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Theranostics 2024To elucidate dynamics and functions in colonic macrophage subsets, and their regulation by () and its associated metabolites in the initiation of colitis-associated...
To elucidate dynamics and functions in colonic macrophage subsets, and their regulation by () and its associated metabolites in the initiation of colitis-associated colorectal cancer (CAC). Azoxymethane (AOM) and dextran sodium sulfate (DSS) were used to create a CAC model. The tumor-suppressive effect of and variations of macrophage subsets were evaluated. Intestinal macrophages were ablated to determine their role in the protective effects of . Efficacious molecules produced by were identified by non-targeted and targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. The molecular mechanism was further verified in murine bone marrow-derived macrophages (BMDMs), macrophages derived from human peripheral blood mononuclear cells (hPBMCs), and demonstrated in CAC mice. alleviated colitis symptoms, delayed colonic tumorigenesis, and promoted phenotypic differentiation of immature inflammatory macrophages into mature homeostatic macrophages. On the contrary, the ablation of intestinal macrophages largely annulled the protective effects of . Microbial analysis of colonic contents revealed the enrichment of probiotics and the depletion of potential pathogens following supplementation. Moreover, indole-3-lactic acid (ILA) was positively correlated with in CAC mice and highly enriched in the culture supernatant of . Also, the addition of ILA directly promoted AKT phosphorylation and restricted the pro-inflammatory response of murine BMDMs and macrophages derived from hPBMCs . The effects of ILA in murine BMDMs and macrophages derived from hPBMCs were abolished by the aryl hydrocarbon receptor (AhR) antagonist CH-223191 or the AKT inhibitor MK-2206. Furthermore, ILA could protect against tumorigenesis by regulating macrophage differentiation in CAC mice; the AhR antagonist largely abrogated the effects of and ILA in relieving colitis and tumorigenesis. -mediated tryptophan metabolism ameliorates the precancerous inflammatory intestinal milieu to inhibit tumorigenesis by directing the differentiation of immature colonic macrophages.
Topics: Animals; Mice; Macrophages; Bifidobacterium breve; Indoles; Humans; Colitis; Cell Differentiation; Probiotics; Disease Models, Animal; Carcinogenesis; Colitis-Associated Neoplasms; Mice, Inbred C57BL; Colon; Dextran Sulfate; Male; Gastrointestinal Microbiome; Colorectal Neoplasms; Azoxymethane
PubMed: 38773969
DOI: 10.7150/thno.92350 -
Cellular and Molecular Gastroenterology... May 2024Dysregulated colonic epithelial cell (CEC) proliferation is a critical feature in the development of colorectal cancer. We show that NF-κB-inducing kinase (NIK)...
BACKGROUND & AIMS
Dysregulated colonic epithelial cell (CEC) proliferation is a critical feature in the development of colorectal cancer. We show that NF-κB-inducing kinase (NIK) attenuates colorectal cancer through coordinating CEC regeneration/differentiation via noncanonical NF-κB signaling that is unique from canonical NF-kB signaling.
METHODS
Initial studies evaluated crypt morphology/functionality, organoid generation, transcriptome profiles, and the microbiome. Inflammation and inflammation-induced tumorigenesis were initiated in whole-body NIK knockout mice (Nik) and conditional-knockout mice following administration of azoxymethane and dextran sulfate sodium.
RESULTS
Human transcriptomic data revealed dysregulated noncanonical NF-kB signaling. In vitro studies evaluating Nik crypts and organoids derived from mature, nondividing CECs, and colonic stem cells exhibited increased accumulation and stunted growth, respectively. Transcriptomic analysis of Nik cells revealed gene expression signatures associated with altered differentiation-regeneration. When assessed in vivo, Nik mice exhibited more severe colitis with dextran sulfate sodium administration and an altered microbiome characterized by increased colitogenic microbiota. In the inflammation-induced tumorigenesis model, we observed both increased tumor burdens and inflammation in mice where NIK is knocked out in CECs (Nik). Interestingly, this was not recapitulated when NIK was conditionally knocked out in myeloid cells (Nik). Surprisingly, conditional knockout of the canonical pathway in myeloid cells (RelA) revealed decreased tumor burden and inflammation and no significant changes when conditionally knocked out in CECs (RelA).
CONCLUSIONS
Dysregulated noncanonical NF-κB signaling is associated with the development of colorectal cancer in a tissue-dependent manner and defines a critical role for NIK in regulating gastrointestinal inflammation and regeneration associated with colorectal cancer.
PubMed: 38750899
DOI: 10.1016/j.jcmgh.2024.05.004 -
Journal of Agricultural and Food... May 2024Colorectal cancer (CRC) is a common malignant tumor that occurs in the colon. Gut microbiota is a complex ecosystem that plays an important role in the pathogenesis of...
Colorectal cancer (CRC) is a common malignant tumor that occurs in the colon. Gut microbiota is a complex ecosystem that plays an important role in the pathogenesis of CRC. Our previous studies showed that the soluble dietary fiber of foxtail millet (FMB-SDF) exhibited significant antitumor activity in vitro. The present study evaluated the anticancer potential of FMB-SDF in the azoxymethane (AOM)- and dextran sodium sulfate (DSS)-induced mouse CRC models. The results showed that FMB-SDF could significantly alleviate colon cancer symptoms in mice. Further, we found that FMB-SDF consumption significantly altered gut microbiota diversity and the overall structure and regulated the abundance of some microorganisms in CRC mice. Meanwhile, KEGG pathway enrichment showed that FMB-SDF can also alleviate the occurrence of colon cancer in mice by regulating certain cancer-related signaling pathways. In conclusion, our findings may provide a novel approach for the prevention and biotherapy of CRC.
Topics: Animals; Gastrointestinal Microbiome; Colorectal Neoplasms; Mice; Setaria Plant; Dietary Fiber; Humans; Bacteria; Male; Plant Extracts; Azoxymethane; Mice, Inbred C57BL
PubMed: 38748495
DOI: 10.1021/acs.jafc.4c00867 -
International Journal of Molecular... Apr 2024Factors that reduce the risk of developing colorectal cancer include biologically active substances. In our previous research, we demonstrated the anti-inflammatory,...
Factors that reduce the risk of developing colorectal cancer include biologically active substances. In our previous research, we demonstrated the anti-inflammatory, immunomodulatory, and antioxidant effects of oat beta-glucans in gastrointestinal disease models. The aim of this study was to investigate the effect of an 8-week consumption of a diet supplemented with low-molar-mass oat beta-glucan in two doses on the antioxidant potential, inflammatory parameters, and colonic metabolomic profile in azoxymethane(AOM)-induced early-stage colorectal cancer in the large intestine wall of rats. The results showed a statistically significant effect of AOM leading to the development of neoplastic changes in the colon. Consumption of beta-glucans induced changes in colonic antioxidant potential parameters, including an increase in total antioxidant status, a decrease in the superoxide dismutase (SOD) activity, and a reduction in thiobarbituric acid reactive substance (TBARS) concentration. In addition, beta-glucans decreased the levels of pro-inflammatory interleukins (IL-1α, IL-1β, IL-12) and C-reactive protein (CRP) while increasing the concentration of IL-10. Metabolomic studies confirmed the efficacy of oat beta-glucans in the AOM-induced early-stage colon cancer model by increasing the levels of metabolites involved in metabolic pathways, such as amino acids, purine, biotin, and folate. In conclusion, these results suggest a wide range of mechanisms involved in altering colonic metabolism during the early stage of carcinogenesis and a strong influence of low-molar-mass oat beta-glucan, administered as dietary supplement, in modulating these mechanisms.
Topics: Animals; beta-Glucans; Azoxymethane; Colorectal Neoplasms; Rats; Male; Antioxidants; Disease Models, Animal; Avena; Superoxide Dismutase; Colon; Oxidative Stress; Rats, Wistar; C-Reactive Protein
PubMed: 38731854
DOI: 10.3390/ijms25094635 -
Cancers Apr 2024Colorectal tumorigenesis involves the development of aberrant crypt foci (ACF) or preneoplastic lesions, representing the earliest morphological lesion visible in colon...
Colorectal tumorigenesis involves the development of aberrant crypt foci (ACF) or preneoplastic lesions, representing the earliest morphological lesion visible in colon cancer. The purpose of this study was to determine changes in protein expression in carcinogen-induced ACF as they mature and transform into adenomas. Protein expression profiles of azoxymethane (AOM)-induced F344 rat colon ACF and adenomas were compared at four time points, 4 (control), 8, 16, and 24 weeks post AOM administration ( = 9/group), with time points correlating with induction and transformation events. At each time point, micro-dissected ACF and/or adenoma tissues were analyzed across multiple quantitative two-dimensional (2D-DIGE) gels using a Cy-dye labeling technique and a pooled internal standard to quantify expression changes with statistical confidence. Western blot and subsequent network pathway mapping were used to confirm and elucidate differentially expressed ( ≤ 0.05) proteins, including changes in vinculin (; = 0.007), scinderin (; = 0.02), and profilin (; = 0.01), By determining protein expression changes in ACF as they mature and transform into adenomas, a "baseline" of altered regulatory proteins associated with adenocarcinoma development in this model has been elucidated. These data will enable future studies aimed at biomarker identification and understanding the molecular biology of intestinal tumorigenesis and adenocarcinoma maturation under varying intestinal conditions.
PubMed: 38730628
DOI: 10.3390/cancers16091678 -
Cancer Letters Jul 2024Decreased levels of β-hydroxybutyrate (BHB), a lipid metabolic intermediate known to slow the progression of colorectal cancer (CRC), have been observed in the colon...
Decreased levels of β-hydroxybutyrate (BHB), a lipid metabolic intermediate known to slow the progression of colorectal cancer (CRC), have been observed in the colon mucosa of patients with inflammatory bowel diseases (IBD). In particular, patients with recurrent IBD present an increased risk of developing colitis-associated colorectal cancer (CAC). The role and molecular mechanism of BHB in the inflammatory and carcinogenic process of CAC remains unclear. Here, the anti-tumor effect of BHB was investigated in the Azoxymethane (AOM)/Dextran Sulfate Sodium (DSS)-induced CAC model and tumor organoids derivatives. The underlying mechanisms were studied using transcriptome and non-target metabolomic assay and further validated in colon tumor cell lineage CT26 in vitro. The tumor tissues and the nearby non-malignant tissues from colon cancer patients were collected to measure the expression levels of ketogenic enzymes. The exogenous BHB supplement lightened tumor burden and angiogenesis in the CAC model. Notably, transcriptome analysis revealed that BHB effectively decreased the expression of VEGFA in the CAC tumor mucosa. In vitro, BHB directly reduced VEGFA expression in hypoxic-treated CT26 cells by targeting transcriptional factor HIF-1α. Conversely, the deletion of HIF-1α largely reversed the inhibitory effect of BHB on CAC tumorigenesis. Additionally, decreased expression of ketogenesis-related enzymes in tumor tissues were associated with poor survival outcomes in patients with colon cancer. In summary, BHB carries out anti-angiogenic activity in CAC by regulating HIF-1α/VEGFA signaling. These findings emphasize the role of BHB in CAC and may provide novel perspectives for the prevention and treatment of colonic tumors.
Topics: 3-Hydroxybutyric Acid; Hypoxia-Inducible Factor 1, alpha Subunit; Animals; Mice; Humans; Neovascularization, Pathologic; Colitis-Associated Neoplasms; Vascular Endothelial Growth Factor A; Cell Line, Tumor; Carcinogenesis; Male; Azoxymethane; Colitis; Dextran Sulfate; Disease Models, Animal; Angiogenesis
PubMed: 38729554
DOI: 10.1016/j.canlet.2024.216940 -
Biomedicine & Pharmacotherapy =... Jun 2024Colitis-associated cancer (CAC) in inflammatory bowel diseases exhibits more aggressive behavior than sporadic colorectal cancer; however, the molecular mechanisms...
Colitis-associated cancer (CAC) in inflammatory bowel diseases exhibits more aggressive behavior than sporadic colorectal cancer; however, the molecular mechanisms remain unclear. No definitive preventative agent against CAC is currently established in the clinical setting. We investigated the molecular mechanisms of CAC in the azoxymethane/dextran sulfate sodium (AOM/DSS) mouse model and assessed the antitumor efficacy of erlotinib, a small molecule inhibitor of the epidermal growth factor receptor (EGFR). Erlotinib premixed with AIN-93 G diet at 70 or 140 parts per million (ppm) inhibited tumor multiplicity significantly by 96%, with ∼60% of the treated mice exhibiting zero polyps at 12 weeks. Bulk RNA-sequencing revealed more than a thousand significant gene alterations in the colons of AOM/DSS-treated mice, with KEGG enrichment analysis highlighting 46 signaling pathways in CAC development. Erlotinib altered several signaling pathways and rescued 40 key genes dysregulated in CAC, including those involved in the Hippo and Wnt signaling. These findings suggest that the clinically-used antitumor agent erlotinib might be repurposed for suppression of CAC, and that further studies are warranted on the crosstalk between dysregulated Wnt and EGFR signaling in the corresponding patient population.
Topics: Animals; Erlotinib Hydrochloride; Disease Models, Animal; Colitis-Associated Neoplasms; Mice; Azoxymethane; Dextran Sulfate; ErbB Receptors; Carcinogenesis; Mice, Inbred C57BL; Male; Signal Transduction; Wnt Signaling Pathway; Antineoplastic Agents; Gene Expression Regulation, Neoplastic; Colitis
PubMed: 38723513
DOI: 10.1016/j.biopha.2024.116580 -
Journal of Cancer Research and Clinical... May 2024The pathogenesis and treatment of colorectal cancer (CRC) continue to be areas of ongoing research, especially the benefits of traditional Chinese medicine (TCM) in...
BACKGROUND
The pathogenesis and treatment of colorectal cancer (CRC) continue to be areas of ongoing research, especially the benefits of traditional Chinese medicine (TCM) in slowing the progression of CRC. This study was conducted to investigate the effectiveness and mechanism of action of modified Lichong decoction (MLCD) in inhibiting CRC progression.
METHODS
We established CRC animal models using azoxymethane/dextran sodium sulfate (AOM/DSS) and administered high, medium, or low doses of MLCD or mesalazine (MS) for 9 weeks to observe MLCD alleviation of CRC. The optimal MLCD dose group was then subjected to metagenomic and RNA sequencing (RNA-seq) to explore the differentially abundant flora and genes in the control, model and MLCD groups. Finally, the mechanism of action was verified using WB, qRT‒PCR, immunohistochemistry and TUNEL staining.
RESULTS
MLCD inhibited the progression of CRC, and the optimal effect was observed at high doses. MLCD regulated the structure and function of the intestinal flora by decreasing the abundance of harmful bacteria and increasing that of beneficial bacteria. The differentially expressed genes were mainly associated with the Wnt/β-catenin pathway and the cell cycle. Molecular biology analysis indicated that MLCD suppressed the Wnt/β-catenin pathway and the epithelial-mesenchymal transition (EMT), inhibited abnormal cell proliferation and promoted intestinal epithelial cell apoptosis.
CONCLUSION
MLCD mitigated the abnormal growth of intestinal epithelial cells and promoted apoptosis, thereby inhibiting the progression of CRC. This inhibition was accomplished by modifying the intestinal microbiota and disrupting the Wnt/β-catenin pathway and the EMT. Therefore, MLCD could serve as a potential component of TCM prescriptions for CRC treatment.
Topics: Wnt Signaling Pathway; Gastrointestinal Microbiome; Animals; Colorectal Neoplasms; Drugs, Chinese Herbal; Mice; Humans; Male; Apoptosis; Epithelial-Mesenchymal Transition; Cell Proliferation; Dextran Sulfate; beta Catenin; Disease Models, Animal
PubMed: 38710918
DOI: 10.1007/s00432-024-05763-w -
Yakugaku Zasshi : Journal of the... 2024Zinc is one of the essential trace elements, and is involved in various functions in the body. Zinc deficiency is known to cause immune abnormalities, but the mechanism...
Zinc is one of the essential trace elements, and is involved in various functions in the body. Zinc deficiency is known to cause immune abnormalities, but the mechanism is not fully understood. Therefore, we focused our research on tumor immunity to elucidate the effect of zinc on colorectal cancer and its mechanisms. Mice were treated with azoxymethane (AOM) and dextran sodium sulfate (DSS) to develop colorectal cancer, then the relationship between zinc content in the diet and the number and area of tumors in the colon was observed. The number of tumors in the colon was significantly higher in the no-zinc-added diet group compared to the normal zinc intake group, and about half the number in the high-zinc-intake group compared to the normal-zinc-intake group. In T-cell-deficient mice, the number of tumors in the high-zinc-intake group was similar to that in the normal-zinc-intake group, suggesting that the inhibitory effect of zinc was dependent on T cells. Furthermore, we found that the amount of granzyme B transcript released by cytotoxic T cells upon antigen stimulation was significantly increased by the addition of zinc. We also showed that granzyme B transcriptional activation by zinc addition was dependent on calcineurin activity. Collectively, we have shown that zinc exerts its tumor-suppressive effect by acting on cytotoxic T cells, the center of cellular immunity, and that it increases the transcription of granzyme B, one of the key molecules involved in tumor immunity. In this symposium, we would like to introduce our latest data on the relationship between zinc and tumor immunity.
Topics: Animals; Humans; Mice; Azoxymethane; Colorectal Neoplasms; Disease Models, Animal; Granzymes; Immunity, Cellular; T-Lymphocytes, Cytotoxic; Zinc
PubMed: 38692920
DOI: 10.1248/yakushi.23-00154-1 -
Nutrients Apr 2024Colorectal cancer stands as the third most prevalent form of cancer worldwide, with a notable increase in incidence in Western countries, mainly attributable to...
Colorectal cancer stands as the third most prevalent form of cancer worldwide, with a notable increase in incidence in Western countries, mainly attributable to unhealthy dietary habits and other factors, such as smoking or reduced physical activity. Greater consumption of vegetables and fruits has been associated with a lower incidence of colorectal cancer, which is attributed to their high content of fiber and bioactive compounds, such as flavonoids. In this study, we have tested the flavonoids quercetin, luteolin, and xanthohumol as potential antitumor agents in an animal model of colorectal cancer induced by azoxymethane and dodecyl sodium sulphate. Forty rats were divided into four cohorts: Cohort 1 (control cohort), Cohort 2 (quercetin cohort), Cohort 3 (luteolin cohort), and Cohort 4 (xanthohumol cohort). These flavonoids were administered intraperitoneally to evaluate their antitumor potential as pharmaceutical agents. At the end of the experiment, after euthanasia, different physical parameters and the intestinal microbiota populations were analyzed. Luteolin was effective in significantly reducing the number of tumors compared to the control cohort. Furthermore, the main significant differences at the microbiota level were observed between the control cohort and the cohort treated with luteolin, which experienced a significant reduction in the abundance of genera associated with disease or inflammatory conditions, such as or . On the other hand, genera associated with a healthy state, such as , showed a significant increase in the luteolin cohort. These results underline the anti-colorectal cancer potential of luteolin, manifested through a modulation of the intestinal microbiota and a reduction in the number of tumors.
Topics: Animals; Luteolin; Colorectal Neoplasms; Gastrointestinal Microbiome; Propiophenones; Flavonoids; Quercetin; Rats; Male; Disease Models, Animal; Azoxymethane; Antineoplastic Agents; Rats, Wistar
PubMed: 38674851
DOI: 10.3390/nu16081161