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Background: Inflammation is the most important deriving force for the development of colitis-associated colorectal cancer (CAC) through the Inflammation-Pretumor dysplasia-CAC sequence. T helper (Th) subsets Th9 and Th17 cells can potentially stimulate inflammation in the ulcerative colitis (UC). Therefore, Th9 and Th17 cells may play a promoting role in the colitis-associated dysplasia (CAD). Methods: Using immunohistochemistry (IHC), we evaluated the presentation patterns and densities of T lymphocytes, Th9 and Th17 cells in human UC and CAD tissues. Results: A general increasing trend of CD3-positive T lymphocytes, P.U.1-positive Th9 and interleukin (IL)-17A-positive Th17 cells was illustrated throughout the normal-UC-CAD sequence, IHC images showed that these cells were very prominent in the lamina propria, and some cells were also observed in the epithelium in the CAD tissues. Density analysis revealed that numbers of Th9 and Th17 cells were progressively increased in the CAD tissues as compared with the UC and control tissues. In general, densities of Th9 and Th17 cells in the lamina propria were slightly higher in the non-adenoma-like dysplasia (NALD) tissues than that in the adenoma-like dysplasia (ALD) tissues. However, densities of neither Th9 nor Th17 cells in both the ALD and NALD subgroups were associated with the degree of dysplasia in CAD lesions. Conclusion: Accumulated Th9 and Th17 cells contribute to the immune cellular composition in the CAD tissues and may represent the early conditional change for the Dysplasia-CAC transition. [ABSTRACT FROM AUTHOR]

Objective To investigate the inhibitory effect and mechanism of lentinan on colitis-associated colorectal cancer (CAC) induced by azomethane (AOM)/dextran sulfate sodium salt (DSS) through the IL-6/ STAT3 pathway. Methods C57BL/6 mice were randomly divided into a control group, a model group, a low-dose group (0.865 mg/kg lentinan), a medium-dose group (1.73 mg/kg lentinan), and a high-dose group (3.46 mg/kg lentinan). Except the control group, CAC was induced by AOM/DSS in the other groups, and corresponding drugs were injected intraperitoneally during the modeling process. Body mass, disease activity index (DAI) score, colon length, and tumor number were compared among all groups. Hematoxylin–eosin staining was used to observe the pathological morphology of colon. ELISA was utilized to detect the IL-6, IL1β, and IL-18 contents in serum. Western blot analysis was conducted to detect the expression levels of IL-6, p-STAT3, and c-Myc in colon tissues. Results The tumor number, DAI score, serum IL-6, IL-1β, and IL-18 contents and the expression levels of IL-6, p-STAT3, and c-Myc in the colon tissue of the model group were higher than those of the control group, while the body mass and colon length were lower than those of the control group (P<0.05). The pathological morphology of colon tissues showed adenocarcinoma formation. After different doses of lentinan intervention, the tumor number, DAI score, serum IL-6, IL-1β, and IL-18 contents and the expression levels of IL-6, p-STAT3, and c-Myc in colon tissues were all lower than those in the model group, while body mass and colon length were higher than those in the model group (P<0.05). The pathological morphology of colon tissues showed adenomas of different grades but no adenocarcinoma was found. Conclusion Lentinan inhibits CAC formation, and its anticancer effect is related to the inhibition of the IL-6/STAT3 pathway. [ABSTRACT FROM AUTHOR]

In the colorectal cancer (CRC) niche, the transcription factors signal transducer and activator of transcription 3 (STAT3) and nuclear factor‐κB (NF‐κB) are hyperactivated in both malignant cells and tumor‐infiltrating leukocytes (TILs) and cooperate to maintain cancer cell proliferation/survival and drive protumor inflammation. Through drug repositioning studies, the anthelmintic drug rafoxanide has recently emerged as a potent and selective antitumor molecule for different types of cancer, including CRC. Here, we investigate whether rafoxanide could negatively modulate STAT3/NF‐κB and inflammation‐associated CRC. The antineoplastic effect of rafoxanide was explored in a murine model of CRC resembling colitis‐associated disease. Cell proliferation and/or STAT3/NF‐κB activation were evaluated in colon tissues taken from mice with colitis‐associated CRC, human CRC cells, and CRC patient‐derived explants and organoids after treatment with rafoxanide. The STAT3/NF‐κB activation and cytokine production/secretion were assessed in TILs isolated from CRC specimens and treated with rafoxanide. Finally, we investigated the effects of TIL‐derived supernatants cultured with or without rafoxanide on CRC cell proliferation and STAT3/NF‐κB activation. The results showed that rafoxanide restrains STAT3/NF‐κB activation and inflammation‐associated colon tumorigenesis in vivo without apparent effects on normal intestinal cells. Rafoxanide markedly reduces STAT3/NF‐κB activation in cultured CRC cells, CRC‐derived explants/organoids, and TILs. Finally, rafoxanide treatment impairs the ability of TILs to produce protumor cytokines and promote CRC cell proliferation. We report the novel observation that rafoxanide negatively affects STAT3/NF‐κB oncogenic activity at multiple levels in the CRC microenvironment. Our data suggest that rafoxanide could potentially be deployed as an anticancer drug in inflammation‐associated CRC. [ABSTRACT FROM AUTHOR]

Background: Chronic inflammation is a significant driver in the development of various diseases, including cancer. Colitis-associated colorectal cancer (CA-CRC) refers to the increased risk of colorectal cancer in individuals with chronic inflammatory bowel diseases (IBD) such as ulcerative colitis and Crohn's disease. Methods: This narrative review examines the link between chronic inflammation and CA-CRC. A comprehensive literature search was conducted using PubMed, Scopus, and Web of Science, focusing on studies published between 2000 and 2024. Studies were selected based on relevance to the role of inflammation in CA-CRC, specifically targeting molecular pathways and clinical implications. Both clinical and mechanistic studies were reviewed. Conclusion: Sustained inflammation in the colon fosters a pro-tumorigenic environment, leading to the initiation and progression of CA-CRC. Prevention strategies must focus on controlling chronic inflammation, optimizing IBD management, and implementing regular screenings. Emerging therapies targeting key inflammatory pathways and immune responses, along with microbiome modulation, hold promise for reducing CA-CRC risk. Understanding these molecular mechanisms provides a path toward personalized treatment and better outcomes for patients with IBD at risk of colorectal cancer. [ABSTRACT FROM AUTHOR]

ObjectiveTo investigate the inhibitory effect and mechanism of lentinan on colitis-associated colorectal cancer (CAC) induced by azomethane (AOM)/dextran sulfate sodium salt (DSS) through the IL-6/ STAT3 pathway. MethodsC57BL/6 mice were randomly divided into a control group, a model group, a low-dose group (0.865 mg/kg lentinan), a medium-dose group (1.73 mg/kg lentinan), and a high-dose group (3.46 mg/kg lentinan). Except the control group, CAC was induced by AOM/DSS in the other groups, and corresponding drugs were injected intraperitoneally during the modeling process. Body mass, disease activity index (DAI) score, colon length, and tumor number were compared among all groups. Hematoxylin–eosin staining was used to observe the pathological morphology of colon. ELISA was utilized to detect the IL-6, IL-1β, and IL-18 contents in serum. Western blot analysis was conducted to detect the expression levels of IL-6, p-STAT3, and c-Myc in colon tissues. ResultsThe tumor number, DAI score, serum IL-6, IL-1β, and IL-18 contents and the expression levels of IL-6, p-STAT3, and c-Myc in the colon tissue of the model group were higher than those of the control group, while the body mass and colon length were lower than those of the control group (P

Abstract Colitis-associated colorectal cancer (CAC) frequently develops in patients with inflammatory bowel disease (IBD) who have been exposed to a prolonged state of chronic inflammation. The investigation of pharmacological agents and their mechanisms to prevent precancerous lesions and inhibit their progression remains a significant focus and challenge in CAC research. Previous studies have demonstrated that vitexin effectively mitigates CAC, however, its precise mechanism of action warrants further exploration. This study reveals that the absence of the Vitamin D receptor (VDR) accelerates the progression from chronic colitis to colorectal cancer. Our findings indicate that vitexin can specifically target the VDR protein, facilitating its translocation into the cell nucleus to exert transcriptional activity. Additionally, through a co-culture model of macrophages and cancer cells, we observed that vitexin promotes the polarization of macrophages towards the M1 phenotype, a process that is dependent on VDR. Furthermore, ChIP-seq analysis revealed that vitexin regulates the transcriptional activation of phenazine biosynthesis-like domain protein (PBLD) via VDR. ChIP assays and dual luciferase reporter assays were employed to identify the functional PBLD regulatory region, confirming that the VDR/PBLD pathway is critical for vitexin-mediated regulation of macrophage polarization. Finally, in a mouse model with myeloid VDR gene knockout, we found that the protective effects of vitexin were abolished in mid-stage CAC. In summary, our study establishes that vitexin targets VDR and modulates macrophage polarization through the VDR/PBLD pathway, thereby alleviating the transition from chronic colitis to colorectal cancer.

Objective To investigate the regulatory mechanism of apurnic/apyrimidinic endonuclease 1(APE1) in the transformation of chronic intestinal inflammation to colitis-associated colorectal cancer (CAC). Methods C64S mutant (APE1C64S) mice and APE1 wild type (APE1WT) mice were randomly divided into experimental group and control group.In vivo CAC model was established by azoxymethane (AOM) and dextran sulfate sodium salt (DSS) solution.Immunohistochemistry (IHC) and multiple IHC (mIHC) assays were used to observe the expression of APE1 and immune cell infiltration in colon tissues of each group.A mouse colon cancer cell line MC38 with stable knockdown of APE1 was constructed by lentivirus transfection, and subcutaneous tumor bearing experiments were performed in APE1WT and APE1C64S mice to confirm that tumor cell-derived APE1 caused immunosuppressive tumor microenvironment.The expression of APE1 and CXCL1[chemokine (C-X-C motif) ligand 1]and the infiltration of immune cells in tumor-bearing specimens were analyzed by IHC and mIHC assays.The tumor specimens of a 28-year-old female patient with CAC from Army Medical Center of PLA were analyzed for the expression of APE1 and CXCL1 and the infiltration of immune cells in the tumor and adjacent inflammatory tissues by IHC and mIHC assays. Results Compared with the control group and APE1WT erperimental group, APE1C64S erperimental group had significantly reduced disease activity index and tumor formation, polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) infiltration, and CD4+ and CD8+T cells (P < 0.05).No significant differences were observed in tumor growth and immune cells between APE1WT and APE1C64S mice bearing subcutaneous tumors.However, in the tumor-bearing experiment using tumor cells with knockdown of APE1, the tumor growth was significantly lower and the number of infiltrated PMN-MDSCs was reduced, while those of CD4+ and CD8+T cells were significantly increased (P < 0.05).Furthermore, high expression of APE1 and increased infiltration of PMN-MDSCs were found in the tumor tissues of the young CAC patient, and CD8+T cells were significantly reduced in the tumor tissues compared with the inflammatory tissues (P < 0.05). Conclusion APE1-redox in tumor cells can promote the infiltration of PMN-MDSCs and reduce the number of T cells, thereby forming an immunosuppressive tumor microenvironment and mediating the occurrence and development of CAC.

Abstract Background Pien Tze Huang (PZH), a traditional Chinese medicine formulation, is recognized for its therapeutic effect on colitis and colorectal cancer. However, its protective role and underlying mechanism in colitis-associated colorectal cancer (CAC) remain to be elucidated. Methods A CAC mouse model was established using AOM/DSS. Twenty mice were randomly divided into four groups (n = 5/group): Control, PZH, AOM/DSS, and AOM/DSS + PZH groups. Mice in the PZH and AOM/DSS + PZH group were orally administered PZH (250 mg/kg/d) from the first day of experiment, while the control and AOM/DSS group received an equivalent volume of distilled water. Parameters such as body weight, disease activity index (DAI), colon weight, colon length, colon histomorphology, intestinal tumor formation, serum concentrations of pro-inflammatory cytokines, proliferation and apoptosis in colon tissue were assessed. RNA sequencing was employed to identify the differentially expressed transcripts (DETs) in colonic tissues and related signaling pathways. Wnt/β-Catenin Pathway-Related genes in colon tissue were detected by QPCR and immunohistochemistry (IHC). Results PZH significantly attenuated AOM/DSS-induced weight loss, DAI elevation, colonic weight gain, colon shortening, histological damage, and intestinal tumor formation in mice. PZH also notably decreased serum concentration of IL-6, IL-1β, and TNF-α. Furthermore, PZH inhibited cell proliferation and promote apoptosis in tumor tissues. RNA-seq and KEGG analysis revealed key pathways influenced by PZH, including Wnt/β-catenin signaling pathway. IHC staining confirmed that PZH suppressed the expression of β-catenin, cyclin D1 and c-Myc in colonic tissues. Conclusions PZH ameliorates AOM/DSS-induced CAC in mice by suppressing the activation of Wnt/β-catenin signaling pathway.

Colitis-associated colorectal cancer (CAC) frequently develops in patients with inflammatory bowel disease (IBD) who have been exposed to a prolonged state of chronic inflammation. The investigation of pharmacological agents and their mechanisms to prevent precancerous lesions and inhibit their progression remains a significant focus and challenge in CAC research. Previous studies have demonstrated that vitexin effectively mitigates CAC, however, its precise mechanism of action warrants further exploration. This study reveals that the absence of the Vitamin D receptor (VDR) accelerates the progression from chronic colitis to colorectal cancer. Our findings indicate that vitexin can specifically target the VDR protein, facilitating its translocation into the cell nucleus to exert transcriptional activity. Additionally, through a co-culture model of macrophages and cancer cells, we observed that vitexin promotes the polarization of macrophages towards the M1 phenotype, a process that is dependent on VDR. Furthermore, ChIP-seq analysis revealed that vitexin regulates the transcriptional activation of phenazine biosynthesis-like domain protein (PBLD) via VDR. ChIP assays and dual luciferase reporter assays were employed to identify the functional PBLD regulatory region, confirming that the VDR/PBLD pathway is critical for vitexin-mediated regulation of macrophage polarization. Finally, in a mouse model with myeloid VDR gene knockout, we found that the protective effects of vitexin were abolished in mid-stage CAC. In summary, our study establishes that vitexin targets VDR and modulates macrophage polarization through the VDR/PBLD pathway, thereby alleviating the transition from chronic colitis to colorectal cancer. Highlights: • Deficiency in VDR accelerates the progression from chronic colitis to colorectal cancer. • Vitexin regulates transcription by targeting VDR and upregulating its nuclear expression. • Vitexin induces M1 polarization of macrophages in the tumor microenvironment via the VDR/PBLD signaling pathway, mitigating the progression from chronic colitis to colorectal cancer in mice. [ABSTRACT FROM AUTHOR]

Intestinal inflammation modifies host physiology to promote the occurrence of colorectal cancer (CRC), as seen in colitis-associated CRC. Gut microbiota is crucial in cancer progression, primarily by inducing intestinal chronic inflammatory microenvironment, leading to DNA damage, chromosomal mutation, and alterations in specific metabolite production. Therefore, there is an increasing interest in microbiota-based prevention and treatment strategies, such as probiotics, prebiotics, microbiota-derived metabolites, and fecal microbiota transplantation. This review aims to provide valuable insights into the potential correlations between gut microbiota and colitis-associated CRC, as well as the promising microbiota-based strategies for colitis-associated CRC. [ABSTRACT FROM AUTHOR]

Simple Summary: Inflammatory bowel disease (IBD) increases the risk of developing colitis-associated colorectal cancer (CAC) compared to the general population. The specific genetic alterations associated with the onset of CAC are largely unknown. In this study, we investigated the role of vitamin D3 upregulated protein 1 (VDUP1) in a CAC mouse model. VDUP1 knockout (KO) increased the severity of colitis and CAC development. Our data suggest that VDUP1 may be explored as a potential therapeutic approach for CAC prevention. VDUP1 acts as a tumor suppressor gene in various cancers. VDUP1 is expressed at low levels in sporadic and ulcerative-colitis-associated colorectal cancer. However, the effects of VDUP1 deficiency on CAC remain unclear. In this study, we found that VDUP1 deficiency promoted CAC development in mice. Wild-type (WT) and VDUP1 KO mice were used to investigate the role of VDUP1 in the development of azoxymethane (AOM)- and dextran sulfate sodium (DSS)-induced CAC. VDUP1 levels significantly decreased in the colonic tumor and adjacent nontumoral tissues of WT mice after AOM/DSS treatment. Moreover, AOM/DSS-treated VDUP1 KO mice exhibited a worse survival rate, disease activity index, and tumor burden than WT mice. VDUP1 deficiency significantly induced cell proliferation and anti-apoptosis in tumor tissues of VDUP1 KO mice compared to WT littermates. Additionally, mRNA levels of interleukin-6 and tumor necrosis factor-alpha and active forms of signal transducer and activator of transcription 3 and nuclear factor-kappa B p65 were significantly increased in the tumor tissues of VDUP1 KO mice. Overall, this study demonstrated that the loss of VDUP1 promoted AOM/DSS-induced colon tumorigenesis in mice, highlighting the potential of VDUP1-targeting strategies for colon cancer prevention and treatment. [ABSTRACT FROM AUTHOR]

One of the factors contributing to colorectal cancer (CRC) development is inflammation, which is mostly hypoxia-associated. This study aimed to characterize the morphological and molecular biological features of colon tumors in mice that were tolerant and susceptible to hypoxia based on colitis-associated CRC (CAC). Hypoxia tolerance was assessed through a gasping time evaluation in a decompression chamber. One month later, the animals were experimentally modeled for colitis-associated CRC by intraperitoneal azoxymethane administration and three dextran sulfate sodium consumption cycles. The incidence of tumor development in the distal colon in the susceptible to hypoxia mice was two times higher and all tumors (100%) were represented by adenocarcinomas, while in the tolerant mice, only 14% were adenocarcinomas and 86% were glandular intraepithelial neoplasia. The tumor area assessed on serially stepped sections was statistically significantly higher in the susceptible animals. The number of macrophages, CD3−CD19+, CD3+CD4+, and NK cells in tumors did not differ between animals; however, the number of CD3+CD8+ and vimentin+ cells was higher in the susceptible mice. Changes in the expression of genes regulating the response to hypoxia, inflammation, cell cycle, apoptosis, and epithelial barrier functioning in tumors and the peritumoral area depended on the initial mouse's hypoxia tolerance, which should be taken into account for new CAC diagnostics and treatment approaches development. [ABSTRACT FROM AUTHOR]

Ulcerative colitis (UC) is a chronic inflammatory disease of the intestines that can significantly impact quality of life and lead to various complications. Currently, 5-aminosalicylic acid derivatives, corticosteroids, immunosuppressants, and biologics are the major treatment strategies for UC, but their limitations have raised concerns. Atractylenolides (ATs), sesquiterpene metabolites found in Atractylodes macrocephala Koidz., have shown promising effects in treating UC by exerting immune barrier modulation, alleviating oxidative stress, gut microbiota regulation, improving mitochondrial dysfunction and repairing the intestinal barrier. Furthermore, ATs have been shown to possess remarkable antifibrosis, anti-thrombus, anti-angiogenesis and anti-cancer. These findings suggest that ATs hold important potential in treating UC and its complications. Therefore, this review systematically summarizes the efficacy and potential mechanisms of ATs in treating UC and its complications, providing the latest insights for further research and clinical applications. [ABSTRACT FROM AUTHOR]

Colitis-associated colorectal cancer (CACC) is one of the devastating complications of long-term inflammatory bowel disease and is associated with substantial morbidity and mortality. Combination of azoxymethane (AOM) and dextran sulfate sodium (DSS) has been extensively used for inflammation-mediated colon tumor development due to its reproducibility, potency, histological and molecular changes, and resemblance to human CACC. In the tumor microenvironment and extra-intestinal tissues, PARP-1, NLRP3 inflammasome, and autophagy's biological functions are complicated and encompass intricate interactions between these molecular components. The focus of the present investigation is to determine the colonic and extra-intestinal tissue damage induced by AOM-DSS and related molecular mechanisms. Azoxymethane (10 mg/kg, i.p.; single injection) followed by DSS (3 cycles, 7 days per cycle) over a period of 10 weeks induced colitis-associated colon cancer in male BALB/c mice. By initiating carcinogenesis with a single injection of azoxymethane (AOM) and then establishing inflammation with dextran sulfate sodium (DSS), a two-stage murine model for CACC was developed. Biochemical parameters, ELISA, histopathological and immunohistochemical analysis, and western blotting have been performed to evaluate the colonic, hepatic, testicular and pancreatic damage. In addition, the AOM/DSS-induced damage has been assessed by analyzing the expression of a variety of molecular targets, including proliferating cell nuclear antigen (PCNA), interleukin-10 (IL-10), AMP-activated protein kinase (AMPK), poly (ADP-ribose) polymerase-1 (PARP-1), cysteine-associated protein kinase-1 (caspase-1), NLR family pyrin domain containing 3 (NLRP3), beclin-1, and interleukin-1β (IL-1β). Present findings revealed that AOM/DSS developed tumors in colon tissue followed by extra-intestinal hepatic, testicular, and pancreatic damages. [ABSTRACT FROM AUTHOR]

Colitis-associated colorectal cancer has been a hot topic in public health issues worldwide. Numerous studies have demonstrated the significance of myeloid-derived suppressor cells (MDSCs) in the progression of this ailment, but the specific mechanism of their role in the transformation of inflammation to cancer is unclear, and potential therapies targeting MDSC are also unclear. This paper outlines the possible involvement of MDSC to the development of colitis-associated colorectal cancer. It also explores the immune and other relevant roles played by MDSC, and collates relevant targeted therapies against MDSC. In addition, current targeted therapies for colorectal cancer are analyzed and summarized. [ABSTRACT FROM AUTHOR]

Background: Ulcerative colitis (UC) is a chronic inflammatory disease of the intestinal mucosa, the incidence of which has increased worldwide. There is still a lack of clear understanding of the pathogenesis of ulcerative colitis that ultimately leads to colitis-associated colorectal cancer. Method: We download UC transcriptome data from the GEO database and pass the limma package in order to identify differentially expressed genes. Gene Set Enrichment Analysis (GSEA) was used to identify potential biological pathways. We identified immune cells associated with UC by CIBERSORT and Weighted coexpression network analysis (WGCNA). We used validation cohorts and mouse models to verify the expression of the hub genes and the role of neutrophils. Result: We identified 65 differentially expressed genes in UC samples and healthy controls. GSEA, KEGG, and GO analyses displayed that DEGs were enriched in immune-related pathways. CIBERSORT analysis revealed increased infiltration of neutrophils in UC tissues. The red module, obtained by WGCNA analysis, was considered to be the most relevant module for neutrophils. Based on neutrophilassociated differentially expressed genes, UC patients were classified into two subtypes of neutrophil infiltration. We discovered that the highly neutrophilinfiltrated subtype B of UC patients had a higher risk of developing CAC. Five genes were identified as biomarkers by searching for DEGs between distinct subtypes. Finally, using the mouse model, we determined the expression of these five genes in the control, DSS, and AOM/DSS groups. The degree of neutrophil infiltration in mice and the percentage of MPO and pSTAT3 expression in neutrophils were analyzed by flow cytometry. In the AOM/DSS model, MPO and pSTAT3 expressions were significantly increased. Conclusions: These findings suggested neutrophils might promote the conversion of UC into CAC. These findings improve our understanding of the pathogenesis of CAC and provide new and more effective insights into the prevention and treatment of CAC. [ABSTRACT FROM AUTHOR]

Background: Inflammatory bowel disease (IBD; mainly ulcerative colitis and Crohn’s disease) is associated with the development of colorectal cancer (CRC) referred to as colitis-associated colorectal cancer (CAC). In inflammatory flares of IBD, the production of luminal nitric oxide (NO) increases due to the increased inducible nitric oxide synthase (iNOS) activity in inflamed tissue. It is believed that iNOS parallels pro-inflammatory interleukin-1β (IL-1β). How these biomarkers relate to CAC pathogenesis or survival is unknown. Aim: The primary aim of this study was to investigate iNOS and IL-1β immunoreactivity in CAC tumors in comparison with CRC and normal colonic mucosa, and the secondary aim was to determine if immunoreactivity correlates with 5-year survival of CAC. Methods: Immunohistochemistry was performed on tissue sections as follows: CAC (n = 59); sporadic CRC (sCRC) (n = 12); colonic mucosa >2 cm outside sCRC margin (normal mucosa) (n = 22); paracancerous IBD (pIBD) (n = 12). The expression of iNOS and IL-1β was quantified separately for epithelium and stroma. Data were evaluated using the Mann-Whitney U-test and the log-rank test for 5-year Kaplan-Meier survival curves. Results were compared with online mRNA databases. Results: Immunoreactivity occurred predominantly in epithelial cells and to lesser extent in stroma. Compared with normal mucosa, immunoreactivity for iNOS (P < 0.01) and IL-1β (P < 0.005) was higher in CAC epithelium. In CAC stroma, iNOS immunoreactivity was lower than normal mucosa (P < 0.001), whereas IL-1β was higher (P < 0.05). Immunoreactivity differences of iNOS or IL-1β among CAC patients failed to correlate with 5-year survival. These findings were supported by online mRNA databases. Conclusion: Consistent with high NO production in IBD, there is more iNOS in CAC epithelium, albeit not in stroma. This immunoreactivity difference exists for IL-1β in both epithelium and stroma. The intervention of arginine or iNOS activity for CAC chemotherapy is not straightforward.

Background: Gliclazide is a potential anti-cancer drug candidate for preventing carcinogenesis. However, the effect of gliclazide on colitis-associated colorectal cancer remains unknown. Aims: We aimed to evaluate whether gliclazide plays a protective role in colitis-associated colorectal cancer and the underlying molecular mechanism. Methods: The administration of azoxymethane (AOM) followed by dextran sulfate sodium (DSS) aimed to induce colitis-associated colorectal cancer in mice. C57BL mice were gavaged with gliclazide (6 mg/kg by gavage 5 days a week) for 12 weeks immediately following AOM administration. After sacrificing the mice, colon tissues were measured for tumor number and tumor burden. The proliferation- and inflammation-related molecular mechanisms were explored. Results: The administration of gliclazide significantly reduced the tumor number and tumor burden in mice. Cell proliferation decreased in the gliclazide group compared with the control group, as indicated by reduced Ki-67 expression. Furthermore, gliclazide alleviated colonic inflammation, significantly decreased pro-inflammatory factor TNF-α levels and increased anti-inflammatory factor IL-10 levels in vivo. In vivo and vitro, it was shown that gliclazide increased the level of phospho-AMPK (p-AMPK) and inhibited NF-κB activity. Further studies demonstrated that the inhibition of NF-κB activity induced by gliclazide was mediated by p-AMPK in vitro. Conclusions: Gliclazide effectively alleviated colonic inflammation and prevented colonic carcinogenesis in an AOM–DSS mouse model by modulating the AMPK-NF-κB signaling pathway. Thus, gliclazide holds potential as a chemopreventive agent for colitis-associated colorectal cancer. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is one of the most common neoplasms worldwide. Among the risk factors of CRC, inflammatory bowel disease (IBD) is one of the most important ones leading to the development of colitis-associated CRC (CAC). G-protein coupled receptors (GPCR) are transmembrane receptors that orchestrate a multitude of signaling cascades in response to external stimuli. Because of their functionality, they are promising targets in research on new strategies for CRC diagnostics and treatment. Recently, regulators of G-proteins (RGS) have been attracting attention in the field of oncology. Typically, they serve as negative regulators of GPCR responses to both physiological stimuli and medications. RGS activity can lead to both beneficial and harmful effects depending on the nature of the stimulus. However, the atypical RGS—AXIN uses its RGS domain to antagonize key signaling pathways in CRC development through the stabilization of the β-catenin destruction complex. Since AXIN does not limit the efficiency of medications, it seems to be an even more promising pharmacological target in CRC treatment. In this review, we discuss the current state of knowledge on RGS significance in sporadic CRC and CAC with particular emphasis on the regulation of GPCR involved in IBD-related inflammation comprising opioid, cannabinoid and serotonin receptors. [ABSTRACT FROM AUTHOR]

Background: Myeloid-derived suppressor cells (MDSCs) played an essential role in tumor microenvironment to suppress host antitumor immunity and help cancer cells escape immune surveillance. However, the molecular mechanism behind tumor evasion mediated by MDSCs is not fully understood. Glycoprotein nonmetastatic melanoma protein B (GPNMB) is considered to associate with tumor initiation, metastasis and angiogenesis. Blocking GPNMB function is a potentially valuable therapy for cancer by eliminating GPNMB+MDSCs. Our previous study has proved that blockage the MyD88 signaling with the MyD88 inhibitor, TJ-M2010-5, may completely prevent the development of CAC in mice, accompanying with downregulation of GPNMB mRNA in the inhibitor-treated mice of CAC. Methods: We here focus on the underlying the relationship between GPNMB function and MyD88 signaling pathway activation in MDSCs' antitumor activity in CAC. Results: CAC development in the mouse model is associated with expanded GPNMB+MDSCs by a MyD88-dependent pathway. The GPNMB expression on MDSCs is associated with MyD88 signaling activation. The inhibitory effect of MDSCs on T cell proliferation, activation and antitumor cytotoxicity in CAC is mediated by GPNMB in a MyD8-dependent manner. Conclusion: MyD88 signaling pathway plays an essential role in GPNMB+MDSCmediated tumor immune escape during CAC development and is a promising focus for revealing the mechanisms of MDSC that facilitate immunosuppression and tumor progression. [ABSTRACT FROM AUTHOR]

The incidence of colitis‐associated colorectal cancer (CAC) has increased due to a high‐nutrient diet, increased environmental stimuli and inherited gene mutations. To adequately treat CAC, drugs should be developed by identifying novel therapeutic targets. E3 ubiquitin‐protein ligase pellino homolog 3 (pellino 3; Peli3) is a RING‐type E3 ubiquitin ligase involved in inflammatory signalling; however, its role in the development and progression of CAC has not been elucidated. In this study, we studied Peli3‐deficient mice in an azoxymethane/dextran sulphate sodium‐induced CAC model. We observed that Peli3 promotes colorectal carcinogenesis with increased tumour burden and oncogenic signalling pathways. Ablation of Peli3 reduced inflammatory signalling activation at the early stage of carcinogenesis. Mechanistic studies indicate that Peli3 enhances toll‐like receptor 4 (TLR4)‐mediated inflammation through ubiquitination‐dependent degradation of interferon regulatory factor 4, a negative regulator of TLR4 in macrophages. Our study suggests an important molecular link between Peli3 and colonic inflammation‐mediated carcinogenesis. Furthermore, Peli3 can be a therapeutic target in the prevention and treatment of CAC.

Background: The edible fungus Auricularia delicate (ADe) is commonly employed in traditional medicine for intestinal disorders; however, its inhibitory effect on colitis-associated colorectal cancer (CAC) and the underlying mechanisms remain unexplored. (2) Methods: The inhibitory effect of ADe on CAC was investigated using a mouse model induced by azoxymethane/dextran sulfate sodium. Results: ADe effectively suppressed the growth and number of intestinal tumors in mice. Intestinal microbiota analyses revealed that ADe treatment increased Akkermansia and Parabacteroides while it decreased Clostridium, Turicibacter, Oscillospira, and Desulfovibrio. ADe regulated the levels of 2′-deoxyridine, creatinine, 1-palmitoyl lysophosphatidylcholine, and choline in serum. Furthermore, the levels of these metabolites were associated with the abundance of Oscillospira and Paraacteroides. ADe up-regulated the free fatty acid receptor 2 and β-Arrestin 2, inhibited the nuclear factor kappa B (NF-κB) pathway, and significantly attenuated the levels of inflammatory cytokines, thereby mitigating the inflammatory in CAC mice. Conclusions: The protective effect of ADe in CAC mice is associated with the regulation of intestinal microbiota, which leads to the inhibition of NF-kB pathway and regulation of inflammation. [ABSTRACT FROM AUTHOR]

The incidence of colitis‐associated colorectal cancer (CAC) has increased due to a high‐nutrient diet, increased environmental stimuli and inherited gene mutations. To adequately treat CAC, drugs should be developed by identifying novel therapeutic targets. E3 ubiquitin‐protein ligase pellino homolog 3 (pellino 3; Peli3) is a RING‐type E3 ubiquitin ligase involved in inflammatory signalling; however, its role in the development and progression of CAC has not been elucidated. In this study, we studied Peli3‐deficient mice in an azoxymethane/dextran sulphate sodium‐induced CAC model. We observed that Peli3 promotes colorectal carcinogenesis with increased tumour burden and oncogenic signalling pathways. Ablation of Peli3 reduced inflammatory signalling activation at the early stage of carcinogenesis. Mechanistic studies indicate that Peli3 enhances toll‐like receptor 4 (TLR4)‐mediated inflammation through ubiquitination‐dependent degradation of interferon regulatory factor 4, a negative regulator of TLR4 in macrophages. Our study suggests an important molecular link between Peli3 and colonic inflammation‐mediated carcinogenesis. Furthermore, Peli3 can be a therapeutic target in the prevention and treatment of CAC. [ABSTRACT FROM AUTHOR]

Simple Summary: Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, is a debilitating condition with chronic inflammation in the digestive tract. Patients with IBD are at higher risk of developing colitis-associated colorectal cancer (CAC) compared with the general population. The etiology of IBD is not well understood, but both genetic and environmental factors have been implicated. In this study, we investigated the role of the pH-sensing GPR4 receptor in colitis and CAC mouse models. GPR4 knockout alleviated intestinal inflammation, reduced tumor angiogenesis, and impeded CAC development. Our data suggest that the inhibition of GPR4 may be explored as a potential therapeutic approach for IBD treatment and CAC prevention. GPR4 is a proton-sensing G protein-coupled receptor highly expressed in vascular endothelial cells and has been shown to potentiate intestinal inflammation in murine colitis models. Herein, we evaluated the proinflammatory role of GPR4 in the development of colitis-associated colorectal cancer (CAC) using the dextran sulfate sodium (DSS) and azoxymethane (AOM) mouse models in wild-type and GPR4 knockout mice. We found that GPR4 contributed to chronic intestinal inflammation and heightened DSS/AOM-induced intestinal tumor burden. Tumor blood vessel density was markedly reduced in mice deficient in GPR4, which correlated with increased tumor necrosis and reduced tumor cell proliferation. These data demonstrate that GPR4 ablation alleviates intestinal inflammation and reduces tumor angiogenesis, development, and progression in the AOM/DSS mouse model. [ABSTRACT FROM AUTHOR]

Simple Summary: Chronic inflammation plays a significant role in colorectal cancer (CRC) development, particularly in colitis-associated CRC (CAC). This study examined immune infiltration patterns in CAC patients compared to sporadic CRC (sCRC) patients and their impact on prognosis. Twenty CAC and twenty sCRC patients, matched by tumor characteristics, were analyzed. Immunohistochemistry targeted various immune markers, including T-cell and B-cell markers, in tumor and adjacent mucosal tissues. The results revealed differences between CAC and sCRC in T-cell exhaustion markers (TOX and TIGIT) and immune cell infiltration. High CD3+ and CD20+ cell levels correlated with improved survival in CAC but not in sCRC. This study highlighted distinct immune profiles in CAC and sCRC, suggesting that T-cell exhaustion might play a different role in CAC development than in sCRC. Understanding these immune differences could impact treatment strategies and prognosis for CAC patients. Background: Chronic inflammation is a significant factor in colorectal cancer (CRC) development, especially in colitis-associated CRC (CAC). T-cell exhaustion is known to influence inflammatory bowel disease (IBD) progression and antitumor immunity in IBD patients. This study aimed to identify unique immune infiltration characteristics in CAC patients. Methods: We studied 20 CAC and 20 sporadic CRC (sCRC) patients, who were matched by tumor stage, grade, and location. Immunohistochemical staining targeted various T-cell markers (CD3, CD4, CD8, and FOXP3), T-cell exhaustion markers (TOX and TIGIT), a B-cell marker (CD20), and a neutrophil marker (CD66b) in tumor and tumor-free mucosa from both groups. The quantification of the tumor immune stroma algorithm assessed immune-infiltrating cells. Results: CAC patients had significantly lower TOX+ cell infiltration than sCRC in tumors (p = 0.02) and paracancerous tissues (p < 0.01). Right-sided CAC showed increased infiltration of TOX+ cells (p = 0.01), FOXP3+ regulatory T-cells (p < 0.01), and CD20+ B-cells (p < 0.01) compared to left-sided CAC. In sCRC, higher tumor stages (III and IV) had significantly lower TIGIT+ infiltrate than stages I and II. In CAC, high CD3+ (p < 0.01) and CD20+ (p < 0.01) infiltrates correlated with improved overall survival. In sCRC, better survival was associated with decreased TIGIT+ cells (p < 0.038) and reduced CD8+ infiltrates (p = 0.02). Conclusion: In CAC, high CD3+ and CD20+ infiltrates relate to improved survival, while this association is absent in sCRC. The study revealed marked differences in TIGIT and TOX expression, emphasizing distinctions between CAC and sCRC. T-cell exhaustion appears to have a different role in CAC development. [ABSTRACT FROM AUTHOR]

Innate lymphoid cells (ILCs) have been shown to play essential roles in tumour immunity. Also, ILCs are involved in both homeostasis and inflammation. Evidence indicates that uncontrolled inflammatory response predisposes the intestine to colonic dysplasia and colorectal cancer (CRC). We investigated the frequency of three subsets of circulating ILCs in the early pathogenesis of colorectal carcinoma in the two distinct mouse models of colorectal cancer (CRC). We developed two mouse models representing the early pathogenic also reversible stages of CRC, including a chemically induced model, by administration of azoxymethane/dextran sulfate sodium (AOM/DSS), and an orthotopic mouse model, using the CT-26 cell line. Based on histopathological examinations, mice were divided into 3 groups including the dysplasia group (which consists of the chemically induced and the orthotopic induced), the chemically induced reparative change group, and a control group which was also considered in which mice were screened for stress originating from interventions and injections. Flow cytometry analysis was performed to evaluate the frequencies of ILC1, ILC2, and ILC3 in the peripheral blood of all studied mice. Altered composition of ILCs was observed in the peripheral blood of mice skewing toward ILC1s in the reparative change group compared to the control group (p value = 0.008); orthotopic-induced dysplasia and the chemically induced dysplasia groups did not differ significantly in terms of ILC subpopulations at the precancerous stages of colorectal dysplasia. A higher frequency of ILC1 in the chemically induced reparative change suggests a potentially anti-tumourigenic role participating in colorectal dysplasia. [ABSTRACT FROM AUTHOR]

The mechanisms underlying the transition from colitis-associated inflammation to carcinogenesis and the cell origin of cancer formation are still unclear. The azoxymethane (AOM)/dextran sodium sulfate (DSS) mouse model reproduces human colitis-associated colorectal cancer. To elucidate the mechanisms of cancer development and dynamics of the linker threonine-phosphorylated Smad2/3 (pSmad2/3L-Thr)-positive cells, we explored the early stages of colitis-associated colorectal cancer in AOM/DSS mice. The AOM/DSS mice were sacrificed at 4 to 6 weeks following AOM administration. To analyze the initial lesions, immunofluorescence staining for the following markers was performed: β-catenin, Ki67, CDK4, Sox9, Bmi1, cyclin D1, and pSmad2/3L-Thr. Micro-neoplastic lesions were flat and unrecognizable, and the uni-cryptal ones were either open to the surfaces or hidden within the mucosae. These neoplastic cells overexpressed β-catenin, Sox9, Ki67, and Cyclin D1 and had large basophilic nuclei in the immature atypical cells. In both the lesions, pSmad2/3L-Thr-positive cells were scattered and showed immunohistochemical co-localization with β-catenin, CDK4, and Bmi1 but never with Ki67. More β-catenin-positive neoplastic cells of both lesions were detected at the top compared to the base or center of the mucosae. We confirmed initial lesions in the colitis-associated colorectal cancer model mice and observed results that suggest that pSmad2/3L-Thr is a biomarker for tissue stem cells and cancer stem cells. [ABSTRACT FROM AUTHOR]

Background: Inflammatory bowel disease (IBD) confers an increased lifetime risk of colorectal cancer (CRC). The pathogenesis of colitis-associated CRC is considered distinct from sporadic CRC, but existing is mixed on long-term oncologic outcomes. This study aims to compare clinicopathological characteristics and survival between colitis-associated and sporadic CRC. Methods: Data was retrospectively extracted and analyzed from a single institutional database of patients with surgically resected CRC between 2004 and 2015. Patients with IBD were identified as having colitis-associated CRC. The remainder were classified as sporadic CRC. Propensity score matching was performed. Univariate and survival analyses were carried out to estimate the differences between the two groups. Results: Of 2275 patients included in this analysis, 65 carried a diagnosis of IBD (2.9%, 33 Crohn's disease, 29 ulcerative colitis, 3 indeterminate colitis). Average age at CRC diagnosis was 62 years for colitis-associated CRC and 65 for sporadic CRC. The final propensity score matched cohort consisted of 65 colitis-associated and 130 sporadic CRC cases. Patients with colitis-associated CRC were more likely to undergo total proctocolectomy (p < 0.01) and had higher incidence of locoregional recurrence (p = 0.026) compared to sporadic CRC patients. There were no significant differences in time to recurrence, tumor grade, extramural vascular invasion, perineural invasion, or rate of R0 resections. Overall survival and disease-free survival did not differ between groups. On multiple Cox regression, IBD diagnosis was not a significant predictor of survival. Conclusions: Patients with colitis-associated CRC who undergo surgical resection have comparable overall and disease-free survival to patients with sporadic CRC. [ABSTRACT FROM AUTHOR]

Simple Summary: Inflammatory bowel disease (IBD) patients with long-standing and extensive colitis have an enhanced risk of developing colorectal cancer and, therefore, they must undergo surveillance colonoscopies at regular intervals. The presence of polyps in an area inside colitis, commonly referred to as "pseudopolyps", seems to increase the risk of CRC in IBD, but it is unclear whether there are some subsets of pseudopolyp-like lesions that might eventually undergo neoplastic transformation. In the present study, we evaluated the frequency and predictors of dysplasia in IBD-associated pseudopolyp-like colorectal lesions. Our study shows that more than one-fifth of pseudopolyp-like lesions are dysplastic, and the majority of such neoplastic lesions are greater than 5 mm and located in the right colon. Therefore, lesions with such morphologic features must be removed even if they are present in an area inside colitis. Current endoscopic surveillance programs do not consider inflammatory bowel disease (IBD)-associated post-inflammatory polyps (pseudopolyps) per se clinically relevant, even though their presence seems to increase the risk of colorectal cancer (CRC). However, it remains unclear whether the link between pseudopolyps and CRC is indirect or whether some subsets of pseudopolyp-like lesions might eventually undergo neoplastic transformation. This study aimed to assess the frequency and predictors of dysplasia in pseudopolyp-like lesions in a population with long-standing colonic IBD. This was a retrospective, single-center study including patients with a colonic IBD (median disease duration of 192 months) and at least a pseudopolyp-like lesion biopsied or resected in the period from April 2021 to November 2022. One hundred and five pseudopolyps were identified in 105 patients (80 with ulcerative colitis and 25 with Crohn's disease). Twenty-three out of 105 pseudopolyp samples (22%) had dysplastic foci, and half of the dysplastic lesions were hyperplastic. Multivariate analysis showed that the age of the patients (odds ratio (OR) 1.1; p = 0.0012), size (OR 1.39; p = 0.0005), and right colonic location (OR 5.32; p = 0.04) were independent predictors of dysplasia, while previous exposure to immunosuppressors/biologics and left colonic location of the lesions were inversely correlated to dysplasia (OR 0.11; p = 0.005, and OR 0.09; p = 0.0008, respectively). No differences were seen between ulcerative colitis and Crohn's disease patients. Lesions with a size greater than 5 mm had a sensitivity of 87% and a specificity of 63% to be dysplastic. These data show that one-fourth of pseudopolyp-like lesions evident during surveillance colonoscopy in patients with longstanding IBD bear dysplastic foci and suggest treating such lesions properly. [ABSTRACT FROM AUTHOR]

Colonic inflammatory bowel disease (IBD) encompasses ulcerative colitis (UC) and Crohn's colitis (CC). Patients with IBD are at increased risk for colitis-associated colorectal cancer (CACRC) compared to the general population. CACRC is preceded by IBD, characterized by highly heterogenous, pharmacologically incurable, pertinacious, worsening, and immune-mediated inflammatory pathologies of the colon and rectum. The molecular and immunological basis of CACRC is highly correlated with the duration and severity of inflammation, which is influenced by the exogenous free hemoglobin alpha chain (HbαC), a byproduct of infiltrating immune cells; extravasated erythrocytes; and macrophage erythrophagocytosis. The exogenous free HbαC prompts oxygen free radical-arbitrated DNA damage (DNAD) through increased cellular reactive oxygen species (ROS), which is exacerbated by decreased tissue antioxidant defenses. Mitigation of the Fenton Reaction via pharmaceutical therapy would attenuate ROS, promote apoptosis and DNAD repair, and subsequently prevent the incidence of CACRC. Three pharmaceutical options that attenuate hemoglobin toxicity include haptoglobin, deferoxamine, and flavonoids (vitamins C/E). Haptoglobin's clearance rate from plasma is inversely correlated with its size; the smaller the size, the faster the clearance. Thus, the administration of Hp1-1 may prove to be beneficial. Further, deferoxamine's hydrophilic structure limits its ability to cross cell membranes. Finally, the effectiveness of flavonoids, natural herb antioxidants, is associated with the high reactivity of hydroxyl substituents. Multiple analyses are currently underway to assess the clinical context of CACRC and outline the molecular basis of HbαC-induced ROS pathogenesis by exposing colonocytes and/or colonoids to HbαC. The molecular immunopathogenesis pathways of CACRC herein reviewed are broadly still not well understood. Therefore, this timely review outlines the molecular and immunological basis of disease pathogenesis and pharmaceutical intervention as a protective measure for CACRC. [ABSTRACT FROM AUTHOR]

Agmatinase (AGMAT) is an enzyme that hydrolyzes agmatine to putrescine and urea. In this study, we explored the functions of AGMAT in colorectal cancer (CRC). By performing gain-of-function and loss-of-function experiments, we investigated the roles of AGMAT in proliferation, cell cycle progression, and apoptosis of CRC cells. We also established a colitis-associated colorectal cancer model by challenging mice with azoxymethane (AOM) and dextran sodium sulfate (DSS), and we subsequently silenced AGMAT expression in mice by adeno-associated virus 9 (AAV9)-mediated delivery of short hairpin RNA (shRNA). In vitro experiments showed that overexpression of AGMAT accelerated the proliferation and inhibited the apoptosis of CRC cells, and AGMAT knockdown exhibited the opposite effects. Interestingly, the oncogenic transcription factor, c-Myc, could bind to the AGMAT promoter and transcriptionally increase AGMAT expression in CRC cells. Additionally, c-Myc and AGMAT were upregulated in the colon of AOM/DSS-treated mice, and AGMAT silencing significantly mitigated colitis in AOM/DSS-treated mice, as evidenced by the increased colon length, attenuated crypt damage, and reduced levels of inflammatory indicators (myeloperoxidase, interleukin-6, tumor necrosis factor-α, inducible nitric oxide synthase, and phosphorylated p65) in colon tissues. Notably, AGMAT silencing decreased both the number and size of tumors, reduced expression of proliferating cell nuclear antigen, and inhibited phosphorylation of protein kinase B (AKT) and extracellular signal-regulated kinase in the colon of AOM/DSS-treated mice. Overall, we determined that AGMAT facilitates tumor progression in CRC. Our findings will be helpful in the search for potential therapeutic targets for CRC. [ABSTRACT FROM AUTHOR]

Hedysari Radix Praeparata Cum Melle (HR) has a potential to decrease the risk of chronic colorectal inflammation developing to colorectal cancer. Our study found that HR attenuated the pathological state, improved survival rate, diminished K-Ras, IL-1β, IL-6 and TNF-α levels, and increased the levels of the intestinal barrier function proteins including claudin-1, E-cadherin and mucin-2 in colitis-associated colorectal cancer (CAC) mice. Moreover, HR maintains intestinal flora homeostasis and fecal metabolic profiling through balancing the abundances of bacteroides prevotellaceae_UCG-001, staphylococcus, turicibacter, and rikenella to further regulates the galactose metabolism. The spearman correlation analysis showed that the intestinal barrier function proteins, gut microbiota and differential metabolism were significantly correlated with each other. This study confirmed a potential mechanism that HR alleviates CAC by diminishing symptoms and the inflammation, thereby improving the function of intestinal barrier and preserving intestinal flora homeostasis and fecal metabolic profiling.

Defatted rice bran (DRB) is a by-product of rice bran derived after the oil extraction. DRB contains several bioactive compounds, including dietary fiber and phytochemicals. The supplementation with DRB manifests chemopreventive effects in terms of anti-chronic inflammation, anti-cell proliferation, and anti-tumorigenesis in the azoxymethane (AOM) and dextran sodium sulfate (DSS)-induced colitis-associated colorectal cancer (CRC) model in rats. However, little is known about its effect on gut microbiota. Herein, we investigated the effect of DRB on gut microbiota and short chain fatty acid (SCFA) production, colonic goblet cell loss, and mucus layer thickness in the AOM/DSS-induced colitis-associated CRC rat model. The results suggested that DRB enhanced the production of beneficial bacteria (Alloprevotella, Prevotellaceae UCG-001, Ruminococcus, Roseburia, Butyricicoccus) and lessened the production of harmful bacteria (Turicibacter, Clostridium sensu stricto 1, Escherichia–Shigella, Citrobacter) present in colonic feces, mucosa, and tumors. In addition, DRB also assisted the cecal SCFAs (acetate, propionate, butyrate) production. Furthermore, DRB restored goblet cell loss and improved the thickness of the mucus layer in colonic tissue. These findings suggested that DRB could be used as a prebiotic supplement to modulate gut microbiota dysbiosis, which decreases the risks of CRC, therefore encouraging further research on the utilization of DRB in various nutritional health products to promote the health-beneficial bacteria in the colon. [ABSTRACT FROM AUTHOR]

Colitis-associated colorectal cancer is the most serious complication of ulcerative colitis. Long-term chronic inflammation increases the incidence of CAC in UC patients. Compared with sporadic colorectal cancer, CAC means multiple lesions, worse pathological type and worse prognosis. Macrophage is a kind of innate immune cell, which play an important role both in inflammatory response and tumor immunity. Macrophages are polarized into two phenotypes under different conditions: M1 and M2. In UC, enhanced macrophage infiltration produces a large number of inflammatory cytokines, which promote tumorigenesis of UC. M1 polarization has an anti-tumor effect after CAC formation, whereas M2 polarization promotes tumor growth. M2 polarization plays a tumor-promoting role. Some drugs have been shown to that prevent and treat CAC effectively by targeting macrophages. [ABSTRACT FROM AUTHOR]

Colitis-associated colorectal cancer serves as a prototype of inflammation-associated cancers which is linked with repeated cycles of inflammation and DNA repair deficits. Several preclinical and clinical data reported that aspirin has a chemo-preventive effect in colorectal cancer and is associated with dose-dependent side effects. Furthermore, it has been reported that zinc supplementation improves the quality of life in patients undergoing chemotherapy by alteration of colonic cancer cell gene expression. However, explication of the detailed molecular mechanisms involved in the combined administration of aspirin and zinc-mediated protection against colitis-associated colorectal cancer deserves further investigation. For the induction of colitis-associated colorectal cancer, male BALB/c mice were administered 1,2-dimethylhydrazine dihydrochloride (DMH) 20 mg/kg/bw thrice before the initiation of every DSS cycle (3%w/v in drinking water). One week after the initiation of DSS treatment, aspirin (40 mg/kg; p.o.) and zinc in the form of zinc sulphate (3 mg/kg; p.o.) were administered for 8 weeks. Combination of aspirin and zinc as intervention significantly ameliorated DAI score, myeloperoxidase activity, histological score, apoptotic cells and protein expression of various inflammatory markers including nuclear factor kappa light chain enhancer of activated B cells (NFκBp65), cycloxygenase-2 (COX-2) and interleukin-6 (IL-6); proliferation markers such as proliferating cell nuclear antigen (PCNA), signal transducer and activator of transcription 3 (STAT3) expression significantly decreased, and antioxidant enzymes nuclear factor erythroid 2–related factor 2 (Nrf-2), metallothionein, catalase and superoxide dismutase (SOD) significantly increased as evaluated by immunohistochemistry and western blot analysis. [ABSTRACT FROM AUTHOR]

Inflammatory bowel disease (IBD) can progress into colitis-associated colorectal cancer (CAC) through the inflammation-cancer sequence. Although the mechanism of carcinogenesis in IBD has not been fully elucidated, the existing research indicates that CAC may represent a fundamentally different pathogenesis pattern of colorectal cancer. At present, there is no proven safe and effective medication to prevent IBD cancer. In recent years, Chinese medicine extracts and Chinese medicine monomers have been the subject of numerous articles about the prevention and treatment of CAC, but their clinical application is still relatively limited. Traditional Chinese Medicine (TCM) formulas are widely applied in clinical practice. TCM formulas have demonstrated great potential in the prevention and treatment of CAC in recent years, although there is still a lack of review. Our work aimed to summarize the effects and potentialmechanisms of TCM formulas for the prevention and treatment of CAC, point out the issues and limitations of the current research, and provide recommendations for the advancement of CAC research in the future. We discovered that TCM formulas regulated many malignant biological processes, such as inflammation-mediated oxidative stress, apoptosis, tumor microenvironment, and intestinal microecology imbalance in CAC, through a review of the articles published in databases such as PubMed, SCOPUS, Web of Science, Embase, and CNKI. Several major signal transduction pathways, including NF-κB, STAT3, Wnt/β-catenin, HIF-1α, and Nrf2, were engaged. TCM formula may be a promising treatment candidate to control the colitis-cancer transformation, however further high-quality research is required. [ABSTRACT FROM AUTHOR]

Yeast ß-glucan is a polysaccharide purified from the Saccharomyces cerevisiae cell wall, and its multiple biological activities are essential for immune regulation. However, the effect of ß-glucan on the intestinal immune response during colitis-associated colorectal cancer (CAC) is unclear. Here, we explore the possible role of ß-glucan in the development of CAC. Wild type (WT) mice with CAC induced by azoxmethane (AOM) and dextran sodium sulfate (DSS) had fewer tumors than untreated mice after oral ß-glucan because of increased antitumor dendritic cells (DCs) in the tumor microenvironment, resulting in more CD8+ T cells and the production of related cytokines. ß-glucan also increased resistance to DSSinduced chronic colitis by reshaping the inflammatory microenvironment. These data suggest that ß-glucan improves experimental intestinal inflammation and delays the development of CAC. Therefore, ß-glucan is feasible for treating chronic colitis and CAC in clinical practice. [ABSTRACT FROM AUTHOR]

Background: Inflammatory bowel disease (IBD; mainly ulcerative colitis and Crohn's disease) is associated with the development of colorectal cancer (CRC) referred to as colitis-associated colorectal cancer (CAC). In inflammatory flares of IBD, the production of luminal nitric oxide (NO) increases due to the increased inducible nitric oxide synthase (iNOS) activity in inflamed tissue. It is believed that iNOS parallels pro-inflammatory interleukin-1β (IL-1β). How these biomarkers relate to CAC pathogenesis or survival is unknown. Aim: The primary aim of this study was to investigate iNOS and IL-1β immunoreactivity in CAC tumors in comparison with CRC and normal colonic mucosa, and the secondary aim was to determine if immunoreactivity correlates with 5-year survival of CAC. Methods: Immunohistochemistry was performed on tissue sections as follows: CAC (n = 59); sporadic CRC (sCRC) (n = 12); colonic mucosa >2 cm outside sCRC margin (normal mucosa) (n = 22); paracancerous IBD (pIBD) (n = 12). The expression of iNOS and IL-1β was quantified separately for epithelium and stroma. Data were evaluated using the Mann-Whitney U-test and the log-rank test for 5-year Kaplan-Meier survival curves. Results were compared with online mRNA databases. Results: Immunoreactivity occurred predominantly in epithelial cells and to lesser extent in stroma. Compared with normal mucosa, immunoreactivity for iNOS (P < 0.01) and IL-1β (P < 0.005) was higher in CAC epithelium. In CAC stroma, iNOS immunoreactivity was lower than normal mucosa (P < 0.001), whereas IL-1β was higher (P < 0.05). Immunoreactivity differences of iNOS or IL-1β among CAC patients failed to correlate with 5-year survival. These findings were supported by online mRNA databases. Conclusion: Consistent with high NO production in IBD, there is more iNOS in CAC epithelium, albeit not in stroma. This immunoreactivity difference exists for IL-1β in both epithelium and stroma. The intervention of arginine or iNOS activity for CAC chemotherapy is not straightforward. [ABSTRACT FROM AUTHOR]

Colitis-associated cancer (CAC) is closely related to chronic inflammation, whose underlying molecular mechanism, however, has not been elaborated comprehensively. In the current study, an investigation was conducted on the role of autophagy in the initiation and progression of azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced colon tumors, a mouse model for CAC in humans. Mice with the intestinal epithelial cell (IEC)-specific deletion of the autophagy-related gene 7 (Atg7) saw a significant decrease in tumor number, burden, and risk of high-grade dysplasia. The autophagy deficiency of IECs resulted in the accumulation of T cells, especially CD8+ T lymphocytes in colon lamina propria. Furthermore, it was found that autophagy protects against DSS-induced intestinal injury through maintaining epithelial barrier function and promoting the survival and proliferation of IECs. Mechanistically, autophagy in IECs enhanced the activation of epithelial STAT3/ERK to promote the survival and proliferation of colonic epithelial cells during the development of CAC. Therefore, the findings unveil the essential role of autophagy in activating the processes of colonic protection, regeneration, and tumorigenesis.

Huangqin Tang (HQT), a traditional Chinese medicine formula, is commonly used in clinical practice for the treatment of inflammatory bowel diseases. It has been reported that HQT exerts antitumor effects on colitis-associated colorectal cancer (CAC). However, the mechanism by which HQT interferes with the inflammation-to-cancer transformation remains unclear. The purpose of this study was to dynamically evaluate the efficacy of HQT in alleviating or delaying CAC and to reveal the underlying mechanism. We established a mouse model of CAC using azoxymethane combined with 1.5% dextran sodium sulphate. The efficacy of HQT was evaluated based on pathological sections and serum biochemical indices. Subsequently, amino acids (AAs) metabolism analyses were performed using ultra-performance liquid chromatography-tandem mass spectrometry, and the phosphatidylinositol 3 kinase/protein kinase B/mechanistic target of rapamycin (PI3K/AKT/mTOR) pathway was detected by western blotting. The data demonstrated that HQT could alleviate the development of CAC in the animal model. HQT effectively reduced the inflammatory response, particularly interleukin-6 (IL-6), in the inflammation induction stage, as well as in the stages of proliferation initiation and tumorigenesis. During the proliferation initiation and tumorigenesis stages, immunohistochemistry staining showed that the expression of the proliferation marker Ki67 was reduced, while apoptosis was increased in the HQT group. Accordingly, HQT substantially decreased the levels of specific AAs in the colon with CAC, including glutamic acid, glutamine, arginine, and isoleucine. Furthermore, HQT significantly inhibited the activated PI3K/AKT/mTOR pathway, which may contribute to suppression of cell proliferation and enhancement of apoptosis. HQT is effective in alleviating and delaying the colon "inflammation-to-cancer". The mechanism of action may involve HQT maintained AAs metabolism homeostasis and regulated PI3K/AKT/mTOR pathway, so as to maintain the balance between proliferation and apoptosis, and then interfere in the occurrence and development of CAC. [Display omitted] [ABSTRACT FROM AUTHOR]

Based on the core pathogenesis of hepatosplenic disorder and qi transformation disorder in ulcerative colitis, Tong-Xie-Yao-Fang (TXYF) is a classical traditional Chinese medicine commonly used to treat ulcerative colitis. Our study revealed that it has the potential to prevent colitis-associated colorectal cancer, which embodies the academic concept in traditional Chinese medicine of treating the disease before it develops. This study was aimed at evaluating the therapeutic role of TXYF in treating colitis-associated colorectal cancer and exploring its possible underlying mechanisms. A colitis-associated colorectal cancer model was established in mice using azoxymethane and dextran sulfate sodium salt to examine the therapeutic effect of TXYF. The mouse body weights were observed. Hematoxylin-eosin staining was used to evaluate mouse colon histopathology. Colon cancer cells and colon epithelial cells were used to explore the potential molecular mechanisms. The proliferation and apoptosis of cells were detected by CCK8 and cell colony assays, flow cytometry and western blotting. The epithelial–mesenchymal transition (EMT) and mitophagy markers were examined by immunohistochemistry, western blotting, quantitative real-time PCR and immunofluorescence staining. TXYF inhibited the tumorigenesis of mice with colitis-associated colorectal cancer and the growth of inflammatory colon cells. TXYF induced mitophagy in colon cancer cells through the PTEN-induced putative kinase 1 (PINK1)/Parkin pathway to reverse EMT, which was consistent with the results in mice with colitis-associated colorectal cancer. The results of the present study demonstrated that TXYF effectively inhibited the progression of colitis-associated colorectal cancer through the PINK1/Parkin pathway, which provides new evidence for prevention strategies for this disease. [Display omitted] [ABSTRACT FROM AUTHOR]

Wumei Wan (WMW), a traditional Chinese medicine prescription, has been proved to be effective in treating Colitis-associated colorectal cancer (CAC), but it has not been proven to be effective in different stages of CAC. The purpose of our study is to investigate the therapeutic effect and mechanism of WMW on the progression of CAC. Azioximethane (AOM) and dextran sulfate sodium (DSS) were used to treat mice for the purpose of establishing CAC models. WMW was administered in different stages of CAC. The presentative chemical components in WMW were confirmed by LC-MS/MS under the optimized conditions. The detection of inflammatory cytokines in the serum and colon of mice were estimated by qRT-PCR and ELISA. The changes of T cells and myeloid-derived suppressor cells (MDSCs) in each group were detected by flow cytometry. The metabolic components in serum of mice were detected by UPLC-MS/MS. Expression of genes and proteins were detected by eukaryotic transcriptomics and Western blot to explore the key pathway of WMW in preventing CAC. WMW had significant effect on inhibiting inflammatory responses and tumors during the early development stage of CAC when compared to other times. WMW increased the length of mice's colons, reduced the level of IL-1β, IL-6, TNF-α in colon tissues, and effectively alleviated colonic inflammation, and improved the pathological damage of colon tissues. WMW could significantly reduce the infiltration of MDSCs in the spleen, increase CD4+ T cells and CD8+ T cells in the spleen of CAC mice, and effectively reform the immune microenvironment in CAC mice. Transcriptomics analysis revealed that 2204 genes had different patterns of overlap in the colon tissues of mice between control group, AOM + DSS group, and early administration of WMW group. And KEGG enrichment analysis showed that PI3K/Akt signaling pathway, ECM-receptor interaction, IL-17 signaling pathway, MAPK signaling pathway, pancreatic secretion, thermogenesis, and Rap1 signaling pathway were all involved. The serum metabolomics results of WMW showed that the metabolic compositions of the control group, AOM + DSS group and the early stage of WMW were different, and 42 differential metabolites with the opposite trends of changes were screened. The metabolic pathways mainly included pyrimidine metabolism, glycine, serine and threonine metabolism, tryptophan metabolism, and purine metabolism. And amino acids and related metabolites may play an important role in WMW prevention of CAC. WMW can effectively prevent the occurrence and development of CAC, especially in the initial stage. WMW can reduce the immune infiltration of MDSCs in the early stage. Early intervention of WMW can improve the metabolic disorder caused by AOM + DSS, especially correct the amino acid metabolism. PI3K/Akt signaling pathway was inhabited in early administration of WMW, which can regulate the amplification and function of MDSCs. [Display omitted] [ABSTRACT FROM AUTHOR]

A type of colorectal cancer (CRC)，Colitis-associated colorectal cancer (CAC)， is closely associated with chronic inflammation and gut microbiota dysbiosis. Berberine (BBR) has a long history in the treatment of intestinal diseases, which has been reported to inhibit colitis and CRC. However, the mechanism of its action is still unclear. Here, this study aimed to explore the potential protective effects of BBR on azoxymethane (AOM)/dextransulfate sodium (DSS)-induced colitis and tumor mice, and to elucidate its potential molecular mechanisms by microbiota, genes and metabolic alterations. The results showed that BBR inhibited the gut inflammation and improved the function of mucosal barrier to ameliorate AOM/DSS-induced colitis. And BBR treatment significantly reduced intestinal tumor development and ki-67 expression of intestinal tissue along with promoted apoptosis. Through microbiota analysis based on the 16 S rRNA gene, we found that BBR treatment improved intestinal microbiota imbalance in AOM/DSS-induced colitis and tumor mice, which were characterized by an increase of beneficial bacteria, for instance Akkermanisa , Lactobacillus , Bacteroides uniformis and Bacteroides acidifaciens. In addition, transcriptome analysis showed that BBR regulated colonic epithelial signaling pathway in CAC mice particularly by tryptophan metabolism and Wnt signaling pathway. Notably, BBR treatment resulted in the enrichment of amino acids metabolism and microbiota-derived SCFA metabolites. In summary, our research findings suggest that the gut microbiota-amino acid metabolism-Wnt signaling pathway axis plays critical role in maintaining intestinal homeostasis, which may provide new insights into the inhibitory effects of BBR on colitis and colon cancer. [Display omitted] • Berberine ameliorate intestinal inflammation and inhibit the growth of colon tumor in AOM/DSS-induced colitis and tumor mice. • Berberine treatment ameliorate AOM/DSS-induced colitis and tumor mice gut microbiota dysbiosis. • Berberine ameliorate CAC by modulating the gut microbita-amino acid metabolism-Wnt signaling pathway axis. [ABSTRACT FROM AUTHOR]

Colitis-associated colorectal cancer is the most serious complication of ulcerative colitis. Long-term chronic inflammation increases the incidence of CAC in UC patients. Compared with sporadic colorectal cancer, CAC means multiple lesions, worse pathological type and worse prognosis. Macrophage is a kind of innate immune cell, which play an important role both in inflammatory response and tumor immunity. Macrophages are polarized into two phenotypes under different conditions: M1 and M2. In UC, enhanced macrophage infiltration produces a large number of inflammatory cytokines, which promote tumorigenesis of UC. M1 polarization has an anti-tumor effect after CAC formation, whereas M2 polarization promotes tumor growth. M2 polarization plays a tumor-promoting role. Some drugs have been shown to that prevent and treat CAC effectively by targeting macrophages.

Context: Chronic inflammation is usually caused by persistent irritation or uncontrolled infection and is characterized by ongoing tissue damage, injury-induced cellular proliferation and tissue repair. Colitis-associated colorectal cancer (CAC) isone of the classic examples of tumors that are tightly related to chronic inflammation. Background: To investigated the key pharmacodynamic genes of HQT interventions in CAC by using transcriptome predictions and experiments.Materials & Methods: We used the azoxymethane/dextran sodium sulfate method to induce the mice CAC model. After preventive administration of HQT to the mice model, colonic tissues were taken for transcriptome sequencing and the transcriptome results were then experimentally validated using quantitative Real-Time PCR technique. Results: Transcriptome sequencing revealed that the effect of the mechanism of HQT on the CAC mice model maybe related to its inhibition of accelerated epithelial mesenchymal transition and induction of pyroptosis. The levels of Matrix-metalloproteinases such as MMP-2, MMP-9 were significantly reduced in CAC mice treated with HQT; The mRNA expression for Krt17, App, CD44 and WNT pathway related sites such as Lrrc15, Cldn-1, Mpc1, Agr2 which are related factors affecting the epithelial mesenchymal transition were significantly reduced in CAC mice treated with HQT; the aberrant mRNA expression of inflammasome components that drive pyroptosis, including Nlrp3, Caspase-1, ASC, GSDMD and its mediated product IL-18 have been improved. Conclusions: Our findings provide preliminary clarification that inhibiting the progression of CAC by using HQT is effective, the mechanism of action may be relatedto the inhibition of epithelial mesenchymal transition and induction of pyroptosis during tumorigenesis.

BackgroundUlcerative colitis (UC) is a chronic inflammatory disease of the intestinal mucosa, the incidence of which has increased worldwide. There is still a lack of clear understanding of the pathogenesis of ulcerative colitis that ultimately leads to colitis-associated colorectal cancer.MethodWe download UC transcriptome data from the GEO database and pass the limma package in order to identify differentially expressed genes. Gene Set Enrichment Analysis (GSEA) was used to identify potential biological pathways. We identified immune cells associated with UC by CIBERSORT and Weighted co-expression network analysis (WGCNA). We used validation cohorts and mouse models to verify the expression of the hub genes and the role of neutrophils.ResultWe identified 65 differentially expressed genes in UC samples and healthy controls. GSEA, KEGG, and GO analyses displayed that DEGs were enriched in immune-related pathways. CIBERSORT analysis revealed increased infiltration of neutrophils in UC tissues. The red module, obtained by WGCNA analysis, was considered to be the most relevant module for neutrophils.Based on neutrophil-associated differentially expressed genes, UC patients were classified into two subtypes of neutrophil infiltration. We discovered that the highly neutrophil-infiltrated subtype B of UC patients had a higher risk of developing CAC. Five genes were identified as biomarkers by searching for DEGs between distinct subtypes. Finally, using the mouse model, we determined the expression of these five genes in the control, DSS, and AOM/DSS groups. The degree of neutrophil infiltration in mice and the percentage of MPO and pSTAT3 expression in neutrophils were analyzed by flow cytometry. In the AOM/DSS model, MPO and pSTAT3 expressions were significantly increased.ConclusionsThese findings suggested neutrophils might promote the conversion of UC into CAC. These findings improve our understanding of the pathogenesis of CAC and provide new and more effective insights into the prevention and treatment of CAC.

Yeast β-glucan is a polysaccharide purified from the Saccharomyces cerevisiae cell wall, and its multiple biological activities are essential for immune regulation. However, the effect of β-glucan on the intestinal immune response during colitis-associated colorectal cancer (CAC) is unclear. Here, we explore the possible role of β-glucan in the development of CAC. Wild type (WT) mice with CAC induced by azoxmethane (AOM) and dextran sodium sulfate (DSS) had fewer tumors than untreated mice after oral β-glucan because of increased antitumor dendritic cells (DCs) in the tumor microenvironment, resulting in more CD8+ T cells and the production of related cytokines. β-glucan also increased resistance to DSS-induced chronic colitis by reshaping the inflammatory microenvironment. These data suggest that β-glucan improves experimental intestinal inflammation and delays the development of CAC. Therefore, β-glucan is feasible for treating chronic colitis and CAC in clinical practice.