Roles of phosphatidylinositol-3-kinases signaling pathway in inflammation-related cancer:Impact of rs10889677 variant and buparlisib in colitis-associated cancer

BACKGROUND Phosphatidylinositol-3-kinases(PI3K)is a well-known route in inflammationrelated cancer.Recent discovery on PI3K-related genes revealed a potential variant that links ulcerative colitis(UC)and colorectal cancer(CRC)with colitisassociated cancer(CAC).PI3K/AKT pathway has been recommended as a potential additional therapeutic option for CRC due to its substantial role in modifying cellular processes.Buparlisib is a pan-class I PI3K inhibitor previously shown to reduce tumor growth.AIM To investigate the regulation of rs10889677 and the role of buparlisib in the PI3K signaling pathway in CAC pathogenesis.METHODS Genomic DNA from 32 colonic samples,including CAC(n=7),UC(n=10)and CRC(n=15),was sequenced for the rs10889677 mutation.The mutant and wildtype fragments were amplified and cloned in the pmirGLO vector.The luciferase activity of cloned vectors was assessed after transfection into the HT29 cell line.CAC mice were induced by a mixture of a single azoxymethane injection and three cycles of dextran sulphate sodium,then buparlisib was administered after 14 d.The excised colon was subjected to immunohistochemistry for Ki67 and Cleaved-caspase-3 markers and quantitative real-time polymerase chain reaction analysis for Pdk1 and Sgk2.RESULTS Luciferase activity decreased by 2.07-fold in the rs10889677 mutant,confirming the hypothesis that the variant disrupted miRNA binding sites,which led to an increase in IL23R expression and the activation of the PI3K signaling pathway.Furthermore,CAC-induced mice had a significantly higher disease activity index(P<0.05).Buparlisib treatment significantly decreased mean weight loss in CAC-induced mice(P<0.05),reduced the percentage of proliferating cells by 5%,and increased the number of apoptotic cells.The treatment also caused a downward trend of Pdk1 expression and significantly decreased Sgk2 expression.CONCLUSION Our findings suggested that the rs10889677 variant as a critical initiator of the PI3K signaling pathway,and buparlisib had the ability to prevent PI3K-non-AKT activation in the pathophysiology of CAC.

Interleukin-34 deficiency aggravates development of colitis and colitis-associated cancer in mice

BACKGROUND Although expression of interleukin(IL)-34 is upregulated in active ulcerative colitis(UC),the molecular function and underlying mechanism are largely unclear.AIM To investigate the function of IL-34 in acute colitis,in a wound healing model and in colitis-associated cancer in IL-34-deficient mice.METHODS Colitis was induced by administration of dextran sodium sulfate(DSS),and carcinogenesis was induced by azoxymethane(AOM).Whether the impact of IL-34 on colitis was dependent on macrophages was validated by depletion of macrophages in a murine model.The association between IL-34 expression and epithelial proliferation was studied in patients with active UC.RESULTS IL-34 deficiency aggravated murine colitis in acute colitis and in wound healing phase.The effect of IL-34 on experimental colitis was not dependent on macrophage differentiation and polarization.IL-34-deficient mice developed more tumors than wild-type mice following administration of AOM and DSS.No significant difference was shown in degree of cellular differentiation in tumors between wild-type and IL-34-deficient mice.IL-34 was dramatically increased in the active UC patients as previously reported.More importantly,expression of IL-34 was positively correlated with epithelial cell proliferation in patients with UC.CONCLUSION IL-34 deficiency exacerbates colonic inflammation and accelerates colitis-associated carcinogenesis in mice.It might be served as a potential therapeutic target in UC.

Lactobacillus bulgaricus inhibits colitis-associated cancer via a negative regulation of intestinal inflammation in azoxymethane/dextran sodium sulfate model

BACKGROUND Colitis-associated cancer(CAC)accounts for 2%-3%of colorectal cancer(CRC)cases preceded by inflammatory bowel diseases(IBD)such as Crohn's disease and ulcerative colitis.Intestinal microbiota has been reported to play a central role in the pathogenesis of IBD and CAC.Recently,numerous prebiotics and probiotics have being investigated as antitumor agents due to their capacity to modulate inflammatory responses.Previous studies have indicated that lactic acid bacteria could be successfully used in managing sporadic CRC,however little is known about their role in CAC.AIM To investigate the effect of the probiotic Lactobacillus bulgaricus(L.bulgaricus)during the development of an experimental model of colitis associated colon cancer(CAC).METHODS C57BL/6 mice received an intraperitoneal injection of azoxymethane(10 mg/kg),followed by three cycles of sodium dextran sulphate diluted in water(5%w/v).Probiotic group received daily L.bulgaricus.Intestinal inflammation was determined by scoring clinical signs.Cytokines levels were determined from colon and/or tumor samples by ELISA BD OptEIATM kits.The level of significance was set at P<0.05.Graphs were generated and statistical analysis performed using the software GraphPad Prism 6.0.RESULTS L.bulgaricus treatment inhibited of total tumor volume and mean size of tumors.In addition,the probiotic also attenuated the clinical signs of intestinal inflammation inducing a decrease in intestinal and tumor levels of IL-6,TNF-α,IL-17,IL-23 and IL-1β.CONCLUSION Our results suggest a potential chemopreventive effect of probiotic on CAC.L.bulgaricus regulates the inflammatory response and preventing CAC.

Status of colitis-associated cancer in ulcerative colitis

Surgical therapy for ulcerative colitis(UC) depends on the medical therapy administered for the patient's condition. UC is a benign disease. However, it has been reported that the rare cases of cancer in UC patients are increasing, and such cases have a worse prognosis. Recently, surgical therapy has greatly changed, there has been quite an increase in the number of UC patients with high-grade dysplasia and/or cancer. These lesions are known as colitis-associated cancer(CAC). The relationship between inflammation and tumorigenesis is well-established, and in the last decade, a great deal of supporting evidence has been obtained from genetic, pharmacological, and epidemiological studies. Inflammatory bowel disease, especially UC, is an important risk factor for the development of colon cancer. We should determine the risk factors for UC patients with cancer based on a large body of data, and we should attempt to prevent the increase in the number of such patients using these newly identified risk factors in the near future. Actively introducing the surgical treatment in addition to medical treatment should be considered. Several physicians should analyze UC from their unique perspectives in order to establish new clinically relevant diagnostic and treatment methods in the future. This article discusses CAC, including its etiology, mechanism, diagnosis, and treatment in UC patients.

Potential of new anti-cancer agents targeting the nuclear translocation signaling of HB-EGF C-terminal fragments during the development of colitis-associated cancer

In inflammatory bowel diseases (IBD) such as ulcerative colitis (UC) and Crohn’s disease (CD), the duration and severity of inflammation are responsible for the development of colorectal cancer. Inflammatory cytokines such as interleukin (IL)-8 and tumor necrotic factor (TNF)-a, which are released by epithelial and immune cells, are involved in the pathogenesis of colitis-associated cancer. Current treatments for advanced colorectal cancers focus primarily on targeting epidermal growth factor receptor (EGFR) signaling. IL-8 (a G-protein coupled receptor (GPCR) agonist), which is involved in neutrophil recruitment and activation in persistent active colitis, also promotes cleavage of theproheparin-binding epidermal growth factor—like growth factor (proHB-EGF) through a disintegrin and metalloproteinase (ADAM), so that the resulting soluble HB-EGF activates EGFR. In parallel, the carboxy-terminal fragment of proHB-EGF (HB-EGF-CTF) translocates into the inner nuclear membrane, where HB-EGF-CTF binds the nuclear promyelocytic leukemia zinc finger (PLZF) protein, resulting in the nuclear export of the PLZF transcriptional repressor and thereby affecting cell proliferation. Screening for potent chemical inhibitors of the interactions between HB-EGF-CTF and PLZF identified telmisartan (and related compounds in corporating a biphenyl tetrazole moiety) as inhibitors of cell proliferation. Here we focus on the inhibitory effects of these compounds on cell proliferation, demonstrating the potential for targeting the nuclear translocation of HB-EGF-CTF in the treatment of colitis-associated cancer.

Diacerein treatment prevents colitis-associated cancer in mice

BACKGROUND Inflammation is a well-established enabling factor for cancer development and provides a framework for the high prevalence of colon cancer in inflammatory bowel disease.In accordance,chronic inflammation has recently been implicated in the development of cancer stem cells(CSCs).However,the mechanism whereby anti-inflammatory drugs act in the prevention of colitis-associated cancer(CAC)is only partially understood.AIM To evaluate the role of diacerein(DAR),an anti-inflammatory drug that mainly acts through the inhibition of interleukin(IL)-1βexpression in the development of CSCs and CAC.METHODS The effects of DAR on colon inflammation in mice with CAC were evaluated by inflammatory index,reverse real-time transcription polymerase chain reaction and western blot.Cytokine levels were measured by enzyme-linked immunosorbent assay.Cells assays evaluated the effects of DAR on CSCs.Immunohistochemistry and apoptosis assays were also used to evaluate the effects of DAR on tumorigenesis associated with inflammation.RESULTS DAR treatment reduced colon inflammation as well as the number and size of tumors in azoxymethane plus dextran sulphate sodium-treated animals.Accordingly,DAR treatment was associated with reduced intracellular signals of inflammation(inhibitor of nuclear factor kappa B kinase and c-Jun N-terminal kinase phosphorylation)in the colon.In addition,DAR treatment was associated with a decrease in colon CSC formation,suggesting that besides reducing colonic inflammation,DAR has a direct effect on the inhibition of colon carcinogenesis.CONCLUSION Together,these data indicate that DAR-mediated IL-1βsuppression attenuates inflammation-induced colon cancer and CSC formation,highlighting DAR as a potential candidate for the chemoprevention of CAC.

Macrophage involvement in the pathological evolution of ulcerative colitis-associated colon cancer and progress of related traditional Chinese medicine drug interventions

Intestinal macrophages are essential players in intestinal inflammation and intestinal immune homeostasis.Intestinal macrophages have the ability to polarize into two distinct phenotypes based on various environmental signals.These phenotypes include the typically activated pro-inflammatory M1 phenotype and the alternatively activated anti-inflammatory M2 phenotype.Under normal circumstances,intestinal macrophages prevent inflammatory damage to the gut.However,when genetic and environmental factors influence the polarization of intestinal macrophages,it can lead to an imbalance in M1/M2 macrophage activation and subsequently an imbalance in the control of intestinal inflammation.It transforms physiological inflammation into pathological intestinal damage.In patients with ulcerative colitis-associated cancer(UC-CRC),intestinal inflammatory disorders are closely associated with intestinal M1/M2 macrophage polarization imbalance.Consequently,restoring the polarization equilibrium of M1/M2 macrophages might be an evidence of traditional Chinese medicine in the treatment of UC-CRC,the pivotal role o effective measure to prevent and treat UC-CRC.This paper aims to examine the clinicalf macrophage polarization in UC-CRC pathogenesis,and the potential mechanisms of traditional Chinese medicine in regulating macrophage polarization to treat UC-CRC.Our goal is to provide novel insights into the clinical practice,basic research,and drug development of UC-CRC.

Update and latest advances in mechanisms and management of colitis-associated colorectal cancer

Colitis-associated colorectal cancer(CAC)is defined as a specific cluster of colorectal cancers that develop as a result of prolonged colitis in patients with inflammatory bowel disease(IBD).Patients with IBD,including ulcerative colitis and Crohn’s disease,are known to have an increased risk of developing CAC.Although the incidence of CAC has significantly decreased over the past few decades,individuals with CAC have increased mortality compared to individuals with sporadic colorectal cancer,and the incidence of CAC increases with duration.Chronic inflammation is generally recognized as a major contributor to the pathogenesis of CAC.CAC has been shown to progress from colitis to dysplasia and finally to carcinoma.Accumulating evidence suggests that multiple immune-mediated pathways,DNA damage pathways,and pathogens are involved in the pathogenesis of CAC.Over the past decade,there has been an increasing effort to develop clinical approaches that could help improve outcomes for CAC patients.Colonoscopic surveillance plays an important role in reducing the risk of advanced and interval cancers.It is generally recommended that CAC patients undergo endoscopic removal or colectomy.This review summarizes the current understanding of CAC,particularly its epidemiology,mechanisms,and management.It focuses on the mechanisms that contribute to the development of CAC,covering advances in genomics,immunology,and the microbiome;presents evidence for management strategies,including endoscopy and colectomy;and discusses new strategies to interfere with the process and development of CAC.These scientific findings will pave the way for the management of CAC in the near future.

Study on the mechanism of action of Feng-Liao-Chang-Wei-Kang combined with 5-fluorouracil in the treatment of colitis-associated colon cancer

Objective:To investigate the therapeutic effects and mechanisms of Feng-Liao-Chang-Wei-Kang combined with 5-fluorouracil administration in mice with colitis-associated colon cancer.Methods:To establish a colitis-associated colon cancer mouse model and observe the behavior and activity of mice after Feng-Liao-Chang-Wei-Kang and 5-fluorouracil administration;HE staining to observe the pathological changes of mouse colonic tissue;Western blot was used to detect the expression of mouse colon tissue in IL-6/STAT3 pathway-related proteins.Results:The survival rate of mice in the co-administered group was significantly increased,and the intestinal wall thickening and interstitial inflammation of mice were significantly reduced.Western blot results showed that the expression levels of P-STAT3 and IL-6 were significantly increased in the colonic tissue of mice after modeling,and the combined administration inhibited the expression of Cyclin D1,CDK4 and Bcl-2 protein in the IL-6/STAT3 pathway and upregulated the expression of Bax(P<0.05).Conclusion:Feng-Liao-Chang-Wei-Kang combined with 5-fluorouracil inhibits IL-6/STAT3 pathway to exert inhibition of colitis-associated colon cancer inhibition of colitis-associated colon cancer.

Evodiamine inhibits high-fat diet-induced colitis-associated cancer in mice through regulating the gut microbiota

Objective:High-fat diet is one of the main risk factors that disrupt the balance of gut microbiota,which eventually will induce colorectal cancer(CRC).Evodiamine(EVO)is a wildly used multifunctional traditional Chinese medicine extract.In this study,we investigated the role of gut microbiota in high-fat dietpropelled CRC and the potential of EVO for CRC chemoprevention.Methods:Gut microbiota,serum D-lactic acid and endotoxin from 38 patients with colon cancer and 18 healthy subjects were detected by quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay(ELISA).In addition,body mass index,phospho-signal transducer and activator of transcription 3(p-STAT3)expression in cancer tissues and paracancerous tissues were detected by immunohistochemistry.A mouse intestinal inflammatory tumor model was established by azomethane/sodium dextran sulfate,followed by treatment with EVO and 5-aminosalicylic acid(ASA).Gut microbiota and inflammatory factors were detected by quantitative polymerase chain reaction,while serum D-lactic acid and endotoxin were detected by ELISA.Furthermore,cell proliferation,cell apoptosis,and interleukin(IL)-6/STAT3/P65 pathway were evaluated by 5-ethynyl-20-deoxyuridine,terminal-deoxynucleotidyl transferase-mediated nick-end labeling,and Western blot assays.Results:In patients with colon cancer,the numbers of Enterococcus faecalis and Escherichia coli were increased,while those of Bifidobacterium,Campylobacter and Lactobacillus were decreased.Serum endotoxin and D-lactic acid levels and p-STAT3 levels were significantly increased.In the mouse model,both EVO and ASA inhibited tumor formation,decreased the proliferation of tumor cells,and induced apoptosis of tumor cells.Compared with the control group,the numbers of E.faecalis and E.coli were decreased,while Bifidobacterium,Campylobacter and Lactobacillus numbers were increased.In the EVO group,serum endotoxin and D-lactic acid levels and inflammatory factors were significantly decreased.Further,the IL6/STAT3/P65 signaling pathway was inhibited in the EVO group.Conclusion:EVO may inhibit the occurrence of colon cancer by regulating gut microbiota and inhibiting intestinal inflammation.The potential mechanism involves inhibition of the IL6/STAT3/P65 signaling pathway,revealing its potential therapeutic significance in clinical applications.

Mitochondrial transcription factor A plays opposite roles in the initiation and progression of colitis-associated cancer

Background:Mitochondria are key regulators in cell proliferation and apoptosis.Alterations in mitochondrial function are closely associated with inflammation and tumorigenesis.This study aimed to investigate whether mitochondrial transcription factor A(TFAM),a key regulator of mitochondrial DNA transcription and replication,is involved in the initiation and progression of colitis-associated cancer(CAC).Methods:TFAM expression was examined in tissue samples of inflammatory bowel diseases(IBD)and CAC by immunohistochemistry.Intestinal epithelial cell(IEC)-specific TFAM-knockout mice(TFAM^(△IEC))and colorectal cancer(CRC)cells with TFAM knockdown or overexpression were used to evaluate the role of TFAMin colitis and the initiation and progression ofCAC.The underlying mechanisms of TFAMwere also explored by analyzingmitochondrial respiration function and biogenesis.Results:The expression of TFAM was downregulated in active IBD and negatively associated with the disease activity.The downregulation of TFAM in IECs was induced by interleukin-6 in a signal transducer and activator of transcription 3(STAT3)/miR-23b-dependent manner.In addition,TFAM knockout impaired IECturnover to promote dextran sulfate sodium(DSS)-induced colitis inmice.Of note,TFAMknockout increased the susceptibility of mice to azoxymethane/DSSinduced CAC and TFAM overexpression protected mice from intestinal inflammation and colitis-associated tumorigenesis.By contrast,TFAM expression was upregulated in CAC tissues and contributed to cell growth.Furthermore,it was demonstrated that β-catenin induced the upregulation of TFAM through c-Myc in CRC cells.Mechanistically,TFAMpromoted the proliferation of both IECs and CRC cells by increasing mitochondrial biogenesis and activity.Conclusions:TFAM plays a dual role in the initiation and progression of CAC,providing a novel understanding of CAC pathogenesis.

Ulcerative colitis-associated colorectal cancer

The association between ulcerative colitis(UC) and colorectal cancer(CRC) has been acknowledged. One of the most serious and life threatening consequences of UC is the development of CRC(UC-CRC). UC-CRC patients are younger, more frequently have multiple cancerous lesions, and histologically show mucinous or signet ring cell carcinomas. The risk of CRC begins to increase 8 or 10 years after the diagnosis of UC. Risk factors for CRC with UC patients include young age at diagnosis, longer duration, greater anatomical extent of colonic involvement, the degree of inflammation, family history of CRC, and presence of primary sclerosing cholangitis. CRC on the ground of UC develop from non-dysplastic mucosa to indefinite dysplasia, lowgrade dysplasia, high-grade dysplasia and finally to invasive adenocarcinoma. Colonoscopy surveillance programs are recommended to reduce the risk of CRC and mortality in UC. Genetic alterations might play a role in the development of UC-CRC. 5-aminosalicylates might represent a favorable therapeutic option for chemoprevention of CRC.

Colitis-associated colon cancer:Is it in your genes?

Colitis-associated colorectal cancer(CA-CRC) is the cause of death in 10%-15% of inflammatory bowel disease(IBD) patients. CA-CRC results from the accumulation of mutations in intestinal epithelial cells and progresses through a well-characterized inflammation to dysplasia to carcinoma sequence. Quantitative estimates of overall CA-CRC risks are highly variable ranging from 2% to 40% depending on IBD severity, duration and location, with IBD duration being the most significant risk factor associated with CA-CRC development. Recently, studies have identified IBD patients with similar patterns of colonic inflammation, but that differ with respect to CA-CRC development, suggesting a role for additional non-inflammatory risk factors in CA-CRC development. One suggestion is that select IBD patients carry polymorphisms in various low penetrance disease susceptibility genes, which predispose them to CA-CRC development, although these loci have proven difficult to identify in human genomewide association studies. Mouse models of CA-CRC have provided a viable alternative for the discovery, validation and study of individual genes in CA-CRC pathology. In this review, we summarize the current CA-CRC literature with a strong focus on genetic predisposition and highlight an emerging role for mouse models in the search for CA-CRC risk alleles.

Landscape of cell heterogeneity and evolutionary trajectory in ulcerative colitis-associated colon cancer revealed by single-cell RNA sequencing

Objective:The goal of this study was to get preliminary insight on the intra-tumor heterogeneity in colitisassociated cancer(CAC)and to reveal a potential evolutionary trajectory from ulcerative colitis(UC)to CAC at the single-cell level.Methods:Fresh samples of tumor tissues and adjacent UC tissues from a CAC patient with pT3N1M0 stage cancer were examined by single-cell RNA sequencing(scRNA-seq).Data from The Cancer Genome Atlas(TCGA)and The Human Protein Atlas were used to confirm the different expression levels in normal and tumor tissues and to determine their relationships with patient prognosis.Results:Ultimately,4,777 single-cell transcriptomes(1,220 genes per cell)were examined,of which 2,250(47%)and 2,527(53%)originated from tumor and adjacent UC tissues,respectively.We defined the composition of cancer-associated stromal cells and identified six cell clusters,including myeloid,T and B cells,fibroblasts,endothelial and epithelial cells.Notable pathways and transcription factors involved in these cell clusters were analyzed and described.Moreover,the precise cellular composition and developmental trajectory from UC to UCassociated colon cancer were graphed,and it was predicted that CD74,CLCA1,and DPEP1 played a potential role in disease progression.Conclusions:scRNA-seq technology revealed intra-tumor cell heterogeneity in UC-associated colon cancer,and might provide a promising direction to identify novel potential therapeutic targets in the evolution from UC to CAC.

Stage at diagnosis of colorectal cancer through diagnostic route:Who should be screened?

BACKGROUND Colorectal cancer(CRC)is a global health concern,with advanced-stage diagnoses contributing to poor prognoses.The efficacy of CRC screening has been well-established;nevertheless,a significant proportion of patients remain unscreened,with>70%of cases diagnosed outside screening.Although identifying specific subgroups for whom CRC screening should be particularly recommended is crucial owing to limited resources,the association between the diagnostic routes and identification of these subgroups has been less appreciated.In the Japanese cancer registry,the diagnostic routes for groups discovered outside of screening are primarily categorized into those with comorbidities found during hospital visits and those with CRC-related symptoms.AIM To clarify the stage at CRC diagnosis based on diagnostic routes.METHODS We conducted a retrospective observational study using a cancer registry of patients with CRC between January 2016 and December 2019 at two hospitals.The diagnostic routes were primarily classified into three groups:Cancer screening,follow-up,and symptomatic.The early-stage was defined as Stages 0 or I.Multivariate and univariate logistic regressions were exploited to determine the odds of early-stage diagnosis in the symptomatic and cancer screening groups,referencing the follow-up group.The adjusted covariates were age,sex,and tumor location.RESULTS Of the 2083 patients,715(34.4%),1064(51.1%),and 304(14.6%)belonged to the follow-up,symptomatic,and cancer screening groups,respectively.Among the 2083 patients,CRCs diagnosed at an early stage were 57.3%(410 of 715),23.9%(254 of 1064),and 59.5%(181 of 304)in the follow-up,symptomatic,and cancer screening groups,respectively.The symptomatic group exhibited a lower likelihood of early-stage diagnosis than the follow-up group[P<0.001,adjusted odds ratio(aOR),0.23;95%confidence interval(95%CI):0.19-0.29].The likelihood of diagnosis at an early stage was similar between the follow-up and cancer screening groups(P=0.493,aOR for early-stage diagnosis in the cancer screening group vs follow-up group=1.11;95%CI=0.82-1.49).CONCLUSION CRCs detected during hospital visits for comorbidities were diagnosed earlier,similar to cancer screening.CRC screening should be recommended,particularly for patients without periodical hospital visits for comorbidities.

Dietary Lactiplantibacillus plantarum KX041 attenuates colitis-associated tumorigenesis and modulates gut microbiota

Colorectal cancer(CRC)is one of the most common cancers and supplementation of probiotics may be a promising intervention method. The present study aimed to investigate the anti-CRC effects of Lactiplantibacillus plantarum KX041 on a CRC mouse model. The CRC mice were induced by 10 mg/kg azoxymethane and 2% dextran sulfate sodium. L. plantarum KX041 was orally administrated once daily(1 × 10^(9) CFU/mouse). Results showed that L. plantarum KX041 could significantly inhibit inflammation, tumor formation, and induce tumor cells apoptosis. Moreover, this probiotic could ameliorate the damage of intestinal barrier by recovering tight junction protein expression(like Occludin, Claudin-1, and ZO-1)and preventing goblet cell loss. Furthermore, the oxidative stress was alleviated by increasing the level of antioxidant mediators(like GSH and SOD)and reducing the level of oxidative mediators(like MDA and MPO). In addition, treatment with L. plantarum KX041 could directly regulate gut microbiota, thereby increasing the abundance of beneficial bacteria(like SCFAs-producing bacteria, Akkermansia)and decreasing the abundance of harmful bacteria(like pro-inflammatory bacteria, Parasutterella), which in turn raised SCFAs levels and lowered LPS levels. In conclusion, L. plantarum KX041 could effectively ameliorate CRC via reshaping intestinal microenvironment, alleviating inflammation, maintaining intestinal permeability, and attenuating oxidative stress.

Biological factors driving colorectal cancer metastasis

Approximately 20%of colorectal cancer(CRC)patients present with metastasis at diagnosis.Among Stage I-III CRC patients who undergo surgical resection,18%typically suffer from distal metastasis within the first three years following initial treatment.The median survival duration after the diagnosis of metastatic CRC(mCRC)is only 9 mo.mCRC is traditionally considered to be an advanced stage malignancy or is thought to be caused by incomplete resection of tumor tissue,allowing cancer cells to spread from primary to distant organs;however,increa-sing evidence suggests that the mCRC process can begin early in tumor development.CRC patients present with high heterogeneity and diverse cancer phenotypes that are classified on the basis of molecular and morphological alterations.Different genomic and nongenomic events can induce subclone diversity,which leads to cancer and metastasis.Throughout the course of mCRC,metastatic cascades are associated with invasive cancer cell migration through the circulatory system,extravasation,distal seeding,dormancy,and reactivation,with each step requiring specific molecular functions.However,cancer cells presenting neoantigens can be recognized and eliminated by the immune system.In this review,we explain the biological factors that drive CRC metastasis,namely,genomic instability,epigenetic instability,the metastatic cascade,the cancer-immunity cycle,and external lifestyle factors.Despite remarkable progress in CRC research,the role of molecular classification in therapeutic intervention remains unclear.This review shows the driving factors of mCRC which may help in identifying potential candidate biomarkers that can improve the diagnosis and early detection of mCRC cases.

Why is early detection of colon cancer still not possible in 2023?

Colorectal cancer(CRC)screening is a fundamental tool in the prevention and early detection of one of the most prevalent and lethal cancers.Over the years,screening,particularly in those settings where it is well organized,has succeeded in reducing the incidence of colon and rectal cancer and improving the prognosis related to them.Despite considerable advancements in screening technologies and strategies,the effectiveness of CRC screening programs remains less than optimal.This paper examined the multifaceted reasons behind the persistent lack of effect-iveness in CRC screening initiatives.Through a critical analysis of current methodologies,technological limitations,patient-related factors,and systemic challenges,we elucidated the complex interplay that hampers the successful reduction of CRC morbidity and mortality rates.While acknowledging the ad-vancements that have improved aspects of screening,we emphasized the necessity of addressing the identified barriers comprehensively.This study aimed to raise awareness of how important CRC screening is in reducing costs for this disease.Screening and early diagnosis are not only important in improving the prognosis of patients with CRC but can lead to an important reduction in the cost of treating a disease that is often diagnosed at an advanced stage.Spending more sooner can mean saving money later.

Analysis of the impact of immunotherapy efficacy and safety in patients with gastric cancer and liver metastasis

BACKGROUND Gastric cancer(GC)is the fifth most common type of cancer and has the fourth highest death rate among all cancers.There is a lack of studies examining the impact of liver metastases on the effectiveness of immunotherapy in individuals diagnosed with GC.AIM To investigate the influence of liver metastases on the effectiveness and safety of immunotherapy in patients with advanced GC.METHODS This retrospective investigation collected clinical data of patients with advanced stomach cancer who had immunotherapy at our hospital from February 2021 to January 2023.The baseline attributes were compared using either the Chi-square test or the Fisher exact probability method.The chi-square test and Kaplan-Meier survival analysis were employed to assess the therapeutic efficacy and survival duration in GC patients with and without liver metastases.RESULTS The analysis comprised 48 patients diagnosed with advanced GC,who were categorized into two groups:A liver metastasis cohort(n=20)and a non-liver metastatic cohort(n=28).Patients with liver metastasis exhibited a more deteriorated physical condition compared to those without liver metastasis.The objective response rates in the cohort with metastasis and the cohort without metastasis were 15.0%and 35.7%(P>0.05),respectively.Similarly,the disease control rates in these two cohorts were 65.0%and 82.1%(P>0.05),respectively.The median progression-free survival was 5.0 months in one group and 11.2 months in the other group,with a hazard ratio of 0.40 and a significance level(P)less than 0.05.The median overall survival was 12.0 months in one group and 19.0 months in the other group,with a significance level(P)greater than 0.05.CONCLUSION Immunotherapy is less effective in GC patients with liver metastases compared to those without liver metastasis.

Colorectal cancer screening:A review of current knowledge and progress in research

Colorectal cancer(CRC)is one of the most prevalent malignancies worldwide,being the third most commonly diagnosed malignancy and the second leading cause of cancer-related deaths globally.Despite the progress in screening,early diagnosis,and treatment,approximately 20%-25%of CRC patients still present with metastatic disease at the time of their initial diagnosis.Furthermore,the burden of disease is still expected to increase,especially in individuals younger than 50 years old,among whom early-onset CRC incidence has been increasing.Screening and early detection are pivotal to improve CRC-related outcomes.It is well established that CRC screening not only reduces incidence,but also decreases deaths from CRC.Diverse screening strategies have proven effective in decreasing both CRC incidence and mortality,though variations in efficacy have been reported across the literature.However,uncertainties persist regarding the optimal screening method,age intervals and periodicity.Moreover,adherence to CRC screening remains globally low.In recent years,emerging technologies,notably artificial intelligence,and non-invasive biomarkers,have been developed to overcome these barriers.However,controversy exists over the actual impact of some of the new discoveries on CRC-related outcomes and how to effectively integrate them into daily practice.In this review,we aim to cover the current evidence surrounding CRC screening.We will further critically assess novel approaches under investigation,in an effort to differentiate promising inno-vations from mere novelties.