Molecular mechanism of pancreatic ductal adenocarcinoma:The heterogeneity of cancer-associated fibroblasts and key signaling pathways

Pancreatic ductal adenocarcinoma stands out as an exceptionally fatal cancer owing to the complexities associated with its treatment and diagnosis,leading to a notably low five-year survival rate.This study offers a detailed exploration of epidemiological trends in pancreatic cancer and key molecular drivers,such as mutations in CDKN2A,KRAS,SMAD4,and TP53,along with the influence of cancer-associated fibroblasts(CAFs)on disease progression.In particular,we focused on the pivotal roles of signaling pathways such as the transforming growth factor-βand Wnt/β-catenin pathways in the development of pancreatic cancer and investigated their application in emerging therapeutic strategies.This study provides new scientific perspectives on pancreatic cancer treatment,especially in the development of precision medicine and targeted therapeutic strategies,and demonstrates the importance of signaling pathway research in the development of effective therapeutic regimens.Future studies should explore the subtypes of CAFs and their specific roles in the tumor microenvironment to devise more effective therapeutic methods.

The diverse functions and therapeutic implications of cancerassociatedfibroblasts in colorectal cancer

In the development of colorectal cancer(CRC),cancer-associatedfibroblasts(CAFs)play a pivotal role in establishing tumor-permissive extracellular matrix structures,angiogenesis,and modulating the immune status of the tumor microenvironment(TME),thereby influencing tumor metastasis and resistance to radiotherapy and chemotherapy.The pleiotropic effects of CAFs in the TME may be attributed to the heterogeneous origin and high plasticity of their population.Given the specificity of CAFs,they provide a variety of potential target molecules for future CRC treatment,which may play an indispensable role in CRC therapeutic strategies.This review summarizes the origin of CAFs and their roles in the CRC tumor microenvironment,including the interaction between exosomes and CAFs in CRC.Additionally,we discuss potential therapeutic strategies targeting CAFs.

Differences in diversity and composition of mucosa-associated colonic microbiota in colorectal cancer and non-colorectal cancer in Indonesia

BACKGROUND Colorectal cancer is the third most common malignancy and the fourth leading cause of cancer-related deaths worldwide.Several studies have shown an association between gut microbiota and colorectal cancer.Gut microbiota is unique and can be influenced by geographic factors and habits.This study aimed to determine the diversity and composition of colonic mucosal microbiota in patients with and without colorectal cancer.AIM To determine the diversity and composition of colonic mucosal microbiota in patients with and without colorectal cancer in Indonesia.METHODS This case-control study included 59 subjects(35 colorectal cancer patients and 24 non-colorectal cancer patients indicated for colonoscopy at Dr.Cipto Mangunkusumo Gastrointestinal Endoscopy Center and Fatmawati Hospital.Microbiota examination was performed using 16S rRNA sequencing.Bioinformatics analysis was performed using the wf-metagenomics pipeline from EPI2Me-Labs(Oxford Nanopore Technologies platform).RESULTS Patients with colorectal cancer had a higher median index value on the Shannon index(3.28 vs 2.82,P>0.05)and a lower value on the Simpson index(0.050 vs 0.060,P>0.05).Significant differences in beta diversity were observed at the genus(P=0.002)and species levels(P=0.001).Firmicutes,Proteobacteria,Bacteroidetes,and Fusobacteria were the dominant phyla.The genera Bacteroides,Campylobacter,Peptostreptococcus,and Parvimonas were found more frequently in colorectal cancer,while Faecalibacterium,Haemophilus,and Phocaeicola were more frequently found in non-colorectal cancer.The relative abundance of Fusobacterium nucleatum,Bacteroides fragilis,Enterococcus faecalis,Campylobacter hominis,and Enterococcus faecalis species was significantly elevated in patients with colorectal cancer.Meanwhile,Faecalibacterium prausnitzii,Faecalibacterium duncaniae,and Prevotella copri were more commonly found in non-colorectal cancer.CONCLUSION Patients with colorectal cancer exhibit distinct differences in the composition and diversity of their colonic mucosal microbiota compared to those with non-colorectal cancer.This study was reviewed and approved by the Ethics Committee of Faculty of Medicine,Universitas Indonesia(No.KET-1517/UN2.F1/ETIK/PPM.00.02/2023).

High expression of SULF1 is associated with adverse prognosis in breast cancer brain metastasis

Background:Breast cancer is the most common cancer in women,and in advanced stages,it often metastasizes to the brain.However,research on the biological mechanisms of breast cancer brain metastasis and potential therapeutic targets are limited.Methods:Differential gene expression analysis(DEGs)for the datasets GSE43837 and GSE125989 from the GEO database was performed using online analysis tools such as GEO2R and Sangerbox.Further investigation related to SULF1 was conducted using online databases such as Kaplan-Meier Plotter and cBioPortal.Thus,expression levels,variations,associations with HER2,biological processes,and pathways involv-ing SULF1 could be analyzed using UALCAN,cBioPortal,GEPIA2,and LinkedOmics databases.Moreover,the sensitivity of SULF1 to existing drugs was explored using drug databases such as RNAactDrug and CADSP.Results:High expression of SULF1 was associated with poor prognosis in advanced breast cancer brain metastasis and was positively correlated with the expression of HER2.In the metastatic breast cancer population,SULF1 ranked top among the 16 DEGs with the highest mutation rate,reaching 11%,primarily due to amplification.KEGG and GSEA analyses revealed that the genes co-expressed with SULF1 were positively enriched in the‘ECM-receptor interaction’gene set and negatively enriched in the‘Ribosome’gene set.Currently,docetaxel and vinorelbine can act as treatment options if the expression of SULF1 is high.Conclusions:This study,through bioinformatics analysis,unveiled SULF1 as a poten-tial target for treating breast cancer brain metastasis(BM).

Unraveling the role of cancer-associated fibroblasts in colorectal cancer

Within the intricate milieu of colorectal cancer(CRC)tissues,cancer-associated fibroblasts(CAFs)act as pivotal orchestrators,wielding considerable influence over tumor progression.This review endeavors to dissect the multifaceted functions of CAFs within the realm of CRC,thereby highlighting their indispensability in fostering CRC malignant microenvironment and indicating the development of CAFs-targeted therapeutic interventions.Through a comprehensive synthesis of current knowledge,this review delineates insights into CAFsmediated modulation of cancer cell proliferation,invasiveness,immune evasion,and neovascularization,elucidating the intricate web of interactions that sustain the pro-tumor metabolism and secretion of multiple factors.Additionally,recognizing the high level of heterogeneity within CAFs is crucial,as they encompass a range of subtypes,including myofibroblastic CAFs,inflammatory CAFs,antigen-presenting CAFs,and vessel-associated CAFs.Innovatively,the symbiotic relationship between CAFs and the intestinal microbiota is explored,shedding light on a novel dimension of CRC pathogenesis.Despite remarkable progress,the orchestrated dynamic functions of CAFs remain incompletely deciphered,underscoring the need for continued research endeavors for therapeutic advancements in CRC management.

Long-term outcomes of endoscopic submucosal dissection for undifferentiated type early gastric cancer over 2 cm with R0 resection

BACKGROUND Endoscopic submucosal dissection(ESD)for over 2 cm in size undifferentiated type(UD type)early gastric cancer(EGC)confined to the mucosa is not only challenging,but also long-term outcomes are not well known.AIM To evaluate the long-term outcomes of ESD done for UD type EGCs confined to the mucosa over 2 cm in size and compare the results with those where the lesions were less than 2 cm.METHODS 143 patients with UD type EGC confirmed on histology after ESD at a tertiary hospital were reviewed.Cases with synchronous and metachronous lesions and a case with emergency surgery after ESD were excluded.A total of 137 cases were enrolled.79 cases who underwent R0 resection were divided into 2 cm or less(group A)and over 2 cm(group B)in size.RESULTS Among 79 patients who underwent R0 resection,the number in group A and B were 51 and 28,respectively.The mean follow-up period(SD)was 79.71±45.42 months.There was a local recurrence in group A(1/51,2%)and group B(1/28,3.6%)respectively.This patient in group A underwent surgery while the patient in group B underwent repeated ESD with no further recurrences in both patients.There was no regional lymph node metastasis,distant metastasis,and deaths in both groups.With R0 resection strategy for ESD on lesions over 2 cm,20.4%(28/137)of patients were able to avoid surgery compared with expanded indication.CONCLUSION If R0 resection is achieved by ESD,UD type EGCs over 2 cm also showed good and similar clinical outcomes as compared to lesions less than 2 cm when followed for over 5 years.With R0 resection strategy,several patients can avoid surgery.

Impact of STAT-signaling pathway on cancer-associated fibroblasts in colorectal cancer and its role in immunosuppression

Colorectal cancer(CRC)remains one of the most commonly diagnosed and deadliest types of cancer worldwide.CRC displays a desmoplastic reaction(DR)that has been inversely associated with poor prognosis;less DR is associated with a better prognosis.This reaction generates excessive connective tissue,in which cancer-associated fibroblasts(CAFs)are critical cells that form a part of the tumor microenvironment.CAFs are directly involved in tumorigenesis through different mechanisms.However,their role in immunosuppression in CRC is not well understood,and the precise role of signal transducers and activators of transcription(STATs)in mediating CAF activity in CRC remains unclear.Among the myriad chemical and biological factors that affect CAFs,different cytokines mediate their function by activating STAT signaling pathways.Thus,the harmful effects of CAFs in favoring tumor growth and invasion may be modulated using STAT inhibitors.Here,we analyze the impact of different STATs on CAF activity and their immunoregulatory role.

Metochalcone induces senescence-associated secretory phenotype via JAK2/STAT3 pathway in breast cancer

Breast and lung cancers are the leading causes of mortality and most frequently diagnosed cancers in women and men,respectively,worldwide.Although the antitumor activity of chalcones has been extensively studied,the molecular mechanisms of isoliquiritigenin analog 2',4',4-trihydroxychalcone(metochalcone;TEC)against carcinomas remain less well understood.In this study,we found that TEC inhibited cell proliferation of breast cancer BT549 cells and lung cancer A549 cells in a concentration-dependent manner.TEC induced cell cycle arrest in the S-phase,cell migration inhibition in vitro,and reduced tumor growth in vivo.Moreover,transcriptomic analysis revealed that TEC modulated the activity of the JAK2/STAT3 and P53 pathways.TEC triggered the senescence-associated secretory phenotype(SASP)by repressing the JAK2/STAT3 axis.The mechanism of metochalcone against breast cancer depended on the induction of SASP via deactivation of the JAK2/STAT3 pathway,highlighting the potential of chalcone in senescence-inducing therapy against carcinomas.

Calculus bovis inhibits M2 tumor-associated macrophage polarization via Wnt/β-catenin pathway modulation to suppress liver cancer

BACKGROUND Calculus bovis(CB),used in traditional Chinese medicine,exhibits anti-tumor effects in various cancer models.It also constitutes an integral component of a compound formulation known as Pien Tze Huang,which is indicated for the treatment of liver cancer.However,its impact on the liver cancer tumor microenvironment,particularly on tumor-associated macrophages(TAMs),is not well understood.AIM To elucidate the anti-liver cancer effect of CB by inhibiting M2-TAM polarization via Wnt/β-catenin pathway modulation.METHODS This study identified the active components of CB using UPLC-Q-TOF-MS,evaluated its anti-neoplastic effects in a nude mouse model,and elucidated the underlying mechanisms via network pharmacology,transcriptomics,and molecular docking.In vitro assays were used to investigate the effects of CB-containing serum on HepG2 cells and M2-TAMs,and Wnt pathway modulation was validated by real-time reverse transcriptase-polymerase chain reaction and Western blot analysis.RESULTS This study identified 22 active components in CB,11 of which were detected in the bloodstream.Preclinical investigations have demonstrated the ability of CB to effectively inhibit liver tumor growth.An integrated approach employing network pharmacology,transcriptomics,and molecular docking implicated the Wnt signaling pathway as a target of the antineoplastic activity of CB by suppressing M2-TAM polarization.In vitro and in vivo experiments further confirmed that CB significantly hinders M2-TAM polarization and suppresses Wnt/β-catenin pathway activation.The inhibitory effect of CB on M2-TAMs was reversed when treated with the Wnt agonist SKL2001,confirming its pathway specificity.CONCLUSION This study demonstrated that CB mediates inhibition of M2-TAM polarization through the Wnt/β-catenin pathway,contributing to the suppression of liver cancer growth.

Risk stratification for radioactive iodine refractoriness using molecular alterations in distant metastatic differentiated thyroid cancer

Objective: Patients with radioactive iodine-refractory differentiated thyroid cancer(RAIR-DTC) are often diagnosed with delay and constrained to limited treatment options. The correlation between RAI refractoriness and the underlying genetic characteristics has not been extensively studied.Methods: Adult patients with distant metastatic DTC were enrolled and assigned to undergo next-generation sequencing of a customized 26-gene panel(Thyro Lead). Patients were classified into RAIR-DTC or non-RAIR groups to determine the differences in clinicopathological and molecular characteristics. Molecular risk stratification(MRS) was constructed based on the association between molecular alterations identified and RAI refractoriness, and the results were classified as high, intermediate or low MRS.Results: A total of 220 patients with distant metastases were included, 63.2% of whom were identified as RAIRDTC. Genetic alterations were identified in 90% of all the patients, with BRAF(59.7% vs. 17.3%), TERT promoter(43.9% vs. 7.4%), and TP53 mutations(11.5% vs. 3.7%) being more prevalent in the RAIR-DTC group than in the non-RAIR group, except for RET fusions(15.8% vs. 39.5%), which had the opposite pattern. BRAF and TERT promoter are independent predictors of RAIR-DTC, accounting for 67.6% of patients with RAIR-DTC. MRS was strongly associated with RAI refractoriness(P<0.001), with an odds ratio(OR) of high to low MRS of 7.52 [95%confidence interval(95% CI), 3.96-14.28;P<0.001] and an OR of intermediate to low MRS of 3.20(95% CI,1.01-10.14;P=0.041).Conclusions: Molecular alterations were associated with RAI refractoriness, with BRAF and TERT promoter mutations being the predominant contributors, followed by TP53 and DICER1 mutations. MRS might serve as a valuable tool for both prognosticating clinical outcomes and directing precision-based therapeutic interventions.

Anti-tumor efficacy of Calculus bovis: Suppressing liver cancer by targeting tumor-associated macrophages

Despite significant advances in our understanding of the molecular pathogenesis of liver cancer and the availability of novel pharmacotherapies,liver cancer remains the fourth leading cause of cancer-related mortality worldwide.Tumor relapse,resistance to current anti-cancer drugs,metastasis,and organ toxicity are the major challenges that prevent considerable improvements in patient survival and quality of life.Calculus bovis(CB),an ancient Chinese medicinal drug,has been used to treat various pathologies,including stroke,convulsion,epilepsy,pain,and cancer.In this editorial,we discuss the research findings recently published by Huang et al on the therapeutic effects of CB in inhibiting the development of liver cancer.Utilizing the comprehensive transcriptomic analyses,in vitro experiments,and in vivo studies,the authors demonstrated that CB treatment inhibits the tumor-promoting M2 phenotype of tumor-associated macrophages via downregulating Wnt pathway.While multiple studies have been performed to explore the molecular mechanisms regulated by CB,this study uniquely shows its role in modulating the M2 phenotype of macrophages present within the tumor microenvironment.This study opens new avenues of future investigations aimed at investigating this drug’s efficacy in various mouse models including the effects of combination therapy,and against drug-resistant tumors.

UBE2T mediates the stemness properties of breast cancer cells through the mTOR signaling pathway

Objectives:This study aimed to reveal the role and possible mechanism of the ubiquitin-conjugating enzyme 2T(UBE2T)in the biological activities of breast cancer stem cells(BCSCs).Methods:The specific protein and gene expression were quantified by Western blotting and quantitative real-time polymerase chain reaction,the proportion of BCSCs was examined by flow cytometry,and the self-renewal and proliferation of BCSCs were verified by serial sphere formation and soft agar.Results:Increasing expression of UBE2T was drastically found in breast cancer than that in adjacent tissues.Furthermore,UBE2T overexpression significantly increased the proportion of BCSCs in breast cancer cells and promoted their self-renewal and proliferation.Silent UBE2T exhibited the opposite functions.UBE2T increased the levels of the mammalian target of rapamycin and the phosphorylated mammalian target of rapamycin.Mammalian target of rapamycin(mTOR)inhibitor rapamycin inhibited the function of UBE2T in BCSCs.Conclusion:UBE2T plays a role in BCSCs through mTOR pathway and may suggest a novel therapeutic strategy for breast cancer.

Identification and validation of a new prognostic signature based on cancer-associated fibroblast-driven genes in breast cancer

BACKGROUND Breast cancer(BC),a leading malignant disease,affects women all over the world.Cancer associated fibroblasts(CAFs)stimulate epithelial-mesenchymal transition,and induce chemoresistance and immunosuppression.AIM To establish a CAFs-associated prognostic signature to improve BC patient out-come estimation.METHODS We retrieved the transcript profile and clinical data of 1072 BC samples from The Cancer Genome Atlas(TCGA)databases,and 3661 BC samples from the The Gene Expression Omnibus.CAFs and immune cell infiltrations were quantified using CIBERSORT algorithm.CAF-associated gene identification was done by weighted gene co-expression network analysis.A CAF risk signature was established via univariate,least absolute shrinkage and selection operator regression,and mul-tivariate Cox regression analyses.The receiver operating characteristic(ROC)and Kaplan-Meier curves were employed to evaluate the predictability of the model.Subsequently,a nomogram was developed with the risk score and patient clinical signature.Using Spearman's correlations analysis,the relationship between CAF risk score and gene set enrichment scores were examined.Patient samples were collected to validate gene expression by quantitative real-time polymerase chain reaction(qRT-PCR).RESULTS Employing an 8-gene(IL18,MYD88,GLIPR1,TNN,BHLHE41,DNAJB5,FKBP14,and XG)signature,we attemp-ted to estimate BC patient prognosis.Based on our analysis,high-risk patients exhibited worse outcomes than low-risk patients.Multivariate analysis revealed the risk score as an independent indicator of BC patient prognosis.ROC analysis exhibited satisfactory nomogram predictability.The area under the curve showed 0.805 at 3 years,and 0.801 at 5 years in the TCGA cohort.We also demonstrated that a reduced CAF risk score was strongly associated with enhanced chemotherapeutic outcomes.CAF risk score was significantly correlated with most hallmark gene sets.Finally,the prognostic signature were further validated by qRT-PCR.CONCLUSION We introduced a newly-discovered CAFs-associated gene signature,which can be employed to estimate BC patient outcomes conveniently and accurately.

Women Breast Cancer: Knowledge, Attitudes, Practices and Factors Associated with Early Screening in the Municipality of Abomey-Calavi in Benin in 2018

Background: Breast cancer is the dominant cancer in women in both developed and developing countries. The objective of this study was to assess the knowledge, attitudes, practices and factors associated with early breast cancer screening among women in the Municipality of Abomey-Calavi in Benin. Methods: This was a cross-sectional, descriptive, analytical study with prospective data collection from October 1 to 8, 2018, involving 1740 women in the Municipality of Abomey-Calavi, aged 18 years or older and selected by WHO four-stage random cluster sampling. Consenting women who were mentally competent, 18 years of age or older at the time of the survey, and residing continuously in the Municipality of Abomey-Calavi for the last six months prior to the survey were included. On the other hand, women who belonged to a breast cancer prevention service, women in whom secondary screening was noted, or non-consenting women were not included. The initial minimum size was estimated by the Schwartz formula with a cluster effect of k = 2. Information was collected by questionnaire survey, entered with Epidata 3.1. Fr and analyzed with R Studio 3.5.1. software. Results: The mean age of the women surveyed was 32.0 ± 11.5 years with a range of 18 and 71 years. Regarding knowledge, the clinical manifestation known by the majority of women was the presence of a nodule (68.50%). In the series, 1308 (75.17%) declared having heard about breast cancer once before, either on the radio, television or from friends and 726 (55.50%) had heard about breast cancer screening. Five hundred and twelve (70.52%) of the 726 who had heard of breast cancer said they knew that breast cancer could be screened earlier. Breast self-examination was the most cited screening method (67.58%). The disease is of natural origin according to 37.84% of them. Regarding attitudes and practices, the prevalence of early breast cancer screening was 12.93%, of which 11.67% declared that they had checked themselves to know whether they were carriers of the disease or not. The main means of the early screening used was breast self-examination (85.78%). Factors associated with early breast cancer screening found in multivariate analysis were age (≤50 years), education level (increasingly higher), marital status (married/coupled), place of residence (downtown), and socioeconomic level (average/high). Conclusion: The frequency of early breast cancer screening among women is still low in the municipality of Abomey-Calavi, although they have a good knowledge of the disease. This raises the need to strengthen awareness of early breast cancer screening.

Breast cancer and rectal cancer associated with Lynch syndrome:A case report

BACKGROUND The development mechanisms of Lynch syndrome(LS)-related breast cancer(BC)and rectal cancer are complex and variable,leading to personalized variations in diagnosis and treatment plans.CASE SUMMARY This paper presents a comprehensive review of clinical diagnosis and treatment data from a patient with LS-associated BC and rectal cancer.Moreover,screening data and management guidelines,as well as relevant literature on LS,are included in this report.This study summarizes the molecular pathogenesis,clinicopathological features,and screening and management protocols for LS-associated BC and rectal cancer.CONCLUSION Implementing early screening,prevention,and timely diagnosis and treatment measures is expected to reduce mitigate the incidence and mortality of LS-related BC and rectal cancer.

Systematic Analysis of Factors Associated with Late Breast Cancer Screening in Women in Sub-Saharan Africa from 2014 to 2020

Research background: Breast cancer remains a major public health problem, with a high number of new cases and deaths each year. However, despite advances in research to improve this disease, there is a high rate of late detection, leading to diagnosis at an advanced stage and a reduced chance of survival. Objective: The aim of this study is to identify the factors associated with late detection of breast cancer in women in Sub-Saharan Africa from 2014 to 2020.Setting: This systematic review focuses on sub-Saharan Africa. Methods: We searched for articles in four databases (PubMed, Embase, Global-Health and CINAHL) between 2014 and 2020 and performed a narrative synthesis to organize and group the different factors associated with late breast cancer detection. Result: After reviewing 583 publications, 6 studies were selected, highlighting factors such as lack of awareness, knowledge gaps, difficulties in accessing health services and financial constraints associated with late breast cancer screening. The participants, who ranged in number from 20 to 1776, were mainly aged between 18 and 25, with a mean age of 25 years and 6 months. Conclusion: The analysis enabled us to identify various factors associated with late breast cancer screening. Collaboration between health professionals, community organizations and policy-makers is essential to foster an environment conducive to the prevention and early detection of breast cancer.

Matrine promotes colorectal cancer apoptosis by downregulating shank-associated RH domain interactor expression

BACKGROUND The 5-year survival rate of patients with colorectal cancer(CRC)in China is only 56.9%,highlighting the need for new therapeutic drugs.Previous studies have shown that matrine exhibits antitumor effects by inducing apoptosis.However,the mechanism by which matrine regulates antiapoptotic proteins in CRC remains unclear.AIM To identify apoptotic proteins from proteomics and investigate the role of matrine in impeding CRC apoptosis by regulating these proteins.METHODS Tumor and adjacent normal tissues were collected from 52 patients with CRC who underwent surgery between January and December 2021.Data-independent acquisition quantitative proteomic analysis was performed to identify differentially expressed apoptotic proteins.The selected apoptotic proteins were identified through their association with tumor-node-metastasis(TNM)stage and prognosis,then confirmed by immunohistochemical(IHC)staining in validation cohort.In vitro,the role of matrine or apoptotic proteins on cancer cells were analyzed.RESULTS Compared to normal tissues,88 anti-apoptotic proteins from proteomic results were selected.Among them,Shankassociated RH domain interactor(SHARPIN)was identified because of its relationship with TNM stage and overall survival in TCGA database.In the IHC-confirmed cohort,SHARPIN was highly expressed in CRC tissues and localized in the cytoplasm.Higher SHARPIN expression was associated with TNM stage,carbohydrate antigen 153 levels,and gross type compared to low expression.SHARPIN knockdown promoted apoptosis,significantly upregulated the expression of Bcl-2 associated agonist of cell death,Bcl-2 associated X protein,caspase 3,and caspase 8,and downregulated B-cell lymphoma-2(P<0.05).Importantly,matrine treatment promoted apoptosis and reversed the proliferation,invasion,and migration of CRC cells by repressing SHARPIN.CONCLUSION SHARPIN was identified as an upregulated anti-apoptotic protein in CRC,and matrine exhibited anticancer effects by downregulating its expression.Thus,matrine appears to be a promising drug for CRC.

Research progress of tumor-associated macrophages in immune checkpoint inhibitor tolerance in colorectal cancer

The relevant mechanism of tumor-associated macrophages(TAMs)in the treatment of colorectal cancer patients with immune checkpoint inhibitors(ICIs)is discussed,and the application prospects of TAMs in reversing the treatment tolerance of ICIs are discussed to provide a reference for related studies.As a class of drugs widely used in clinical tumor immunotherapy,ICIs can act on regulatory molecules on cells that play an inhibitory role-immune checkpoints-and kill tumors in the form of an immune response by activating a variety of immune cells in the immune system.The sensitivity of patients with different types of colorectal cancer to ICI treatment varies greatly.The phenotype and function of TAMs in the colorectal cancer microenvironment are closely related to the efficacy of ICIs.ICIs can regulate the phenotypic function of TAMs,and TAMs can also affect the tolerance of colorectal cancer to ICI therapy.TAMs play an important role in ICI resistance,and making full use of this target as a therapeutic strategy is expected to improve the immunotherapy efficacy and prognosis of patients with colorectal cancer.

Carnitine palmitoyltransferase-II inactivity promotes malignant progression of metabolic dysfunction-associated fatty liver disease via liver cancer stem cell activation

BACKGROUND Metabolic dysfunction-associated fatty liver disease(MAFLD)is one of the main chronic liver diseases.However,the roles of mitochondrial carnitine palmitoyl transferase-II(CPT-II)downregulation and liver cancer stem cell(LCSC)activation remain to be identified.AIM To investigate the dynamic alterations in CPT-II inactivity and LCSC activation during the malignant progression of MAFLD.METHODS Dynamic models of mouse MAFLD were generated via the consumption of a high-fat diet or the addition of 2-fluorenylacetamide for hepatocarcinogenesis.The mice were divided into groups on the basis of hematoxylin and eosin staining.Biochemistries,CPT-II,intrahepatic T cells,and LCSCs were determined and confirmed in clinical samples.The mitochondrial membrane potential(MMP)was analyzed.Differentially expressed genes were screened via RNA sequencing and enriched in KEGG pathways or GO functions.RESULTS Dynamic models of MAFLD malignant transformation were successfully generated on the basis of pathological examination.Hepatic lipid accumulation was associated with the loss of mitochondrial CPT-II activity and alterations in the MMP,with decreases in liver CD3+or CD4+T cells and increased AFP levels.In the lipid accumulation microenvironment,mitochondrial CPT-II was inactivated,followed by aberrant activation of CD44+or CD24+LCSCs,as validated in MAFLD or hepatocellular carcinoma patient samples.In terms of mechanism,the biological process category focused mainly on the metabolic regulation of cells in response to external stimuli.The enriched molecular functions included protein binding,cell apoptosis,and cell proliferation.CONCLUSION CPT-II inactivity promotes the malignant progression of MAFLD via the loss of innate immune function and abnormal LCSC activation.

Inhibition of M2 tumor-associated macrophages polarization by modulating the Wnt/β-catenin pathway as a possible liver cancer therapy method

The problem of liver cancer is becoming increasingly important due to the epi-demic of metabolic diseases and persistent high alcohol consumption.This deter-mines great attention to the development and improvement of methods for early diagnosis and treatment of liver cancer.Huang et al presented a study in the World Journal of Gastroenterology,in which they showed that the use of the traditional Chinese medicine Calculus bovis(CB)can suppress tumor growth in mice by inhibiting M2 tumor-associated macrophages(TAM)through modulating the activity of the Wnt/β-catenin pathway.The interaction of CB components with the Wnt/β-catenin pathway,M2 TAM polarization,and tumor dynamics were studied using network pharmacology,transcriptomics,and molecular docking.It is now generally accepted that the polarization of TAM and the differentiation of the functions of M1 and M2 phagocytes are of great importance for the progression of neoplasms.It is assumed that M2 TAM promote proliferation and migration of tumor cells.Attempts to medicinally influence the Wnt/β-catenin pathway in order to modulate phagocyte polarization now belong to one of the most promising areas of immunotherapy of oncological diseases.Undoubtedly,the work of the Chinese authors deserves attention and further development.