Introduction,Breast cancer is the most common cancer type in adolescents and young adults<40 years of age,accounting for 30%of cancers in this age group1.Breast cancer in the young presents significant challenges f...Introduction,Breast cancer is the most common cancer type in adolescents and young adults<40 years of age,accounting for 30%of cancers in this age group1.Breast cancer in the young presents significant challenges for patients and society,including more aggressive tumor biology,poor prognosis,genetic susceptibility,fertility preservation,and complex psychosocial issues.Moreover,because of the markedly younger median age of breast cancer,the proportion of young breast cancer patients in China is significantly higher than Western countries2.The first Young Breast Cancer in China(YBCC)consensus meeting was held in Guangzhou,China in December 2021 to address exclusive challenges and requirements facing young patients with breast cancer.Chinese medical experts from multiple specialties had an extensive discussion and formulated a consensus over several hot topics in young patients with breast cancer.The“Expert Consensus on the Diagnosis and Treatment of Young Breast Cancer in China(2022 edition)”published in the Chinese Medical Journal has garnered significant attention3,highlighting enormous interest in the YBCC consensus in the medical community and public.展开更多
Background:In clinical practice,approximately 80%of prostate cancer(PC)cases are localized and can achieve favorable outcomes with appropriate treatment.Conversely,some remaining cases exhibit an aggressive phenotype ...Background:In clinical practice,approximately 80%of prostate cancer(PC)cases are localized and can achieve favorable outcomes with appropriate treatment.Conversely,some remaining cases exhibit an aggressive phenotype or develop resistance to therapeutic interventions,leading to tumor metastasis and a poorer prognosis.When PC metastasizes to distant sites,the bone remains the predominant location,and brain metastases are regarded as exceedingly rare.Case Description:The current study focused on a rare clinical PC case that presented multiple brain metastases after prostate surgery.The patient was initially diagnosed with PC through prostate biopsy and subsequently underwent prostate debulking surgery while continuing androgen deprivation therapy,which maintained low prostatespecific antigen(PSA)levels for 4 years.However,a sudden PSA surge to 7.858 ng/mL led to the emergence of two brain metastatic tumors,which were confirmed to have originated from the prostate.Conclusions:Patients with advanced PC require comprehensive evaluations to detect rare metastatic sites,such as the brain,to avoid missed diagnoses.For patients with brain metastases,a multimodal approach combining surgical resection,postoperative radiotherapy,and endocrine therapy can effectively alleviate symptoms and enhance survival.展开更多
Background Neuroendocrine prostate cancer(NEPC)is an aggressive subtype of castration-resistant prostate cancer(CRPC)that is typically resistant to nearly all current therapies.Methods In this study,single-cell RNA se...Background Neuroendocrine prostate cancer(NEPC)is an aggressive subtype of castration-resistant prostate cancer(CRPC)that is typically resistant to nearly all current therapies.Methods In this study,single-cell RNA sequencing(scRNA-seq)and bioinformatic analysis identified centrosomal protein 55(CEP55)as a critical factor in the transformation from hormone-sensitive prostate cancer(HSPC)to CRPC and,ultimately to,NEPC.Results Subsequent bioinformatics analyses and clinical sample validation showed that CEP55 is significantly upregulated in NEPC tissues relative to HSPC and CRPC.Furthermore,while CEP55 show no significant association with the immune microenvironment or cancer-associated fibroblasts(CAFs),our findings indicated that it directly mediates the plasticity of prostate cancer cells,thereby driving NEPC progression.Specifically,in vivo and in vitro experiments confirmed that CEP55 enhances cell proliferation,migration,invasion and the expression of NEPC biomarkers in prostate cancer.Importantly,although cisplatin is the primary treatment for NEPC clinically,CEP55 has been shown to regulate cisplatin resistance through the phosphorylation of cyclin-dependent kinase 1(CDK1)at the tyrosine 15(Tyr15)site.Conclusions In summary,our study identifies a key gene that influences the neuroendocrine differentiation process in prostate cancer,suggesting its potential as an important therapeutic target.展开更多
Breast cancer(BC)remains the most frequently diagnosed malignancy worldwide,with an estimated 2.3 million new cases and approximately 685,000 deaths reported in 2020.Forecasts suggest a substantial rise in global inci...Breast cancer(BC)remains the most frequently diagnosed malignancy worldwide,with an estimated 2.3 million new cases and approximately 685,000 deaths reported in 2020.Forecasts suggest a substantial rise in global incidence,with new annual cases projected to reach 3.2 million by 2050,representing a 39%increase.Additionally,BC is expected to account for approximately 7.7%of the anticipated$25.2 trillion global economic burden associated with cancer by 2050.These trends underscore an urgent need for affordable,widely accessible and effective therapeutic strategies,particularly in low-and middle-income countries.Statins,commonly prescribed for the treatment of hypercholesterolaemia via inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A(HMG-CoA)reductase,have garnered increasing interest for their potential anticancer properties.This review focuses on the mechanistic underpinnings and therapeutic implications of statin use,particularly simvastatin,in the context of BC.Statins exert their primary effect through inhibition of the mevalonate pathway,which is crucial for cholesterol and isoprenoid biosynthesis.Disruption of this pathway impairs the prenylation of key signalling proteins,including members of the Ras and Rho GTPase families,which are essential for cancer cell proliferation,survival and metastasis.Preclinical evidence has demonstrated that simvastatin can induce tumour cell apoptosis,arrest cell-cycle progression and inhibit oncogenic signalling pathways.These effects have been particularly pronounced in hormone receptor-negative and triple-negative breast cancer(TNBC)subtypes,which are often associated with poor prognosis and limited treatment options.Epidemiological and observational studies further support a potential association between statin use and reduced BC recurrence and mortality.Nevertheless,robust evidence from randomised controlled trials remains limited,and further investigation is required to establish causality and define optimal therapeutic regimens.Given their well-established safety profile,global accessibility and pleiotropic effects,statins,especially simvastatin,represent a promising class of repurposed drugs in the adjuvant treatment of BC.This review synthesises evidence from the past two decades,highlighting the need for continued clinical research to validate and optimise the use of statins as adjunctive agents in BC therapy.展开更多
Cancer pain is one of the most prevalent and debilitating symptoms in patients with advanced malignancies,arising from multifactorial mechanisms involving peripheral,central,and systemic pathways.Conventional analgesi...Cancer pain is one of the most prevalent and debilitating symptoms in patients with advanced malignancies,arising from multifactorial mechanisms involving peripheral,central,and systemic pathways.Conventional analgesics,including opioids and nonsteroidal anti-inflammatory drugs,are often limited by their insufficient efficacy,tolerance,and risk of dependence.Traditional Chinese Medicine(TCM),characterized by its multi-component,multi-target,and systemic regulatory properties,has shown promising potential in cancer pain management.This review provides a comprehensive overview of the clinical classification and underlying mechanisms of cancer pain(including nerve infiltration,dysregulation of inflammatory mediators and ion channels,central sensitization,neuro-immune crosstalk,metabolic reprogramming,and gut-brain axis impairment),as well as the analgesic effects of representative TCM agents in cancer pain management.For example,bioactive components such as tetrahydroberberine,levo-tetrahydropalmatine,and piperine exert analgesic effects,thereby improving the quality of life of patients by inhibiting inflammatory cascades,regulating neurotransmitter systems,and preserving neural integrity.Commonly used preclinical models,including bone cancer pain,pancreatic cancer pain,and chemotherapy-induced peripheral neuropathy models,are summarized for their utility in mechanistic studies and efficacy evaluations.This review also discusses the current limitations of clinical evidence,such as small sample sizes,short follow-up periods,and limited translation from animal models,alongside major challenges in standardization,mechanistic elucidation,and clinical trial design.Future directions should focus on precise pain phenotyping,integrated multi-target interventions,rigorous efficacy safety validation,and innovations in drug delivery to facilitate the standardization and global adoption of TCM in cancer pain management.展开更多
Lung cancer is the most common but fatal malignant tumor worldwide.Patients with lung cancer experienced a relatively low 5-year overall survival rate,and issues such as metastasis and drug resistance remain prominent...Lung cancer is the most common but fatal malignant tumor worldwide.Patients with lung cancer experienced a relatively low 5-year overall survival rate,and issues such as metastasis and drug resistance remain prominent challenges in its clinical management.Neddylation,a novel type of post-translational modification,was overactivated in lung cancer and was closely associated with its occurrence,development,metastasis,and drug resistance.This review systematically summarizes the biological process of neddylation and deeply explores the latest research progress on how neddylation affects lung cancer cell proliferation,metastasis,and drug resistance mechanisms,with a focus on its regulation of key molecules such as Cullin-RING E3 ligases and the SCCRO family.Meanwhile,it concludes the current advances in potential therapeutic agents targeting neddylation-related targets,including small-molecule compounds(such as Pevonedistat)and natural extracts(such as arctigenin).Finally,the review prospectively evaluates the application potential and questions requiring further exploration of neddylation in lung cancer treatment.In conclusion,we aim to systematically summarize the biological process of neddylation,critically explore its roles in lung cancer proliferation,metastasis,and drug resistance,and evaluate the therapeutic potential of neddylation-targeting agents.展开更多
BACKGROUND Gastric cancer(GC)is one of the most common malignant tumors of the digestive system worldwide,the prognosis of patients with advanced GC remains poor.AIM To evaluate the combined expression characteristics...BACKGROUND Gastric cancer(GC)is one of the most common malignant tumors of the digestive system worldwide,the prognosis of patients with advanced GC remains poor.AIM To evaluate the combined expression characteristics of cancer stem cell markers CD24 and CD133 in GC pathological tissues,and to explore their association with patients’clinicopathological parameters and postoperative survival outcomes.METHODS A total of 304 GC patients who underwent surgical treatment in our hospital from January 2018 to January 2020 were retrospectively included.Immunohistochemistry was used to detect the protein expression of CD24 and CD133 in tumor tissues,adjacent tissues,and normal gastric mucosa tissues.Based on staining intensity and the proportion of positive cells,expression levels were classified into low and high expression,while clinicopathological parameters were recorded.χ2 test was used to evaluate the correlation between expression and categorical variables,Spearman rank correlation analysis was performed to assess the correlation between the expression intensities of the two markers,and multivariate regression models were applied to identify independent risk factors influencing co-expression.Kaplan-Meier survival curves and Log-rank test were used to compare survival differences among groups with different expression patterns.RESULTS Among the 304 patients,155 cases(50.99%)were CD24 positive,including 91 low-expression and 64 highexpression;133 cases(43.75%)were CD133 positive,including 81 low-expression and 52 high-expression.There were 74 cases(24.34%)with double positivity and 81 cases(26.64%)with double negativity.Compared with tumor tissues,the positive rates of CD24 and CD133 in normal gastric tissues and adjacent tissues were significantly lower(P<0.05).Univariate analysis showed that co-expression of CD24 and CD133 in GC tissues was significantly correlated with tumor size,Lauren classification,T stage,N stage,and vascular invasion(P<0.05),but not with patient age,gender,tumor site,World Health Organization histological classification,or M stage(P>0.05).Further multivariate regression analysis suggested that tumor size,T stage,N stage,and vascular invasion were independent risk factors promoting CD24 and CD133 double positivity.Spearman rank correlation analysis indicated a moderate positive correlation between their expression intensities(r=0.420,P<0.001).During follow-up,29 of 304 patients were lost(loss rate 9.54%);146 deaths occurred.According to expression combination,there were 89 cases of CD24 single positivity(39 deaths),68 cases of CD133 single positivity(31 deaths),81 cases of double negativity(25 deaths),and 66 cases of double positivity(51 deaths).Log-rank test showed significant differences in overall survival among the four groups(χ2=20.89,P<0.001),with CD24+/CD133+group showing the worst prognosis.CONCLUSION CD24 and CD133 exhibit high positive detection rates in GC tissues,and their co-positivity is closely associated with tumor stage progression and significantly indicates unfavorable survival outcomes.The co-expression of CD24/CD133 may reflect higher aggressiveness and metastatic potential of GC,serving as a potential prognostic marker and a direction for targeted therapeutic strategies.However,as this is a single-center retrospective study with limitations such as patient loss to follow-up and sample size,further prospective,multicenter,and mechanistic studies are required to validate its clinical applicability and biological role.展开更多
Colorectal cancer remains one of the leading causes of morbidity and mortality worldwide.Despite notable advances in early detection and therapeutic strategies,the molecular mechanisms underlying tumor survival,chemot...Colorectal cancer remains one of the leading causes of morbidity and mortality worldwide.Despite notable advances in early detection and therapeutic strategies,the molecular mechanisms underlying tumor survival,chemotherapy resistance,and metastasis are not yet fully understood.MicroRNAs(miRNAs)have emerged as pivotal regulators of cancer development,as they modulate gene expression and orchestrate key signaling pathways.However,the epigenetic mechanisms that control miRNA expression and their downstream gene targets remain largely unclear.In this review,we highlight the critical role of the colorectal cancer microenvironment in influencing miRNA expression and discuss how this regulation contributes to tumorigenesis.A better understanding of these processes may lead to the identification of novel therapeutic targets and strategies to prevent recurrence.展开更多
Objective:This study aimed to evaluate the associations of baseline income,cumulative income exposure,and income volatility with the incidence of pancreatic and biliary tract cancers in a nationwide Korean cohort.Meth...Objective:This study aimed to evaluate the associations of baseline income,cumulative income exposure,and income volatility with the incidence of pancreatic and biliary tract cancers in a nationwide Korean cohort.Methods:We analyzed 3,361,091 adults aged 30-65 years who underwent the 2012 National Health Insurance Service(NHIS)health screening.Income level was derived from insurance premium data assessed over the five years preceding baseline(2008-2012)and categorized into baseline income quartiles,cumulative exposure to low or high income,and income volatility based on annual percentage changes.Incident pancreatic and biliary tract cancers were identified using diagnostic codes and the copayment reduction registry.Associations were evaluated using Cox proportional hazards models with adjustment for demographic,lifestyle,and clinical covariates,and cumulative incidence was compared using Kaplan-Meier curves.Results:During a median follow-up of 9.6 years,14,469 pancreatic cancers and 6,647 biliary tract cancers were newly diagnosed.Lower baseline income was associated with a higher risk of pancreatic and biliary tract cancers,whereas sustained high-income exposure was associated with reduced risk.Cumulative low-income exposure showed a positive linear trend with pancreatic cancer incidence.Income volatility was modestly associated with pancreatic cancer and was positively associated with biliary tract cancer in the fully adjusted model.These associations were generally consistent across subgroups,with a stronger inverse association between prolonged high-income exposure and pancreatic cancer among individuals without diabetes.Conclusions:Income level and income stability were significantly associated with the incidence of pancreatic and biliary tract cancers.Lower baseline income was associated with higher risk,whereas sustained high-income exposure was protective.Income volatility was associated with increased cancer risk,particularly for biliary tract cancer.These findings highlight the importance of incorporating income dynamics into cancer prevention strategies and addressing socioeconomic instability among vulnerable populations.展开更多
Breast cancer remains a global health challenge with greater than 2.3 million new cases diagnosed annually 1,according to the World Health Organization1.Management of breast cancer is shaped by a complex interplay of ...Breast cancer remains a global health challenge with greater than 2.3 million new cases diagnosed annually 1,according to the World Health Organization1.Management of breast cancer is shaped by a complex interplay of international guidelines,regional adaptations,and the rapidly evolving fields of precision medicine and artificial intelligence(AI).展开更多
Primary liver cancer (PLC) is a major global healthchallenge, ranking as the sixth most common andthird most fatal malignancy worldwide, according toGLOBOCAN 2022 estimates[1]. This high mortalityrate underscores the ...Primary liver cancer (PLC) is a major global healthchallenge, ranking as the sixth most common andthird most fatal malignancy worldwide, according toGLOBOCAN 2022 estimates[1]. This high mortalityrate underscores the aggressive nature of thedisease and the significant burden it places on globalhealthcare systems. Although primary preventionremains the cornerstone of liver cancer control,improving outcomes for patients already diagnosedis equally critical for mitigating the impact of thedisease.展开更多
Realistic models for cancer research representing disease progression that commensurately respond to therapeutics consistent with clinical observation are the holy grail for pre-clinical research and screening.Althoug...Realistic models for cancer research representing disease progression that commensurately respond to therapeutics consistent with clinical observation are the holy grail for pre-clinical research and screening.Although such an ideal is elusive,well-characterized in vivo models facilitate our understanding of disease,progression,and therapeutic opportunities.Here,we characterize a commonly used syngeneic BALB/c mouse model of triple negative breast cancer(4T1)after establishing tumors in their flanks.Tumors developed at the subcutaneous injection site for all experimental mice and their volumes were monitored.We quantified a rare subset of breast cancer stemlike cells(CSCs),classified as CD44^(+)/CD24^(−)phenotypes in in vitro and ex vivo cell populations.Chromosome numbers in ex vivo metaphase cells were greater than cells cultured in vitro(89.4±3.4,range of 70-132 and 82.6±1.1,range of 70-128;respectively).Further,we observed different types of chromosome aberrations,including gap,deletion,exchange,interstitial deletion,terminal deletion,ring,dicentric,and Robertsonian translocations.For both sources of cells,the number of aberrations was dominated by deletions,terminal deletions,and Robertsonian translocations.Ex vivo cells exhibited greater prevalence of deletions and terminal deletions,whereas in vitro cells displayed more ring aberrations and Robertsonian translocations.In conclusion,we successfully characterized cancer cells from a syngeneic mouse model of breast cancer in terms of rare CSC proportion and a variety of chromosomal aberrations,which is useful for understanding tumor traits associated with cancer development and therapeutic action.The data act as a valuable resource for other studies using the 4T1 BALB/c model.展开更多
Hepatocellular carcinoma(HCC)is a pressing global health problem and is the sixth most common cancer and the third leading cause of cancer mortality worldwide.Despite continuous advances in treatment modalities,the 5-...Hepatocellular carcinoma(HCC)is a pressing global health problem and is the sixth most common cancer and the third leading cause of cancer mortality worldwide.Despite continuous advances in treatment modalities,the 5-year survival rate is low with a high propensity for recurrence and metastasis1.This clinical challenge in treating HCC is largely attributed to the heterogeneity and intrinsic therapy resistance of cancer stem cells(CSCs),which are a subpopulation of cells with self-renewal capability and multidirectional differentiation potential to induce tumorigenicity2.The behavior and maintenance of CSCs are not autonomous but critically dependent on the complex bidirectional crosstalk between CSCs and the tumor immune microenvironment(TIME)1.In this review we first summarize the recent progress in characterizing CSCs and the interactions between CSCs and the TIME in HCC.Next,we discuss the emerging therapeutic strategies targeting CSC populations with the ongoing challenges.Finally,we give our perspectives on the future directions in HCC CSC research.展开更多
BACKGROUNDCancer stem cells(CSCs)drive recurrence and therapeutic resistance in triplenegativebreast cancer(TNBC),a highly aggressive breast cancer subtype.Intratumoralhypoxia,a common feature of solid tumors,promotes...BACKGROUNDCancer stem cells(CSCs)drive recurrence and therapeutic resistance in triplenegativebreast cancer(TNBC),a highly aggressive breast cancer subtype.Intratumoralhypoxia,a common feature of solid tumors,promotes CSCs enrichment,yet the mechanisms sustaining CSCs stemness remain poorly understood.Hypoxia-induced reactive oxygen species can oxidatively activate ataxia telangiectasiamutated(ATM)kinase(oxidized ATM,p-ATM)independently of DNA breaks.AIMTo investigate the role of hypoxia-induced oxidized ATM in sustaining TNBCCSCstemness through c-Myc-mediated regulation of one-carbon metabolism.METHODSHs578T and MDA-MB-231 TNBC cells were cultured under normoxia or hypoxia.CSC stemness was assessed by mammosphere assays and flow cytometry.ATMactivity was assessed by pharmacological inhibition(Ku60019)and short hairpinRNA knockdown.c-Myc binding to serine hydroxymethyltransferase 2(SHMT2)and methylenetetrahydrofolate dehydrogenase 2(MTHFD2)promoters was analyzedby dual-luciferase reporter assays and chromatin immunoprecipitation.NADPH/NADP+ratios were quantified,and metabolic reprogramming was profiledby liquid chromatography-tandem mass spectrometry metabolomics.RESULTSHypoxia significantly increased mammosphere formation in both Hs578T and MDA-MB-231 cells,as reflected byhigher numbers of mammospheres(Hs578T:214±18;MDA-MB-231:198±16;both P<0.01)and larger meandiameters(P<0.01).Hypoxia also elevated CD44+/CD24-cell proportions and stemness gene expression(P<0.01).Oxidized ATM was activated under hypoxia withoutγH2AX induction,confirming DNA damage independence.ATM inhibition reduced mammosphere growth and suppressed c-Myc,SHMT2,and MTHFD2.Luciferase and chromatin immunoprecipitation assays confirmed direct c-Myc binding to SHMT2 and MTHFD2promoters,while mutation of the binding sites abolished promoter activity.NADPH/NADP+ratios were significantlyelevated under hypoxia but reduced following ATM inhibition(P<0.05).Metabolomics revealed enrichmentof serine/glycine one-carbon pathways.CONCLUSIONHypoxia-induced oxidized ATM maintains TNBC-CSC stemness by promoting c-Myc-dependent upregulation ofMTHFD2 and SHMT2,linking hypoxia,redox signaling,and one-carbon metabolism.These findings suggest apotential therapeutic axis that could be exploited for TNBC treatment.展开更多
Background:Minimally invasive distal pancreatectomy(MIDP)is increasingly being used,although its oncologic safety for pancreatic ductal adenocarcinoma(PDAC)remains controversial.In Japan,MIDP for PDAC has limited endo...Background:Minimally invasive distal pancreatectomy(MIDP)is increasingly being used,although its oncologic safety for pancreatic ductal adenocarcinoma(PDAC)remains controversial.In Japan,MIDP for PDAC has limited endorsement due to insufficient data.This study aimed to compare the perioperative and long-term outcomes of open distal pancreatectomy(ODP)and MIDP for PDAC.Methods:We retrospectively analyzed patients with resectable pancreatic body and tail cancer treated with ODP or MIDP(laparoscopic or robotic)between January 2007 and July 2022.The surgical procedures(ODP and MIDP)were compared and the patient characteristics,perioperative outcomes,and long-term outcomes were analyzed.We also compared the outcomes of patients with neoadjuvant chemotherapy(NAC)and without NAC.Results:A total of 72 distal pancreatectomies were performed(37 ODPs and 35 MIDPs).In the upfront group,MIDP resulted in significantly less blood loss than ODP(P<0.01),despite similar operative time.There was no statistically significant difference in the 2-year recurrence-free survival(RFS)rates between ODP and MIDP(39.7%vs.57.8%,P=0.60)or in the overall survival(OS)rates(66.7%vs.74.1%,P=0.43).Similarly,in the NAC group,MIDP resulted in significantly less blood loss than ODP(P=0.01);ODP and MIDP had similar 2-year RFS rates(41.7%and 60.0%,P=0.75)and OS rates(50.0%and 70.0%,P=0.36).The interval from surgery to adjuvant chemotherapy initiation did not significantly differ between the ODP and MIDP subgroups in both the upfront group(P=0.13)and the NAC group(P=0.14).The incidence of recurrence was 64.8%for ODP and 42.8%for MIDP(P=0.06).Both procedures showed similar distributions of local and distant recurrence.Conclusions:MIDP caused less blood loss and had similar oncologic safety compared with ODP.MIDP could become a feasible,minimally invasive option with sufficient oncologic safety for pancreatic body and tail cancers.展开更多
The landscape of breast cancer treatment has undergone a transformative shift with the integration of immunotherapy.Historically considered a“cold”tumor with limited immunogenicity,breast cancer management was domin...The landscape of breast cancer treatment has undergone a transformative shift with the integration of immunotherapy.Historically considered a“cold”tumor with limited immunogenicity,breast cancer management was dominated by surgery,chemotherapy,radiotherapy,and targeted therapies1.However,the advent of immune checkpoint inhibitors(ICIs)has challenged this paradigm,opening a new frontier.The initial breakthrough in triple-negative breast cancer(TNBC)demonstrated that a subset of patients could derive profound and durable clinical benefit from pembrolizumab and atezolizumab2,3.Today,precision immunotherapy aims to identify the patients most likely to respond,to convert immunologically silent tumors into responsive tumors,and to strategically combine immunotherapies with other modalities to overcome resistance.This evolution from empirical application to biomarker-driven strategies marks the critical juncture at which we stand,transitioning promising clinical trial data into refined,effective,and accessible clinical practice4.Recent key clinical studies on breast cancer immunotherapy are summarized in Table 1.展开更多
Objectives:Tamoxifen is a key drug that provides endocrine therapy for estrogen receptor(ER)α-positive breast cancer;however,resistance remains a significant clinical challenge.This study aims to investigate the mole...Objectives:Tamoxifen is a key drug that provides endocrine therapy for estrogen receptor(ER)α-positive breast cancer;however,resistance remains a significant clinical challenge.This study aims to investigate the molecular mechanisms of tamoxifen resistance in ERα-positive breast cancer,with particular focus on the role of SET Domain Containing 1A(SETD1A)-driven forkhead box A2(FOXA2)as a key regulator of this resistance.Methods:FOXA2 expression and its regulation by SETD1A were assessed via(quantitative polymerase chain reaction),western blotting,transcriptome profiling,and chromatin immunoprecipitation analyses.The effects of FOXA2 on cell proliferation,migration,invasion,and cancer stem cell traits were evaluated using small interfering RNA(siRNA)-mediated silencing.Clinical relevance was examined by analyzing patient datasets and tumor tissue microarrays.Results:FOXA2 expression was significantly elevated in tamoxifen-resistant(TamR)and ERα-negative breast cancer cells compared to that in ERα-positive MCF-7 cells,regardless of tamoxifen treatment or ERαdepletion.Transcriptome and chromatin immunoprecipitation analyses revealed that SETD1A,a histone methyltransferase,directly regulated FOXA2 expression.Functionally,FOXA2 knockdown inhibited the proliferation,migration,invasion,and cancer stem cell properties of TamR cells while restoring tamoxifen sensitivity.High FOXA2 expression was correlated with poor survival and reduced responsiveness to tamoxifen in patients with ER-positive breast cancer.Conclusion:Our findings identified FOXA2 as a key mediator of tamoxifen resistance regulated by SETD1A and suggested that targeting the SETD1A-FOXA2 axis may offer a novel strategy for overcoming endocrine resistance in breast cancer.展开更多
The global burden of cancer,with over 19 million new cases annually,underscores the urgent need for effective therapies.Among the most promising anticancer compounds is camptothecin(CPT),a monoterpene alkaloid predomi...The global burden of cancer,with over 19 million new cases annually,underscores the urgent need for effective therapies.Among the most promising anticancer compounds is camptothecin(CPT),a monoterpene alkaloid predominantly derived from Nothapodytes species.Despite its significantpharmaceutical value,the exploitation of such Threatened Plant Species with Widespread Distribution(TPSWD),particularly driven by the global demand for natural compounds in anticancer therapies,presents a paradox in which their widespread distribution fails to ensure their secure conservation status.Furthermore,the lack of in-depth biogeographic and systematic studies complicates efforts to balance resource utilization with biodiversity preservation.The asymmetric distribution of CPT within plant taxa,along with limited knowledge of its biosynthetic pathways and the enzymes and genes involved,further hampers sustainable production.Here,we review the current knowledge on the production and protection of Nothapodytes,focusing on their plant resources,active ingredients,and natural drug derivatives.We also explore strategies for rescuing and sustainably utilizing Nothapodytes,including biotechnological advancements and integrated conservation practices.Finally,we propose future directions to address conservation challenges,ensuring a sustainable supply of CPT while safeguarding these TPSWD species.展开更多
The metastatic pattern of colon cancer is typically well characterized,with initial dissemination occurring through regional lymphatics,followed by hematogenous spread.The most frequent sites of metastasis in colorect...The metastatic pattern of colon cancer is typically well characterized,with initial dissemination occurring through regional lymphatics,followed by hematogenous spread.The most frequent sites of metastasis in colorectal cancer(CRC)include regional lymph nodes(50%–70%),liver(35%–50%),lungs(21%),peritoneum(15%),and ovaries(13%).1 Isolated distant lymph node metastasis,particularly in the absence of concurrent systemic disease,is exceedingly rare in CRC.To date,only six cases of isolated axillary lymph node metastasis(ALNM)from colorectal primaries have been documented in the literature.1–6 Even more uncommon is the incidental discovery of malignant cells in anastomotic doughnuts following stoma reversal procedures.Herein,we report a rare case involving both the incidental histopathological detection of tumor cells within doughnuts during stoma closure and the subsequent development of isolated ALNM after curative resection of sigmoid colon carcinoma.展开更多
Prostate cancer(PCa)remains a major cause of cancer-related mortality in men,largely due to therapy resistance and metastatic progression.Increasing evidence highlights the tumor microenvironment(TME),particularly can...Prostate cancer(PCa)remains a major cause of cancer-related mortality in men,largely due to therapy resistance and metastatic progression.Increasing evidence highlights the tumor microenvironment(TME),particularly cancer-associated fibroblasts(CAFs),as a critical determinant of disease behavior.CAFs constitute a heterogeneous population originating from fibroblasts,mesenchymal stem cells,endothelial cells,epithelial cells undergoing epithelial-mesenchymal transition(EMT),and adipose tissue.Through dynamic crosstalk with tumor,immune,endothelial,and adipocyte compartments,CAFs orchestrate oncogenic processes including tumor proliferation,invasion,immune evasion,extracellular matrix remodeling,angiogenesis,and metabolic reprogramming.This review comprehensively summarizes the cellular origins,phenotypic and functional heterogeneity,and spatial distribution of CAFs within the prostate TME.We further elucidate the molecular mechanisms by which CAFs regulate PCa progression and therapeutic resistance,and critically evaluate emerging strategies to therapeutically target CAFmediated signaling,metabolic,and immune pathways.By integrating recent advances from single-cell and spatial transcriptomics(ST),our objective is to provide a holistic framework for understanding CAF biology and to highlight potential avenues for stromal reprogramming as an adjunct to current PCa therapies.展开更多
基金supported by the National Natural Science Foundation of China(Grant Nos.82230057 and 82272859)the National Key R&D Program of China(Grant No.2022YFC2505101).
文摘Introduction,Breast cancer is the most common cancer type in adolescents and young adults<40 years of age,accounting for 30%of cancers in this age group1.Breast cancer in the young presents significant challenges for patients and society,including more aggressive tumor biology,poor prognosis,genetic susceptibility,fertility preservation,and complex psychosocial issues.Moreover,because of the markedly younger median age of breast cancer,the proportion of young breast cancer patients in China is significantly higher than Western countries2.The first Young Breast Cancer in China(YBCC)consensus meeting was held in Guangzhou,China in December 2021 to address exclusive challenges and requirements facing young patients with breast cancer.Chinese medical experts from multiple specialties had an extensive discussion and formulated a consensus over several hot topics in young patients with breast cancer.The“Expert Consensus on the Diagnosis and Treatment of Young Breast Cancer in China(2022 edition)”published in the Chinese Medical Journal has garnered significant attention3,highlighting enormous interest in the YBCC consensus in the medical community and public.
基金supported by the National Natural Science Foundation[Grant Number:82102788]Anhui Province Key Project for Clinical Medical Research Translation and Advancement[202204295107020031,202204295107020007]Anhui Provincial University Excellent Scientific Research and Innovation Team Project[2022AH010071].
文摘Background:In clinical practice,approximately 80%of prostate cancer(PC)cases are localized and can achieve favorable outcomes with appropriate treatment.Conversely,some remaining cases exhibit an aggressive phenotype or develop resistance to therapeutic interventions,leading to tumor metastasis and a poorer prognosis.When PC metastasizes to distant sites,the bone remains the predominant location,and brain metastases are regarded as exceedingly rare.Case Description:The current study focused on a rare clinical PC case that presented multiple brain metastases after prostate surgery.The patient was initially diagnosed with PC through prostate biopsy and subsequently underwent prostate debulking surgery while continuing androgen deprivation therapy,which maintained low prostatespecific antigen(PSA)levels for 4 years.However,a sudden PSA surge to 7.858 ng/mL led to the emergence of two brain metastatic tumors,which were confirmed to have originated from the prostate.Conclusions:Patients with advanced PC require comprehensive evaluations to detect rare metastatic sites,such as the brain,to avoid missed diagnoses.For patients with brain metastases,a multimodal approach combining surgical resection,postoperative radiotherapy,and endocrine therapy can effectively alleviate symptoms and enhance survival.
基金supported by the Guangdong Basic and Applied Basic Research Foundation(Nos:2024A1515012687)the National Natural Science Foundation of China(No.82303052).
文摘Background Neuroendocrine prostate cancer(NEPC)is an aggressive subtype of castration-resistant prostate cancer(CRPC)that is typically resistant to nearly all current therapies.Methods In this study,single-cell RNA sequencing(scRNA-seq)and bioinformatic analysis identified centrosomal protein 55(CEP55)as a critical factor in the transformation from hormone-sensitive prostate cancer(HSPC)to CRPC and,ultimately to,NEPC.Results Subsequent bioinformatics analyses and clinical sample validation showed that CEP55 is significantly upregulated in NEPC tissues relative to HSPC and CRPC.Furthermore,while CEP55 show no significant association with the immune microenvironment or cancer-associated fibroblasts(CAFs),our findings indicated that it directly mediates the plasticity of prostate cancer cells,thereby driving NEPC progression.Specifically,in vivo and in vitro experiments confirmed that CEP55 enhances cell proliferation,migration,invasion and the expression of NEPC biomarkers in prostate cancer.Importantly,although cisplatin is the primary treatment for NEPC clinically,CEP55 has been shown to regulate cisplatin resistance through the phosphorylation of cyclin-dependent kinase 1(CDK1)at the tyrosine 15(Tyr15)site.Conclusions In summary,our study identifies a key gene that influences the neuroendocrine differentiation process in prostate cancer,suggesting its potential as an important therapeutic target.
基金supported by Rural Health Research Institute,Charles Sturt University.
文摘Breast cancer(BC)remains the most frequently diagnosed malignancy worldwide,with an estimated 2.3 million new cases and approximately 685,000 deaths reported in 2020.Forecasts suggest a substantial rise in global incidence,with new annual cases projected to reach 3.2 million by 2050,representing a 39%increase.Additionally,BC is expected to account for approximately 7.7%of the anticipated$25.2 trillion global economic burden associated with cancer by 2050.These trends underscore an urgent need for affordable,widely accessible and effective therapeutic strategies,particularly in low-and middle-income countries.Statins,commonly prescribed for the treatment of hypercholesterolaemia via inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A(HMG-CoA)reductase,have garnered increasing interest for their potential anticancer properties.This review focuses on the mechanistic underpinnings and therapeutic implications of statin use,particularly simvastatin,in the context of BC.Statins exert their primary effect through inhibition of the mevalonate pathway,which is crucial for cholesterol and isoprenoid biosynthesis.Disruption of this pathway impairs the prenylation of key signalling proteins,including members of the Ras and Rho GTPase families,which are essential for cancer cell proliferation,survival and metastasis.Preclinical evidence has demonstrated that simvastatin can induce tumour cell apoptosis,arrest cell-cycle progression and inhibit oncogenic signalling pathways.These effects have been particularly pronounced in hormone receptor-negative and triple-negative breast cancer(TNBC)subtypes,which are often associated with poor prognosis and limited treatment options.Epidemiological and observational studies further support a potential association between statin use and reduced BC recurrence and mortality.Nevertheless,robust evidence from randomised controlled trials remains limited,and further investigation is required to establish causality and define optimal therapeutic regimens.Given their well-established safety profile,global accessibility and pleiotropic effects,statins,especially simvastatin,represent a promising class of repurposed drugs in the adjuvant treatment of BC.This review synthesises evidence from the past two decades,highlighting the need for continued clinical research to validate and optimise the use of statins as adjunctive agents in BC therapy.
基金supported by the National Natural Science Foundation of China(No.82360238,82071245)。
文摘Cancer pain is one of the most prevalent and debilitating symptoms in patients with advanced malignancies,arising from multifactorial mechanisms involving peripheral,central,and systemic pathways.Conventional analgesics,including opioids and nonsteroidal anti-inflammatory drugs,are often limited by their insufficient efficacy,tolerance,and risk of dependence.Traditional Chinese Medicine(TCM),characterized by its multi-component,multi-target,and systemic regulatory properties,has shown promising potential in cancer pain management.This review provides a comprehensive overview of the clinical classification and underlying mechanisms of cancer pain(including nerve infiltration,dysregulation of inflammatory mediators and ion channels,central sensitization,neuro-immune crosstalk,metabolic reprogramming,and gut-brain axis impairment),as well as the analgesic effects of representative TCM agents in cancer pain management.For example,bioactive components such as tetrahydroberberine,levo-tetrahydropalmatine,and piperine exert analgesic effects,thereby improving the quality of life of patients by inhibiting inflammatory cascades,regulating neurotransmitter systems,and preserving neural integrity.Commonly used preclinical models,including bone cancer pain,pancreatic cancer pain,and chemotherapy-induced peripheral neuropathy models,are summarized for their utility in mechanistic studies and efficacy evaluations.This review also discusses the current limitations of clinical evidence,such as small sample sizes,short follow-up periods,and limited translation from animal models,alongside major challenges in standardization,mechanistic elucidation,and clinical trial design.Future directions should focus on precise pain phenotyping,integrated multi-target interventions,rigorous efficacy safety validation,and innovations in drug delivery to facilitate the standardization and global adoption of TCM in cancer pain management.
基金supported by the National Natural Science Foundation of China(No.82574683)the National Natural Science Foundation of Science and Technology Department of Sichuan Province(Nos.2023NSFSC1928 and 2023NSFSC1992)+2 种基金Project of State Administration of Traditional Chinese Medicine of China(No.ZYYCXTD-D-202209)Project of Sichuan Provincial Administration of Traditional Chinese Medicine(No.2022C001)Fundamental Research Funds for the Central Universities(No.YJ201880).
文摘Lung cancer is the most common but fatal malignant tumor worldwide.Patients with lung cancer experienced a relatively low 5-year overall survival rate,and issues such as metastasis and drug resistance remain prominent challenges in its clinical management.Neddylation,a novel type of post-translational modification,was overactivated in lung cancer and was closely associated with its occurrence,development,metastasis,and drug resistance.This review systematically summarizes the biological process of neddylation and deeply explores the latest research progress on how neddylation affects lung cancer cell proliferation,metastasis,and drug resistance mechanisms,with a focus on its regulation of key molecules such as Cullin-RING E3 ligases and the SCCRO family.Meanwhile,it concludes the current advances in potential therapeutic agents targeting neddylation-related targets,including small-molecule compounds(such as Pevonedistat)and natural extracts(such as arctigenin).Finally,the review prospectively evaluates the application potential and questions requiring further exploration of neddylation in lung cancer treatment.In conclusion,we aim to systematically summarize the biological process of neddylation,critically explore its roles in lung cancer proliferation,metastasis,and drug resistance,and evaluate the therapeutic potential of neddylation-targeting agents.
基金National Natural Science Foundation of China,No.82003223and China Postdoctoral Science Foundation,No.2020M671398.
文摘BACKGROUND Gastric cancer(GC)is one of the most common malignant tumors of the digestive system worldwide,the prognosis of patients with advanced GC remains poor.AIM To evaluate the combined expression characteristics of cancer stem cell markers CD24 and CD133 in GC pathological tissues,and to explore their association with patients’clinicopathological parameters and postoperative survival outcomes.METHODS A total of 304 GC patients who underwent surgical treatment in our hospital from January 2018 to January 2020 were retrospectively included.Immunohistochemistry was used to detect the protein expression of CD24 and CD133 in tumor tissues,adjacent tissues,and normal gastric mucosa tissues.Based on staining intensity and the proportion of positive cells,expression levels were classified into low and high expression,while clinicopathological parameters were recorded.χ2 test was used to evaluate the correlation between expression and categorical variables,Spearman rank correlation analysis was performed to assess the correlation between the expression intensities of the two markers,and multivariate regression models were applied to identify independent risk factors influencing co-expression.Kaplan-Meier survival curves and Log-rank test were used to compare survival differences among groups with different expression patterns.RESULTS Among the 304 patients,155 cases(50.99%)were CD24 positive,including 91 low-expression and 64 highexpression;133 cases(43.75%)were CD133 positive,including 81 low-expression and 52 high-expression.There were 74 cases(24.34%)with double positivity and 81 cases(26.64%)with double negativity.Compared with tumor tissues,the positive rates of CD24 and CD133 in normal gastric tissues and adjacent tissues were significantly lower(P<0.05).Univariate analysis showed that co-expression of CD24 and CD133 in GC tissues was significantly correlated with tumor size,Lauren classification,T stage,N stage,and vascular invasion(P<0.05),but not with patient age,gender,tumor site,World Health Organization histological classification,or M stage(P>0.05).Further multivariate regression analysis suggested that tumor size,T stage,N stage,and vascular invasion were independent risk factors promoting CD24 and CD133 double positivity.Spearman rank correlation analysis indicated a moderate positive correlation between their expression intensities(r=0.420,P<0.001).During follow-up,29 of 304 patients were lost(loss rate 9.54%);146 deaths occurred.According to expression combination,there were 89 cases of CD24 single positivity(39 deaths),68 cases of CD133 single positivity(31 deaths),81 cases of double negativity(25 deaths),and 66 cases of double positivity(51 deaths).Log-rank test showed significant differences in overall survival among the four groups(χ2=20.89,P<0.001),with CD24+/CD133+group showing the worst prognosis.CONCLUSION CD24 and CD133 exhibit high positive detection rates in GC tissues,and their co-positivity is closely associated with tumor stage progression and significantly indicates unfavorable survival outcomes.The co-expression of CD24/CD133 may reflect higher aggressiveness and metastatic potential of GC,serving as a potential prognostic marker and a direction for targeted therapeutic strategies.However,as this is a single-center retrospective study with limitations such as patient loss to follow-up and sample size,further prospective,multicenter,and mechanistic studies are required to validate its clinical applicability and biological role.
文摘Colorectal cancer remains one of the leading causes of morbidity and mortality worldwide.Despite notable advances in early detection and therapeutic strategies,the molecular mechanisms underlying tumor survival,chemotherapy resistance,and metastasis are not yet fully understood.MicroRNAs(miRNAs)have emerged as pivotal regulators of cancer development,as they modulate gene expression and orchestrate key signaling pathways.However,the epigenetic mechanisms that control miRNA expression and their downstream gene targets remain largely unclear.In this review,we highlight the critical role of the colorectal cancer microenvironment in influencing miRNA expression and discuss how this regulation contributes to tumorigenesis.A better understanding of these processes may lead to the identification of novel therapeutic targets and strategies to prevent recurrence.
基金supported and funded by Korea University Guro Hospital(KOREA RESEARCH-DRIVEN HOSPITAL)(No.O2208261)supported by the Korea University Guro Hospital(KOREA RESEARCH-DRIVEN HOSPITAL)+1 种基金grant funded by Korea University Medicine(No.K2313971)by Korea University。
文摘Objective:This study aimed to evaluate the associations of baseline income,cumulative income exposure,and income volatility with the incidence of pancreatic and biliary tract cancers in a nationwide Korean cohort.Methods:We analyzed 3,361,091 adults aged 30-65 years who underwent the 2012 National Health Insurance Service(NHIS)health screening.Income level was derived from insurance premium data assessed over the five years preceding baseline(2008-2012)and categorized into baseline income quartiles,cumulative exposure to low or high income,and income volatility based on annual percentage changes.Incident pancreatic and biliary tract cancers were identified using diagnostic codes and the copayment reduction registry.Associations were evaluated using Cox proportional hazards models with adjustment for demographic,lifestyle,and clinical covariates,and cumulative incidence was compared using Kaplan-Meier curves.Results:During a median follow-up of 9.6 years,14,469 pancreatic cancers and 6,647 biliary tract cancers were newly diagnosed.Lower baseline income was associated with a higher risk of pancreatic and biliary tract cancers,whereas sustained high-income exposure was associated with reduced risk.Cumulative low-income exposure showed a positive linear trend with pancreatic cancer incidence.Income volatility was modestly associated with pancreatic cancer and was positively associated with biliary tract cancer in the fully adjusted model.These associations were generally consistent across subgroups,with a stronger inverse association between prolonged high-income exposure and pancreatic cancer among individuals without diabetes.Conclusions:Income level and income stability were significantly associated with the incidence of pancreatic and biliary tract cancers.Lower baseline income was associated with higher risk,whereas sustained high-income exposure was protective.Income volatility was associated with increased cancer risk,particularly for biliary tract cancer.These findings highlight the importance of incorporating income dynamics into cancer prevention strategies and addressing socioeconomic instability among vulnerable populations.
文摘Breast cancer remains a global health challenge with greater than 2.3 million new cases diagnosed annually 1,according to the World Health Organization1.Management of breast cancer is shaped by a complex interplay of international guidelines,regional adaptations,and the rapidly evolving fields of precision medicine and artificial intelligence(AI).
基金National Key Project of Research and Development Program of China[2021YFC2500404].
文摘Primary liver cancer (PLC) is a major global healthchallenge, ranking as the sixth most common andthird most fatal malignancy worldwide, according toGLOBOCAN 2022 estimates[1]. This high mortalityrate underscores the aggressive nature of thedisease and the significant burden it places on globalhealthcare systems. Although primary preventionremains the cornerstone of liver cancer control,improving outcomes for patients already diagnosedis equally critical for mitigating the impact of thedisease.
基金National Research,Development and Innovation Fund of the Ministry of Culture and Innovation under the National Laboratories Program(National Tumor Biology Laboratory,Grant/Award Number:2022-2.1.1-NL-2022-00010)Senior Research Fellowship from National Health and Medical Research Council of Australia,Grant/Award Number:1156693+1 种基金Hungarian Thematic Excellence Program,Grant/Award Number:TKP2021-EGA-44Tour de Cure,Pioneering Grant,Grant/Award Number:RSP-253-18/19。
文摘Realistic models for cancer research representing disease progression that commensurately respond to therapeutics consistent with clinical observation are the holy grail for pre-clinical research and screening.Although such an ideal is elusive,well-characterized in vivo models facilitate our understanding of disease,progression,and therapeutic opportunities.Here,we characterize a commonly used syngeneic BALB/c mouse model of triple negative breast cancer(4T1)after establishing tumors in their flanks.Tumors developed at the subcutaneous injection site for all experimental mice and their volumes were monitored.We quantified a rare subset of breast cancer stemlike cells(CSCs),classified as CD44^(+)/CD24^(−)phenotypes in in vitro and ex vivo cell populations.Chromosome numbers in ex vivo metaphase cells were greater than cells cultured in vitro(89.4±3.4,range of 70-132 and 82.6±1.1,range of 70-128;respectively).Further,we observed different types of chromosome aberrations,including gap,deletion,exchange,interstitial deletion,terminal deletion,ring,dicentric,and Robertsonian translocations.For both sources of cells,the number of aberrations was dominated by deletions,terminal deletions,and Robertsonian translocations.Ex vivo cells exhibited greater prevalence of deletions and terminal deletions,whereas in vitro cells displayed more ring aberrations and Robertsonian translocations.In conclusion,we successfully characterized cancer cells from a syngeneic mouse model of breast cancer in terms of rare CSC proportion and a variety of chromosomal aberrations,which is useful for understanding tumor traits associated with cancer development and therapeutic action.The data act as a valuable resource for other studies using the 4T1 BALB/c model.
基金supported by the Hong Kong Research Grants Council Theme-based Research Scheme(Grant No.T12-716/22-R)Innovation and Technology Commission grant for State Key Laboratory of Liver Research(Grant No.ITC PD/17-9)University Development Fund of The University of Hong Kong,and Loke Yew Endowed Professorship award.I.O.L.Ng is Loke Yew Professor in Pathology.
文摘Hepatocellular carcinoma(HCC)is a pressing global health problem and is the sixth most common cancer and the third leading cause of cancer mortality worldwide.Despite continuous advances in treatment modalities,the 5-year survival rate is low with a high propensity for recurrence and metastasis1.This clinical challenge in treating HCC is largely attributed to the heterogeneity and intrinsic therapy resistance of cancer stem cells(CSCs),which are a subpopulation of cells with self-renewal capability and multidirectional differentiation potential to induce tumorigenicity2.The behavior and maintenance of CSCs are not autonomous but critically dependent on the complex bidirectional crosstalk between CSCs and the tumor immune microenvironment(TIME)1.In this review we first summarize the recent progress in characterizing CSCs and the interactions between CSCs and the TIME in HCC.Next,we discuss the emerging therapeutic strategies targeting CSC populations with the ongoing challenges.Finally,we give our perspectives on the future directions in HCC CSC research.
文摘BACKGROUNDCancer stem cells(CSCs)drive recurrence and therapeutic resistance in triplenegativebreast cancer(TNBC),a highly aggressive breast cancer subtype.Intratumoralhypoxia,a common feature of solid tumors,promotes CSCs enrichment,yet the mechanisms sustaining CSCs stemness remain poorly understood.Hypoxia-induced reactive oxygen species can oxidatively activate ataxia telangiectasiamutated(ATM)kinase(oxidized ATM,p-ATM)independently of DNA breaks.AIMTo investigate the role of hypoxia-induced oxidized ATM in sustaining TNBCCSCstemness through c-Myc-mediated regulation of one-carbon metabolism.METHODSHs578T and MDA-MB-231 TNBC cells were cultured under normoxia or hypoxia.CSC stemness was assessed by mammosphere assays and flow cytometry.ATMactivity was assessed by pharmacological inhibition(Ku60019)and short hairpinRNA knockdown.c-Myc binding to serine hydroxymethyltransferase 2(SHMT2)and methylenetetrahydrofolate dehydrogenase 2(MTHFD2)promoters was analyzedby dual-luciferase reporter assays and chromatin immunoprecipitation.NADPH/NADP+ratios were quantified,and metabolic reprogramming was profiledby liquid chromatography-tandem mass spectrometry metabolomics.RESULTSHypoxia significantly increased mammosphere formation in both Hs578T and MDA-MB-231 cells,as reflected byhigher numbers of mammospheres(Hs578T:214±18;MDA-MB-231:198±16;both P<0.01)and larger meandiameters(P<0.01).Hypoxia also elevated CD44+/CD24-cell proportions and stemness gene expression(P<0.01).Oxidized ATM was activated under hypoxia withoutγH2AX induction,confirming DNA damage independence.ATM inhibition reduced mammosphere growth and suppressed c-Myc,SHMT2,and MTHFD2.Luciferase and chromatin immunoprecipitation assays confirmed direct c-Myc binding to SHMT2 and MTHFD2promoters,while mutation of the binding sites abolished promoter activity.NADPH/NADP+ratios were significantlyelevated under hypoxia but reduced following ATM inhibition(P<0.05).Metabolomics revealed enrichmentof serine/glycine one-carbon pathways.CONCLUSIONHypoxia-induced oxidized ATM maintains TNBC-CSC stemness by promoting c-Myc-dependent upregulation ofMTHFD2 and SHMT2,linking hypoxia,redox signaling,and one-carbon metabolism.These findings suggest apotential therapeutic axis that could be exploited for TNBC treatment.
文摘Background:Minimally invasive distal pancreatectomy(MIDP)is increasingly being used,although its oncologic safety for pancreatic ductal adenocarcinoma(PDAC)remains controversial.In Japan,MIDP for PDAC has limited endorsement due to insufficient data.This study aimed to compare the perioperative and long-term outcomes of open distal pancreatectomy(ODP)and MIDP for PDAC.Methods:We retrospectively analyzed patients with resectable pancreatic body and tail cancer treated with ODP or MIDP(laparoscopic or robotic)between January 2007 and July 2022.The surgical procedures(ODP and MIDP)were compared and the patient characteristics,perioperative outcomes,and long-term outcomes were analyzed.We also compared the outcomes of patients with neoadjuvant chemotherapy(NAC)and without NAC.Results:A total of 72 distal pancreatectomies were performed(37 ODPs and 35 MIDPs).In the upfront group,MIDP resulted in significantly less blood loss than ODP(P<0.01),despite similar operative time.There was no statistically significant difference in the 2-year recurrence-free survival(RFS)rates between ODP and MIDP(39.7%vs.57.8%,P=0.60)or in the overall survival(OS)rates(66.7%vs.74.1%,P=0.43).Similarly,in the NAC group,MIDP resulted in significantly less blood loss than ODP(P=0.01);ODP and MIDP had similar 2-year RFS rates(41.7%and 60.0%,P=0.75)and OS rates(50.0%and 70.0%,P=0.36).The interval from surgery to adjuvant chemotherapy initiation did not significantly differ between the ODP and MIDP subgroups in both the upfront group(P=0.13)and the NAC group(P=0.14).The incidence of recurrence was 64.8%for ODP and 42.8%for MIDP(P=0.06).Both procedures showed similar distributions of local and distant recurrence.Conclusions:MIDP caused less blood loss and had similar oncologic safety compared with ODP.MIDP could become a feasible,minimally invasive option with sufficient oncologic safety for pancreatic body and tail cancers.
基金supported by the Non-communicable Chronic Diseases National Science and Technology Major Project(Grant No.2025ZD0544003).
文摘The landscape of breast cancer treatment has undergone a transformative shift with the integration of immunotherapy.Historically considered a“cold”tumor with limited immunogenicity,breast cancer management was dominated by surgery,chemotherapy,radiotherapy,and targeted therapies1.However,the advent of immune checkpoint inhibitors(ICIs)has challenged this paradigm,opening a new frontier.The initial breakthrough in triple-negative breast cancer(TNBC)demonstrated that a subset of patients could derive profound and durable clinical benefit from pembrolizumab and atezolizumab2,3.Today,precision immunotherapy aims to identify the patients most likely to respond,to convert immunologically silent tumors into responsive tumors,and to strategically combine immunotherapies with other modalities to overcome resistance.This evolution from empirical application to biomarker-driven strategies marks the critical juncture at which we stand,transitioning promising clinical trial data into refined,effective,and accessible clinical practice4.Recent key clinical studies on breast cancer immunotherapy are summarized in Table 1.
基金supported by the Basic Science Research Program through the National Research Foundation of Korea(NRF),funded by the Ministry of Education(RS-2023-00248378 and NRF-2020R1A6A1A03043708).
文摘Objectives:Tamoxifen is a key drug that provides endocrine therapy for estrogen receptor(ER)α-positive breast cancer;however,resistance remains a significant clinical challenge.This study aims to investigate the molecular mechanisms of tamoxifen resistance in ERα-positive breast cancer,with particular focus on the role of SET Domain Containing 1A(SETD1A)-driven forkhead box A2(FOXA2)as a key regulator of this resistance.Methods:FOXA2 expression and its regulation by SETD1A were assessed via(quantitative polymerase chain reaction),western blotting,transcriptome profiling,and chromatin immunoprecipitation analyses.The effects of FOXA2 on cell proliferation,migration,invasion,and cancer stem cell traits were evaluated using small interfering RNA(siRNA)-mediated silencing.Clinical relevance was examined by analyzing patient datasets and tumor tissue microarrays.Results:FOXA2 expression was significantly elevated in tamoxifen-resistant(TamR)and ERα-negative breast cancer cells compared to that in ERα-positive MCF-7 cells,regardless of tamoxifen treatment or ERαdepletion.Transcriptome and chromatin immunoprecipitation analyses revealed that SETD1A,a histone methyltransferase,directly regulated FOXA2 expression.Functionally,FOXA2 knockdown inhibited the proliferation,migration,invasion,and cancer stem cell properties of TamR cells while restoring tamoxifen sensitivity.High FOXA2 expression was correlated with poor survival and reduced responsiveness to tamoxifen in patients with ER-positive breast cancer.Conclusion:Our findings identified FOXA2 as a key mediator of tamoxifen resistance regulated by SETD1A and suggested that targeting the SETD1A-FOXA2 axis may offer a novel strategy for overcoming endocrine resistance in breast cancer.
基金supported by the National Key R&D Program of China(2024YFF1306700)the Key Project of Basic Research of Yunnan Province,China(202301AS070001)the Regional Innovative Development Joint Fund of NSFC(U23A20149).
文摘The global burden of cancer,with over 19 million new cases annually,underscores the urgent need for effective therapies.Among the most promising anticancer compounds is camptothecin(CPT),a monoterpene alkaloid predominantly derived from Nothapodytes species.Despite its significantpharmaceutical value,the exploitation of such Threatened Plant Species with Widespread Distribution(TPSWD),particularly driven by the global demand for natural compounds in anticancer therapies,presents a paradox in which their widespread distribution fails to ensure their secure conservation status.Furthermore,the lack of in-depth biogeographic and systematic studies complicates efforts to balance resource utilization with biodiversity preservation.The asymmetric distribution of CPT within plant taxa,along with limited knowledge of its biosynthetic pathways and the enzymes and genes involved,further hampers sustainable production.Here,we review the current knowledge on the production and protection of Nothapodytes,focusing on their plant resources,active ingredients,and natural drug derivatives.We also explore strategies for rescuing and sustainably utilizing Nothapodytes,including biotechnological advancements and integrated conservation practices.Finally,we propose future directions to address conservation challenges,ensuring a sustainable supply of CPT while safeguarding these TPSWD species.
文摘The metastatic pattern of colon cancer is typically well characterized,with initial dissemination occurring through regional lymphatics,followed by hematogenous spread.The most frequent sites of metastasis in colorectal cancer(CRC)include regional lymph nodes(50%–70%),liver(35%–50%),lungs(21%),peritoneum(15%),and ovaries(13%).1 Isolated distant lymph node metastasis,particularly in the absence of concurrent systemic disease,is exceedingly rare in CRC.To date,only six cases of isolated axillary lymph node metastasis(ALNM)from colorectal primaries have been documented in the literature.1–6 Even more uncommon is the incidental discovery of malignant cells in anastomotic doughnuts following stoma reversal procedures.Herein,we report a rare case involving both the incidental histopathological detection of tumor cells within doughnuts during stoma closure and the subsequent development of isolated ALNM after curative resection of sigmoid colon carcinoma.
文摘Prostate cancer(PCa)remains a major cause of cancer-related mortality in men,largely due to therapy resistance and metastatic progression.Increasing evidence highlights the tumor microenvironment(TME),particularly cancer-associated fibroblasts(CAFs),as a critical determinant of disease behavior.CAFs constitute a heterogeneous population originating from fibroblasts,mesenchymal stem cells,endothelial cells,epithelial cells undergoing epithelial-mesenchymal transition(EMT),and adipose tissue.Through dynamic crosstalk with tumor,immune,endothelial,and adipocyte compartments,CAFs orchestrate oncogenic processes including tumor proliferation,invasion,immune evasion,extracellular matrix remodeling,angiogenesis,and metabolic reprogramming.This review comprehensively summarizes the cellular origins,phenotypic and functional heterogeneity,and spatial distribution of CAFs within the prostate TME.We further elucidate the molecular mechanisms by which CAFs regulate PCa progression and therapeutic resistance,and critically evaluate emerging strategies to therapeutically target CAFmediated signaling,metabolic,and immune pathways.By integrating recent advances from single-cell and spatial transcriptomics(ST),our objective is to provide a holistic framework for understanding CAF biology and to highlight potential avenues for stromal reprogramming as an adjunct to current PCa therapies.
