Search Results (88)

Background/Objectives: Recent studies suggest that angiopoietin-like protein 2 (ANGPTL2) is one of the factors contributing to disease progression in distant organs associated with periodontitis. We previously reported that periodontitis promotes hepatocellular carcinoma and that ANGPTL2 may be involved in tumor progression. Based on these findings, we herein investigated the role of periodontitis-induced ANGPTL2 in the progression of colorectal cancer (CRC) in mice. Methods: Male C57BL/6 mice were divided into control and periodontitis groups. Colorectal tumors were induced using azoxymethane (AOM) and dextran sulfate sodium (DSS). Periodontitis was induced by silk ligation. In addition, the model was enhanced by repeated gingival administration of lipopolysaccharide (LPS) derived from Porphyromonas gingivalis, a periodontal pathogen, to better mimic clinical conditions. Tumor development and ANGPTL2 expression in periodontal tissues, colorectal tumors, and serum were assessed by histology, immunostaining, and enzyme-linked immunosorbent assay. Results: Ligation and administration of P. gingivalis LPS resulted in significant alveolar bone resorption. The periodontitis group exhibited a significantly increased colorectal tumor burden compared with the control group. ANGPTL2 expression was markedly elevated in periodontal tissues, serum, and colorectal tumors in the periodontitis group. Histological analysis revealed increased tumor cell proliferation and enhanced inflammation in the periodontitis group relative to controls. These findings suggest a possible association between periodontitis-associated inflammation, elevated ANGPTL2 levels, and CRC progression in this experimental model. Conclusions: In this experimental model, experimental periodontitis was accompanied by concurrent increases in both local and systemic ANGPTL2 expression and accelerated growth of colorectal tumors. These findings suggest a potential association between periodontal inflammation, increased ANGPTL2 levels, and colorectal tumor progression. Full article

Oxygen nanobubble (NBO₂) water is reportedly a promising therapeutic and radiosensitizing agent against solid cancers. However, the significance of nanobubble size in inflammation-associated colorectal carcinogenesis in vivo remains elusive. We investigated whether small NBO₂ water exerts stronger preventive effects against colitis and colorectal carcinogenesis in an azoxymethane/dextran sulfate sodium–induced mouse model of colitis-associated cancer. Differences in particle size between the small and large NBO₂ water samples were confirmed by atomic force microscopy. The mice received drinking water containing either small or large sized NBO₂ throughout the experiment. Small NBO₂ water significantly reduced disease activity index scores, histopathological colitis scores, colonic shortening, CD68-positive inflammatory macrophage density, and tumor numbers. However, body weight, water intake, food intake, and spleen weight were unaffected. Immunohistochemistry revealed that small NBO₂ water reduced the percentage of Ki-67-positive tumor cells and the proportions of hypoxia-inducible factor-1α–positive epithelial and stromal cells, whereas no significant differences were observed in CD8- or forkhead box P3-positive cells. We conclude that nanometer-sized oxygen bubbles prevent inflammation-associated colorectal carcinogenesis, and that particle size is a critical determinant of biological effects. Small amounts of NBO₂ water may help control colitis and tumor development by alleviating hypoxia in the tumor microenvironment. Full article

Chronic inflammation-driven colorectal cancer (CRC) is critically mediated by interleukin-17A (IL-17A)-dependent immune responses and nuclear factor-κB (NF-κB) signaling, which promote immune cell infiltration and tumor progression. In this study, the anti-tumor efficacy and molecular mechanisms of a standardized extract of Hedyotis diffusa Willd. (HD) and its constituent, ferulic acid (FA), were investigated using an azoxymethane/dextran sulfate sodium (AOM/DSS)-induced colitis-associated CRC mouse model. HD and FA treatment markedly alleviated colitis, reduced tumor number and size, improved survival, and attenuated histopathological damage. Transcriptomic analysis revealed significant modulation of immune-related pathways, with prominent suppression of IL-17A and NF-κB signaling. Molecular docking demonstrated binding of FA to IL-17A at Pro59 and Arg101, suggesting potential disruption of the IL-17A/IL-17RA interaction. Consistently, both HD and FA reduced immune cell infiltration, downregulated IL-17A production, and inhibited NF-κB activation in colonic tissues. Collectively, these findings demonstrated that HD exerted protective effects against inflammation-associated CRC through targeting the IL-17A/IL-17RA axis and downstream NF-κB signaling, providing mechanistic insight into IL-17A-centered immunomodulation in colorectal tumorigenesis. Full article

Bioactive compounds in food contribute to reducing the risk of developing colon cancer by modulating the gut microbiota. We have recently demonstrated that garambullo (Myrtillocactus geometrizans), an endemic fruit of Mexico rich in bioactive compounds, attenuates aberrant crypt foci in an animal model. However, its potential to modulate the gut microbiota is unknown. The main objective of this study was to evaluate whether its consumption modulates colon carcinogenesis by altering the microbiota in an in vivo model induced by azoxymethane and dextran sulfate sodium (AOM/DSS). Fecal samples were collected from twelve male Sprague-Dawley rats and analyzed for microbiota composition after 0, 8, and 16 weeks of treatment with saline (control), AOM/DSS, garambullo (G), or residue of garambullo (RG) with AOM/DSS (G+AOM/DSS and RG+AOM/DSS, respectively). Characterization of the microbiome was based on the conserved region of the 16S rRNA V3-V4 gene, and analyzed by the ZymoBIOMICS’ Targeted Metagenomics Sequencing (Zymo Research) service. In an animal model induced with AOM/DSS for 8 weeks, consumption of G and its residue increased the bacterial genera Shuttleworthiia, Subdoligranulum, Lactobacillus, Faecalibacterium, and Alloprevotella (p < 0.05). Consumption of G and its residue allowed the proliferation of bacteria that produce short-chain fatty acids and are associated with protective mechanisms of the colon. Full article

(E)-Flavokawain A (FKA), the primary chalcone constituent of Piper methysticum, exhibits diverse pharmacological properties and holds significant potential for therapeutic development. Objectives: This study aims to investigate the anti-colorectal cancer effects and mechanisms of FKA. Methods: Using AOM/DSS-induced colorectal cancer models in C57 mice, the research examines the impact of different FKA doses, employing 16S rRNA and metabolomics to explore the potential mechanism. Results: The findings indicated that FKA significantly inhibited the progression of colorectal cancer in C57 mice by modulating the composition of the gut microbiota. This modulation involved the suppression of endotoxin secretion by pathogenic bacteria and the concurrent augmentation of beneficial bacteria. Furthermore, in the context of metabolic pathways, FKA regulates lipid metabolism and arachidonic acid metabolism, thereby mitigating the inflammatory transformation associated with colorectal cancer. Conclusions: These findings provide valuable insights supporting the potential of FKA as a viable preventive strategy against CRC. Full article

The rising global burden of colorectal cancer (CRC) has now positioned it as the third most common cancer worldwide. Chemotherapy regimens are known to disrupt the composition of the gut microbiota and lead to long-term health consequences for cancer patients. However, the alteration of gut microbiota by specific chemotherapeutic agents has been insufficiently explored until now. The purpose of this study was to assess changes in the gut microbiota following treatment with VERU-111 as a chemotherapy agent for the treatment of CRC. We thus performed a metagenomic study using 16S rRNA gene amplicon sequencing of fecal samples from different experimental groups in the azoxymethane (AOM) and dextran sodium sulfate (DSS)-induced murine model of CRC. To predict the functional potential of microbial communities, we used the resulting 16S rRNA gene sequencing data to perform Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. We found that the administration of VERU-111 led to a restructured microbial community that was characterized by increased alpha and beta diversity. Compared to the mice treated with DSS alone, VERU-111 treatment significantly increased the relative abundance of several bacterial species, including Verrucomicrobiota species, Muribaculum intestinale, Alistipes finegoldii, Turicibacter, and the well-known gut-protective bacterial species Akkermansia muciniphila. The relative abundance of Ruminococcus, which is negatively correlated with immune checkpoint blockade therapy, was diminished following VERU-111 administration. Overall, this metagenomic study suggests that the microbial shift after administration of VERU-111 is associated with suppression of several metabolic and cancer-related pathways that might, at least in part, facilitate the suppression of CRC. These favorable shifts in gut microbiota suggest a novel therapeutic dimension of using VERU-111 to treat CRC and emphasize the need for further mechanistic exploration. Full article

Background/Objectives: Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality worldwide, with its development influenced by diet, obesity, and gut microbiota (GM) alterations. This study aimed to evaluate the impact of human fecal microbiota transplantation (FMT) on the progression of CRC in a murine model. Methods: CRC was chemically induced in BALB/c mice using azoxymethane/dextran sulfate sodium (AOM/DSS). Mice were transferred with GM via FMT and divided into two experimental groups according to the microbiota source (healthy donors or CRC patients). A positive control group (AOM/DSS without FMT) and a negative control group (no CRC induction or FMT) were included. Clinical parameters, histopathological analyses, and cytokine profiling were performed. Results: Mice receiving FMT, particularly from CRC patients, exhibited increased mitotic activity, dysplasia, neoplastic proliferation, structural alterations in the colon, and more pronounced GALT hyperplasia. At the immunological level, both FMT groups (healthy and CRC-derived) showed modulation of IL-1β, IL-4, IL-6, IL-10, IL-17A, and TNF-α compared to the positive control. Conclusions: Human GM transplantation modulated the colonic microenvironment through histopathological and immunological changes, influencing CRC progression in this murine model. These findings highlight the role of GM in shaping CRC development and suggest that human-derived microbiota may significantly impact tumor dynamics. Full article

Recently, evidence indicating that microplastics (MPs) have a hazardous effect on human health is accumulating. The potential of MPs having a role in carcinogenesis was suggested. Therefore, the aim of this study was to evaluate MPs’ effect on colitis-associated colorectal cancer (CAC) development. The AOM/DSS-induced CAC model was reproduced in two groups of adult male C56BL/6 mice. One of these groups received MPs (5 μm polystyrene microbeads) with drinking water at a dose of 1.48 mg/kg/day throughout the experiment (12 weeks), and the other received water untreated with MPs. In the colons of mice that consumed MPs, there was a higher number of tumor nodules at the macroscopic level, a greater tumor prevalence on histological sections, more pronounced inflammatory infiltration, a higher goblet cell volume fraction, the content of highly sulfated mucins was found in them, and there were more tumors with increased enteroendocrine cell content. We did not find any MP effects on the claudins, mucins, proapoptotic factor Bax, or on the proliferation marker Mki67 gene expression in the medial colon, nor on the serum level of TNFα, IL-1β, IL-6, and IL-10 cytokines. Thus, MPs promote the CAC development in mice by exacerbating intestinal local inflammation and damaging the epithelial barrier, and MPs may represent a potential environmental cofactor contributing to CAC risk. Full article

In patients with inflammatory bowel disease (IBD), colorectal cancer (CRC) occurs with 20-to-30-fold higher frequency, is more advanced at diagnosis, and has a worse prognosis than in the general population. To improve their treatment options, we determined if targeting STAT3 with TTI-101, a small-molecule STAT3 inhibitor, was beneficial in the azoxymethane (AOM)-disodium sulfate (DSS) mouse model of colitis-associated CRC. C57BL/6 mice received a single intraperitoneal injection of AOM followed by three cycles of 5% DSS in drinking water before receiving TTI-101 (50 mg/kg by oral gavage, OG, and daily) or vehicle for 28 days. TTI-101 treatment reduced adenoma numbers by 89% from 1.14 ± 1.07 in vehicle-treated mice to 0.13 ± 0.35 in TTI-101-treated mice (p ≤ 0.05, Kruskal–Wallis test). Levels of activated STAT3 (pY-STAT3) were increased 3.3-fold in the epithelium and stroma of dysplastic mucosa (147 ± 46; mean ± SD; and n = 4) vs. normal mucosa (45 ± 26; n = 7; and p ≤ 0.05, Kruskal–Wallis test) and were correlated with the adenoma number. TTI-101 was detected at pharmacologically relevant levels in the plasma and colons of TTI-101-treated AOM-DSS mice and was concentrated within colon tissue; plasma TTI-101 levels inversely correlated to pY-STAT3 levels. Importantly, TTI-101 normalized the colon transcriptome of AOM-DSS mice and reduced the expression of STAT3- and STAT1-upregulated genes associated with CRC oncogenesis. Thus, TTI-101 treatment may benefit IBD patients with CRC. Full article

Colitis-associated colorectal cancer (CAC) is a type of colorectal cancer (CRC) that develops as a result of chronic inflammation, particularly in patients with inflammatory bowel diseases such as ulcerative colitis and Crohn’s disease. Persistent intestinal inflammation and dysbiosis of gut microbiota under these conditions are major contributors to CRC progression. Doenjang, a traditional Korean fermented soybean paste, contains probiotics that influence intestinal microbiota composition, as well as biogenic amines (BAs), harmful compounds generated during fermentation. We analyzed the bacterial composition and BA content of Doenjang and evaluated its effects on CAC in a mouse model of AOM/DSS-induced CAC. Results revealed that Doenjang contains diverse beneficial probiotics alongside BAs. Doenjang significantly reduced tumor formation and attenuated CAC progression by modulating inflammatory and apoptotic pathways and suppressed the expression of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) by inhibiting the NF-κB pathway. Additionally, Doenjang restored intestinal epithelial barrier integrity by increasing the expression of mucin-related genes (MUC-2, MUC-3) and protective factors like TFF-3. Gut microbiota analysis revealed that Doenjang promoted a healthier gut environment by increasing microbial diversity and reducing inflammation-related bacterial populations. These findings suggest that Doenjang helps prevent and manage CAC by modulating inflammatory responses and gut microbiota composition. Full article

Background: Despite considerable advances to improve colorectal cancer (CRC) survival over the last decade, therapeutic challenges remain due to the rapid metastatic dissemination of primary tumors. This study revealed the apoptotic and anti-growth mechanism of VTD, a previously used anti-hypertensive supplement, can elevate UBXN2A, a known tumor suppressor protein in CRC, and simultaneously enhance intrinsic and extrinsic apoptosis in metastatic cancer cells. Methods and Results: An AOM/DSS mouse model of CRC showed that UBXN2A haplosufficient (UBXN2A +/−) mice treated with VTD had less tumor burden than mice with the full UBXN2A gene treated with vehicle. We have previously shown that casein-coated mesoporous silica nanoparticles (MSNs) offer an effective local delivery of drugs at tumor sites. Our findings demonstrate that the high rate of extracellular release of matrix metalloproteinases (MMPs), particularly MMP-7, by metastatic colon cancer cells, triggers the release of VTD from casein-coated mesoporous MSNs. This shows the “Zip Code” mechanism for the local enrichment of VTD at the tumor sites. After in vitro drug release verification, two independent mouse experiments, a xenograft and a splenolepatic metastatic mouse model of CRC, were used to evaluate the therapeutic efficacy of VTD-loaded and casein-coated carboxylated mesoporous silica nanoparticles, MSN-COOH/VTD/CAS (VTD, 0.2 mg/kg). Animal experiments revealed that MSN-COOH/VTD/CAS (VTD, 0.2 mg/kg) slows down the progress of tumors. Mass spectrometry (MS) revealed improved pharmacokinetics (PK) profile as MSN-COOH/VTD/CAS had less VTD accumulation in non-cancerous organs compared to pure VTD. We further improved nanoparticle targeting and drug release by shifting to calcium-based particles (CBPs). The engineered CBPs demonstrated higher drug-releasing performance. Without the MMPs trigger, MSNs show slow and continuous “drug leak” over longer period of time whereas CCSMPs stops leakage within an hour. Additionally, CBPs showed higher sensitivity to MMP-7 than MMP-9, enhancing the targetability of CBPs for CRC metastatic tumors with excessive extracellular MMP-7. Conclusions: This study introduces a new platform utilizing nanoparticle-based site-specific delivery of a plant-based anti-metastatic molecule, veratridine, with enhanced safety and therapeutic efficacy for the treatment of metastatic CRC. Full article

Background/Objectives: Chronic inflammation and Western-style diets elevate colorectal cancer (CRC) risk, particularly in individuals with colitis, a feature of inflammatory bowel disease (IBD). Diets rich in polyphenol-containing functional foods, such as cocoa, may reduce gut inflammation and modulate the gut microbiome. This study investigated the impact of cocoa polyphenol (CP) supplementation on inflammation and microbiome composition in mice with colitis, fed either a healthy or Western diet, before, during, and after the onset of disease. We hypothesized that CPs would attenuate inflammation and promote distinct shifts in the microbiome, especially in the context of a Western diet. Methods: A 2 × 2 factorial design tested the effects of the basal diet (AIN93G vs. total Western diet [TWD]) and CP supplementation (2.6% w/w CocoaVia™ Cardio Health Powder). Inflammation was induced using the AOM/DSS model of colitis. Results: CP supplementation did not reduce the severity of colitis, as measured by disease activity index or histopathology. CPs did not alter gene expression in healthy tissue or suppress the colitis-associated pro-inflammatory transcriptional profile in either of the two diet groups. However, fecal microbiome composition shifted significantly with CPs before colitis induction, with persistent effects on several rare taxa during colitis and recovery. Conclusions: CP supplementation did not mitigate inflammation or mucosal injury at the tissue level, nor did it affect the expression of immune-related genes. While CPs altered microbiome composition, most notably in healthy mice before colitis, these shifts did not correspond to changes in inflammatory signaling. Basal diet remained the primary determinant of inflammation, mucosal damage, and colitis severity in this model. Full article

Enterotoxigenic Bacteroides fragilis (ETBF) promotes colitis-associated cancer through the Bacteroides fragilis toxin (BFT), which induces colonic inflammation that can be exacerbated by external stimuli. We found that BALB/c mice infected with ETBF and treated with azoxymethane and dextran sodium sulfate (DSS) developed numerous distal colon polyps more rapidly than B6 mice, suggesting strain differences in ETBF-induced tumorigenicity. Using a bft gene-deficient ETBF strain, we confirmed BFT’s crucial role in ETBF-promoted tumorigenesis and inflammation. While both 1% and 2% DSS induced comparable polyp formation, 1% DSS minimized mortality, proving sufficient for maximizing polyp development. Mechanistically, BFT-mediated tumorigenesis involves NF-κB/CXCL1 signaling in colonic epithelial cells exposed to BFT and DSS, a pathway known to be critical for inflammation and cancer progression. This model provides a valuable platform for dissecting ETBF’s colitis-associated cancer-promoting mechanisms, particularly those involving BFT, and for evaluating BFT-targeted therapeutic interventions. Full article

Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide with limited treatment options for advanced disease stages. Growing evidence implicates the gut microbiota in CRC pathogenesis, prompting interest in probiotics as a potential therapeutic strategy. In this study, we evaluated the effects of two probiotic compositions, CI (a mix of lactobacilli and bifidobacteria) and CII (bifidobacteria alone), in two murine CRC models: the orthotopic MC-38 cecum injection model and the inflammation-driven azoxymethane/dextran sodium sulfate (AOM/DSS) model. CI showed significant anti-tumor effects in the orthotopic model, reducing tumor weight and volume, which was, however, not associated with robust immune activation, suggesting microbiota-driven mechanisms. In contrast, CII was more effective in the AOM/DSS model, reducing colonic inflammation and completely preventing tumor development. Our study demonstrates that probiotics might have great therapeutic potential via modulation of the gut microbiota, and they can exert anti-tumor effects in murine models of CRC with distinct compositions showing differential efficacy depending on the model. CI stabilized the gut microbiome and inhibited pro-tumorigenic taxa in the MC-38 cecum injection model, while CII exhibited anti-inflammatory properties in the AOM/DSS model, highlighting the potential of probiotics as context-specific interventions for CRC. These findings contribute to the growing body of evidence supporting microbiota-targeted strategies in oncology and their relevance for therapeutic applications. Full article

Background. Worldwide, colorectal cancer is the third most commonly diagnosed cancer. It is the second leading cause of cancer-related mortality. Recent studies establish a relationship between natural compounds from plants with the prevention and treatment of cancer. Specifically, glucosinolates with antitumoral capacity and polyphenols with the ability to scavenge free radicals that can cause cell damage have been identified in the Brassicaceae family. Objectives. Based on the previously mentioned factors, this study aimed to develop a nutraceutical made with extracts from different Brassicaceae seeds and study its antioxidant and antiproliferative action in vitro and in vivo using the AOM/DSS model in CC57BL6J mice. Results. Extract from the seeds of Eruca sativa and Sinapis alba showed the highest antioxidant capacity among the different species studied and were selected for nutraceutical formulation, which was potentially absorbable (73%) after an in vitro digestion process. In total, thirty compounds were identified in the nutraceutical that could be responsible for its antioxidant and tumoral prevention capacity. The intake of nutraceutical was a successful intervention to prevent the development of polyps by 31.6% and their size by 53.9%. When the nutritional intervention was used in combination with a physical exercise protocol, these parameters dropped to 52.3% and 62.6%, respectively. Conclusions. These findings suggest that the consumption of a diet rich in bioactive compounds from Brassica species, in combination with physical activity, is a valuable prevention strategy for colorectal cancer. However, more research is required to evaluate the efficacy and safety of these interventions in clinical settings. Full article