beads were used to sort umbilical cord-derived MSCs into CD146+and CD146-subsets.The pro-angiogenic factors(hepatocyte growth factor,prostaglandin E2,vascular endothelial growth factor,angiopoietin-1)production and immunomodulatory effects on T lymphocyte subsets were evaluated in vitro.The therapeutic efficacy was assessed in an acute respiratory distress syndrome(ARDS)mouse model via tail vein injection.RESULTS Cytokine secretion and angiogenesis:CD146+MSCs significantly increased the production of hepatocyte growth factor,prostaglandin E2,vascular endothelial growth factor,and angiopoietin-1 and exhibited increased pro-angiogenic activity in vitro.Immunomodulatory effects:CD146+MSCs potently inhibited the differentiation and proliferation of pro-inflammatory T helper type 1/T helper type 17 cells while promoting the expansion of regulatory T cells during T lymphocyte activation.ARDS therapy:In a mouse ARDS model,compared with CD146-MSCs,CD146+MSCs demonstrated superior therapeutic efficacy,as evidenced by improved clinical scores.Mechanistically,CD146+MSCs activated the nuclear factor kappa B pathway,upregulated cyclooxygenase 2 expression,and facilitated damaged epithelial cell repair.CONCLUSION CD146+MSCs show stronger ARDS therapeutic potential than CD146-MSCs via pro-angiogenic/immunomodulatory traits.Nuclear factor kappa B/cyclooxygenase 2 activation aids epithelial repair,highlighting CD146+MSCs as promising targets.
基金Supported by the National Natural Science Foundation of China(No.81873345,No.82274585)Qingdao Key Health Discipline Development Fund.
文摘AIM:To investigate the role of Forkhead box protein P3(FOXP3)in choroidal melanoma(CM)metastases and elucidate its underlying mechanisms.METHODS:FOXP3 protein expression was analyzed in CM clinical specimens and cell lines.A stable FOXP3 knockout cell line and a transient FOXP3-overexpressing cell line were established,with transfection efficiencies confirmed by Western blotting(WB).Functional assays,including monoclonal formation,cell counting kit-8(CCK-8)proliferation,migration,invasion,and in vivo tumorigenesis assays in nude mice,were performed to assess the biological effects of FOXP3.Additionally,WB was employed to evaluate epithelial-mesenchymal transition(EMT)markers and the activation of the Wnt5a/CaMKII signaling pathway.RESULTS:FOXP3 expression was significantly elevated in both CM clinical specimens and cell lines.Functional analyses revealed that FOXP3 enhanced CM cell proliferation,migration,and invasion in vitro and promoted tumorigenesis in vivo.Mechanistically,FOXP3 upregulated EMT-related proteins and activated the Wnt5a/CaMKII signaling pathway.Rescue experiments further confirmed that the oncogenic effects of FOXP3 were mediated via modulation of the Wnt5a/CaMKII axis.CONCLUSION:This study identifies FOXP3 as an oncogenic driver in CM,promoting tumor progression through the Wnt5a/CaMKII signaling pathway.These findings provide new insights into the molecular mechanisms of CM pathogenesis and highlight FOXP3 as a potential therapeutic target.
基金supported by CAMS Innovation Fund for Medical Sciences(CIFMS)(2024-I2M-C&T-B-089)National Key Research and Development Program(2022YFC2504700,2022YFC2504701,2022YFC2504705)National Natural Science Foundation of China(NSFC81872216).
文摘Introduction:Acral melanoma(AM)is the predominant subtype of cutaneous melanoma in Asian populations,characterized by more aggressive clinical features and limited neoadjuvant therapy response.Centrosomal protein 55 kDa(CEP55)has been implicated in the pathogenesis of various malignancies,but its role in AM remains undefined.Methods:CEP55 expression in melanoma tissues and cell lines was analyzed by RT-qPCR,Western blotting,and immunohistochemistry(IHC).Databases(GEPIA,Sangerbox,Kaplan-Meier plotter,and TIMER)were used to analyze the expression of CEP55 and its correlation with clinical data of melanoma patients.Functional assays were conducted in vitro and in vivo.RNA sequencing(RNA-seq)and rescue experiments were used to explore underlying mechanisms.Tissue microarrays were used to verify the relationship between CEP55 and immune checkpoints.Results:CEP55 overexpression is associated with Breslow thickness and TNM stage in melanoma tissues and cell lines.CEP55 knockdown inhibited melanoma cell proliferation,migration,and invasion.And CEP55 activated mitogen-activated protein kinase(MAPK)signaling,leading to BRAF inhibitor resistance.Besides,CEP55 overexpression was associated with more favorable responses to immunotherapy in melanoma patients.Conclusions:CEP55 plays a critical role in AM progression and immunotherapy.Targeting CEP55 may be a promising therapeutic strategy for AM.
