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Gastroenterology Dec 2023Pien Tze Huang (PZH) is a well-established traditional medicine with beneficial effects against inflammation and cancer. We aimed to explore the chemopreventive effect...
BACKGROUND & AIMS
Pien Tze Huang (PZH) is a well-established traditional medicine with beneficial effects against inflammation and cancer. We aimed to explore the chemopreventive effect of PZH in colorectal cancer (CRC) through modulating gut microbiota.
METHODS
CRC mouse models were established by azoxymethane plus dextran sulfate sodium treatment or in Apc mice treated with or without PZH (270 mg/kg and 540 mg/kg). Gut barrier function was determined by means of intestinal permeability assays and transmission electron microscopy. Fecal microbiota and metabolites were analyzed by means of metagenomic sequencing and liquid chromatography mass spectrometry, respectively. Germ-free mice or antibiotic-treated mice were used as models of microbiota depletion.
RESULTS
PZH inhibited colorectal tumorigenesis in azoxymethane plus dextran sulfate sodium-treated mice and in Apc mice in a dose-dependent manner. PZH treatment altered the gut microbiota profile, with an increased abundance of probiotics Pseudobutyrivibrio xylanivorans and Eubacterium limosum, while pathogenic bacteria Aeromonas veronii, Campylobacter jejuni, Collinsella aerofaciens, and Peptoniphilus harei were depleted. In addition, PZH increased beneficial metabolites taurine and hypotaurine, bile acids, and unsaturated fatty acids, and significantly restored gut barrier function. Transcriptomic profiling revealed that PZH inhibited PI3K-Akt, interleukin-17, tumor necrosis factor, and cytokine-chemokine signaling. Notably, the chemopreventive effect of PZH involved both microbiota-dependent and -independent mechanisms. Fecal microbiota transplantation from PZH-treated mice to germ-free mice partly recapitulated the chemopreventive effects of PZH. PZH components ginsenoside-F2 and ginsenoside-Re demonstrated inhibitory effects on CRC cells and primary organoids, and PZH also inhibited tumorigenesis in azoxymethane plus dextran sulfate sodium-treated germ-free mice.
CONCLUSIONS
PZH manipulated gut microbiota and metabolites toward a more favorable profile, improved gut barrier function, and suppressed oncogenic and pro-inflammatory pathways, thereby suppressing colorectal carcinogenesis.
Topics: Mice; Animals; Signal Transduction; Gastrointestinal Microbiome; Dextran Sulfate; Phosphatidylinositol 3-Kinases; Apoptosis; Medicine, Traditional; Colorectal Neoplasms; Carcinogenesis; Azoxymethane
PubMed: 37704113
DOI: 10.1053/j.gastro.2023.08.052 -
Methods in Molecular Biology (Clifton,... 2016Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), significantly increases the risk for development of colorectal cancer.... (Review)
Review
Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), significantly increases the risk for development of colorectal cancer. Specifically, dysplasia and cancer associated with IBD (colitis-associated cancer or CAC) develop as a result of repeated cycles of injury and healing in the intestinal epithelium. Animal models are utilized to examine the mechanisms of CAC, the role of epithelial and immune cells in this process, as well as the development of novel therapeutic targets. These models typically begin with the administration of a carcinogenic compound, and inflammation is caused by repeated cycles of colitis-inducing agents. This review describes a common CAC model that utilizes the pro-carcinogenic compound azoxymethane (AOM) followed by dextran sulfate sodium (DSS) which induces the inflammatory insult.
Topics: Animals; Azoxymethane; Colitis; Colonic Neoplasms; Dextran Sulfate; Disease Models, Animal; Female; Humans; Male; Mice
PubMed: 27150094
DOI: 10.1007/978-1-4939-3661-8_14 -
PeerJ 2023Colorectal cancer (CRC) is the third most common cancer. It is a heterogeneous disease, including both hereditary and sporadic types of tumors. CRC results from complex... (Review)
Review
BACKGROUND
Colorectal cancer (CRC) is the third most common cancer. It is a heterogeneous disease, including both hereditary and sporadic types of tumors. CRC results from complex interactions between various genetic and environmental factors. Inflammatory bowel disease is an important risk factor for developing CRC. Despite growing understanding of the CRC biology, preclinical models are still needed to investigate the etiology and pathogenesis of the disease, as well as to find new methods of treatment and prevention.
OBJECTIVES
The purpose of this review is to describe existing murine models of CRC with a focus on the models of colitis-associated CRC. This manuscript could be relevant for experimental biologists and oncologists.
METHODOLOGY
We checked PubMed and Google from 01/2018 to 05/2023 for reviews of CRC models. In addition, we searched PubMed from 01/2022 to 01/2023 for articles using the azoxymethane (AOM)/dextran sulfate sodium (DSS) CRC model.
RESULTS
Existing murine models of CRC include spontaneous, genetically engineered, transplantation, and chemically induced models. For the study of colitis-associated cancer (CAC), the AOM/DSS model is predominantly used. This model is very similar in histological and molecular characteristics to the human CAC, and is highly reproducible, inexpensive, and easy to use. Despite its popularity, the AOM/DSS model is not standardized, which makes it difficult to analyze and compare data from different studies.
CONCLUSIONS
Each model demonstrates particular advantages and disadvantages, and allows to reproduce different subtypes or aspects of the pathogenesis of CRC.
Topics: Mice; Humans; Animals; Azoxymethane; Dextran Sulfate; Colitis-Associated Neoplasms; Colitis; Disease Models, Animal; Colorectal Neoplasms
PubMed: 37927787
DOI: 10.7717/peerj.16159 -
Azoxymethane-induced rat aberrant crypt foci: relevance in studying chemoprevention of colon cancer.World Journal of Gastroenterology Nov 2008The pathogenesis of colon cancer involves sequential and multistep progression of epithelial cells initiated to a cancerous state with defined precancerous... (Review)
Review
The pathogenesis of colon cancer involves sequential and multistep progression of epithelial cells initiated to a cancerous state with defined precancerous intermediaries. Aberrant crypt foci (ACF) represent the earliest identifiable intermediate precancerous lesions during colon carcinogenesis in both laboratory animals and humans. ACF are easily induced by colon-specific carcinogens in rodents and can be used to learn more about the process of colon carcinogenesis. For over two decades, since its first discovery, azoxymethane (AOM)-induced rodent ACF have served as surrogate biomarkers in the screening of various anticarcinogens and carcinogens. Several dietary constituents and phytochemicals have been tested for their colon cancer chemopreventive efficacy using the ACF system. There has been substantial effort in defining and refining ACF in terms of understanding their molecular make-up, and extensive research in this field is currently in progress. In chemoprevention studies, AOM-induced rat ACF have been very successful as biomarkers, and have provided several standardized analyses of data. There have been several studies that have reported that ACF data do not correlate to actual colon tumor outcome, however, and hence there has been an ambiguity about their role as biomarkers. The scope of this mini-review is to provide valuable insights and limitations of AOM-induced rat ACF as biomarkers in colon cancer chemoprevention studies. The role of the dynamics and biological heterogeneity of ACF is critical in understanding them as biomarkers in chemoprevention studies.
Topics: Animals; Azoxymethane; Biomarkers, Tumor; Carcinogens; Chemoprevention; Colon; Colonic Neoplasms; Disease Models, Animal; Humans; Precancerous Conditions; Rats
PubMed: 19034964
DOI: 10.3748/wjg.14.6632 -
Methods in Molecular Biology (Clifton,... 2024Recent progress in developing new vaccination strategies against cancer requires the production of complex and reliable animal models reflecting the complexity of the...
Recent progress in developing new vaccination strategies against cancer requires the production of complex and reliable animal models reflecting the complexity of the tumors with their microenvironment. Mice can be considered a good source due to low cost and ease of being genetically modified, inoculated with tumor cell lines or treated by chemicals to induce different cancers. Despite significant limitations in modeling human cancer complexity, preclinical trials conducted in mice can efficiently contribute to understand molecular mechanisms of cancer, to closely resemble and follow carcinogenesis steps impossible to study into humans, and to test new anticancer therapies. In this chapter, we generally describe the different mouse models developed for cancer vaccines' preclinical trials. A particular focus is dedicated to a chemically-induced colorectal cancer model in use in our laboratories.
Topics: Humans; Animals; Mice; Dextrans; Azoxymethane; Carcinogenesis; Disease Models, Animal; Colorectal Neoplasms; Tumor Microenvironment; Sulfates
PubMed: 38236535
DOI: 10.1007/978-1-0716-3714-2_5 -
Cancer Biology & Therapy Jul 2009Colon cancer is the third most common cancer and third most common cause of cancer-related death in the USA according to 2008 American Cancer Society statistics. The... (Review)
Review
Colon cancer is the third most common cancer and third most common cause of cancer-related death in the USA according to 2008 American Cancer Society statistics. The carcinogenesis of colon cancer has been associated with both genetics and environmental factors. It has been found that several signal pathways, including K-ras, Src/PI3K/Akt, beta-catenin, TGFbeta and p53 play critical roles in its pathogenesis. The 5 y survival rate of metastatic colon cancer is below 10%. Thus, it is necessary to further understand its biology and search for effective therapy. Azoxymethane (AOM) is a common model for colon cancer. It can specifically induce colon cancer similar to the pathogenesis of human sporadic colon cancer. Thus, it has been extensively used in the study of the molecular biology, prevention and treatment of colon cancer. After administration, AOM is metabolised into methylazoxymethanol by CYP2E1, which causes DNA mutations. Mutation of K-ras activates this pathway and its downstream PI3K/Akt pathway and MAPK pathway. Mutation of beta-catenin also prevents it from being degraded by GSK-3 and accumulation of beta-catenin leads to cell proliferation. TGFbeta, a pro-apoptotic protein, is inhibited. All of these changes form the basis of AOM carcinogenesis. This model has been used in the study of the genetic deficiencies of colon cancer and in the prevention and treatment of the disease. For example, TGF-betaR2 and adiponectin knockout mice are more susceptible to AOM, while high amylose cornstarch, green tea and artemisia have protective effects.
Topics: Adenocarcinoma; Adenoma; Adiponectin; Animals; Anticarcinogenic Agents; Apoptosis; Azoxymethane; Carcinogens; Colonic Neoplasms; Cytochrome P-450 CYP2E1; DNA Damage; Diet; Genes, ras; Humans; MAP Kinase Signaling System; Methylazoxymethanol Acetate; Mice; Mice, Knockout; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats; Signal Transduction; Transforming Growth Factor beta; Transforming Growth Factor beta2
PubMed: 19502780
DOI: 10.4161/cbt.8.14.8983 -
Journal of Biomedicine & Biotechnology 2011The dimethyhydrazine (DMH) or azoxymethane (AOM) model is a well-established, well-appreciated, and widely used model of experimental colon carcinogenesis. It has many... (Review)
Review
The dimethyhydrazine (DMH) or azoxymethane (AOM) model is a well-established, well-appreciated, and widely used model of experimental colon carcinogenesis. It has many morphological as well as molecular similarities to human sporadic colorectal cancer (CC), which are summarized and discussed in this paper. In addition, the paper combines present knowledge of morphological and molecular features in the multistep development of CC recognized in the DMH/AOM rat model. This understanding is necessary in order to accurately identify and interpret alterations that occur in the colonic mucosa when evaluating natural or pharmacological compounds in DMH/AOM rat colon carcinogenesis. The DMH/AOM model provides a wide range of options for investigating various initiating and environmental factors, the role of specific dietary and genetic factors, and therapeutic options in CC. The limitations of this model and suggested areas in which more research is required are also discussed.
Topics: 1,2-Dimethylhydrazine; Animals; Azoxymethane; Biomarkers, Tumor; Colonic Neoplasms; Humans; Precancerous Conditions; Rats; Terminology as Topic
PubMed: 21253581
DOI: 10.1155/2011/473964 -
Environmental Toxicology Feb 2020Colorectal cancer (CRC) is a major health problem and third most common deaths in western world. Dietary interventions together with modified dietary style can prevent...
Colorectal cancer (CRC) is a major health problem and third most common deaths in western world. Dietary interventions together with modified dietary style can prevent the CRC in humans. Xanthohumol (XHA), a polyphenol isolated from Humulus lupulus L. contains many beneficial effects. The aim of the study is to analyze the effect of XHA on Azoxymethane (AOM)-induced experimental CRC in rats. Levels of MDA were increased and enzymic antioxidants levels were decreased in AOM-induced rats. However, these levels were reversed upon XHA treatment. Further, the mRNA expressions of iNOS and COX-2 were also downregulated in XHA treated rats compared to AOM-induced rats. Further, we found that administration of XHA suppressed the wnt/β-catenin signaling together with modulation of apoptotic proteins Bax, Bcl-2, and caspase 3. We conclude that XHA can able to quench the free radicals, inhibits cell proliferation and induces apoptosis, thus it can be a chemopreventive/therapeutic agent against CRC.
Topics: Aberrant Crypt Foci; Animals; Antioxidants; Apoptosis; Apoptosis Regulatory Proteins; Azoxymethane; Cell Proliferation; Colorectal Neoplasms; Flavonoids; Humans; Male; Propiophenones; Rats; Rats, Sprague-Dawley
PubMed: 31714664
DOI: 10.1002/tox.22849 -
Gastroenterology Mar 2021RNA N-methyladenosine (mA) modification has recently emerged as a new regulatory mechanism in cancer progression. We aimed to explore the role of the mA regulatory... (Observational Study)
Observational Study
BACKGROUND & AIMS
RNA N-methyladenosine (mA) modification has recently emerged as a new regulatory mechanism in cancer progression. We aimed to explore the role of the mA regulatory enzyme METTL3 in colorectal cancer (CRC) pathogenesis and its potential as a therapeutic target.
METHODS
The expression and clinical implication of METTL3 were investigated in multiple human CRC cohorts. The underlying mechanisms of METTL3 in CRC were investigated by integrative mA sequencing, RNA sequencing, and ribosome profiling analyses. The efficacy of targeting METTL3 in CRC treatment was elucidated in CRC cell lines, patient-derived CRC organoids, and Mettl3-knockout mouse models.
RESULTS
Using targeted clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 dropout screening, we identified METTL3 as the top essential mA regulatory enzyme in CRC. METTL3 was overexpressed in 62.2% (79/127) and 88.0% (44/50) of primary CRCs from 2 independent cohorts. High METTL3 expression predicted poor survival in patients with CRC (n = 374, P < .01). Functionally, silencing METTL3 suppressed tumorigenesis in CRC cells, human-derived primary CRC organoids, and Mettl3-knockout mouse models. We discovered the novel functional mA methyltransferase domain of METTL3 in CRC cells by domain-focused CRISPR screening and mutagenesis assays. Mechanistically, METTL3 directly induced the mA-GLUT1-mTORC1 axis as identified by integrated mA sequencing, RNA sequencing, ribosome sequencing, and functional validation. METTL3 induced GLUT1 translation in an mA-dependent manner, which subsequently promoted glucose uptake and lactate production, leading to the activation of mTORC1 signaling and CRC development. Furthermore, inhibition of mTORC1 potentiated the anticancer effect of METTL3 silencing in CRC patient-derived organoids and METTL3 transgenic mouse models.
CONCLUSIONS
METTL3 promotes CRC by activating the mA-GLUT1-mTORC1 axis. METTL3 is a promising therapeutic target for the treatment of CRC.
Topics: Adenosine; Aged; Animals; Azoxymethane; Carcinogenesis; Cell Line, Tumor; Cohort Studies; Colorectal Neoplasms; DNA Methylation; Dextran Sulfate; Female; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Glucose Transporter Type 1; Humans; Male; Mechanistic Target of Rapamycin Complex 1; Methyltransferases; Mice, Knockout; Middle Aged; Neoplasms, Experimental; Signal Transduction; Up-Regulation; Mice
PubMed: 33217448
DOI: 10.1053/j.gastro.2020.11.013 -
Metallomics : Integrated Biometal... Feb 2021Zinc is an essential micronutrient involved in various biological processes. It is also argued that tumors need zinc for maintenance and proliferation and tumor cell...
Zinc is an essential micronutrient involved in various biological processes. It is also argued that tumors need zinc for maintenance and proliferation and tumor cell apoptosis. Zinc homeostasis is regulated by the gastrointestinal tract and involves interplay of host, dietary, environmental and social factors such as alcohol consumption. The DNA alkylation agent azoxymethane (AOM), which is primarily activated in the liver, induces a high incidence of initiation and promotion steps of precancerous lesions in the colon of rats. The altered expression of hepatic zinc transporters by AOM may lead to zinc dyshomeostasis in liver. Decreased serum zinc concentration, despite increased liver zinc also indicates altered liver zinc mobilization and failure to regulate zinc homeostasis. During the transformation from normal colonic mucosa to colonic epithelial hyperplasia and aberrant crypt formation, a reduction in zinc concentration is observed. It will be interesting to study further if the same trend continues throughout tumor progression towards adenocarcinomas. Lowered local zinc concentrations in the colon epithelium may not just reflect a bystander effect, but may induce cell proliferation and compromise DNA integrity due to impairment of zinc-containing proteins. In congruence with the tissue zinc concentrations, metallothionein levels were found to be less induced in AOM -administered colon compared to normal healthy colon. Lowered tissue zinc levels in small and large intestine were also associated with increased expression of mRNA and protein ZnT1. In this regard, the mode of zinc responsiveness to ZnT1 mimics that of metallothionein, albeit at a lower level for ZnT1.
Topics: Animals; Azoxymethane; Carcinogens; Colonic Neoplasms; Male; Precancerous Conditions; Rats, Inbred F344; Zinc; Rats
PubMed: 33595654
DOI: 10.1093/mtomcs/mfaa009