-
Frontiers in Immunology 2020The intestinal microbiota, composed of a large population of microorganisms, is often considered a "forgotten organ" in human health and diseases. Increasing evidence... (Review)
Review
The intestinal microbiota, composed of a large population of microorganisms, is often considered a "forgotten organ" in human health and diseases. Increasing evidence indicates that dysbiosis of the intestinal microbiota is closely related to colorectal cancer (CRC). The roles for intestinal microorganisms that initiated and facilitated the CRC process are becoming increasingly clear. Hypothesis models have been proposed to illustrate the complex relationship between the intestinal microbiota and CRC. Recent studies have identified , enterotoxigenic , , , , and as CRC candidate pathogens. In this review, we summarized the mechanisms involved in microbiota-related colorectal carcinogenesis, including inflammation, pathogenic bacteria, and their virulence factors, genotoxins, oxidative stress, bacterial metabolites, and biofilm. We also described the clinical values of intestinal microbiota and novel strategies for preventing and treating CRC.
Topics: Adenocarcinoma; Animals; Bacteria; Biodiversity; Biofilms; Carcinogenesis; Cell Transformation, Neoplastic; Colorectal Neoplasms; Diet; Gastrointestinal Microbiome; Genes, APC; Humans; Inflammation; Mice; Models, Biological; Mutagens; Neoplastic Syndromes, Hereditary; Oxidative Stress; Rats; Virulence
PubMed: 33329610
DOI: 10.3389/fimmu.2020.615056 -
Gastroenterology Jan 2022Dietary fat intake is associated with increased risk of colorectal cancer (CRC). We examined the role of high-fat diet (HFD) in driving CRC through modulating gut...
BACKGROUND AND AIMS
Dietary fat intake is associated with increased risk of colorectal cancer (CRC). We examined the role of high-fat diet (HFD) in driving CRC through modulating gut microbiota and metabolites.
METHODS
HFD or control diet was fed to mice littermates in CRC mouse models of an azoxymethane (AOM) model and Apc model, with or without antibiotics cocktail treatment. Germ-free mice for fecal microbiota transplantation were used for validation. Gut microbiota and metabolites were detected using metagenomic sequencing and high-performance liquid chromatography-mass spectrometry, respectively. Gut barrier function was determined using lipopolysaccharides level and transmission electron microscopy.
RESULTS
HFD promoted colorectal tumorigenesis in both AOM-treated mice and Apc mice compared with control diet-fed mice. Gut microbiota depletion using antibiotics attenuated colon tumor formation in HFD-fed mice. A significant shift of gut microbiota composition with increased pathogenic bacteria Alistipessp.Marseille-P5997 and Alistipessp.5CPEGH6, and depleted probiotic Parabacteroides distasonis, along with impaired gut barrier function was exhibited in HFD-fed mice. Moreover, HFD-modulated gut microbiota promotes colorectal tumorigenesis in AOM-treated germ-free mice, indicating gut microbiota was essential in HFD-associated colorectal tumorigenesis. Gut metabolites alteration, including elevated lysophosphatidic acid, which was confirmed to promote CRC cell proliferation and impair cell junction, was also observed in HFD-fed mice. Moreover, transfer of stools from HFD-fed mice to germ-free mice without interference increased colonic cell proliferation, impaired gut barrier function, and induced oncogenic genes expression.
CONCLUSIONS
HFD drives colorectal tumorigenesis through inducing gut microbial dysbiosis, metabolomic dysregulation with elevated lysophosphatidic acid, and gut barrier dysfunction in mice.
Topics: Animals; Anti-Bacterial Agents; Azoxymethane; Bacteria; Bacterial Translocation; Cell Proliferation; Cell Transformation, Neoplastic; Colon; Colorectal Neoplasms; Diet, High-Fat; Disease Models, Animal; Dysbiosis; Fecal Microbiota Transplantation; Feces; Gastrointestinal Microbiome; Genes, APC; Germ-Free Life; Humans; Lysophospholipids; Male; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Transgenic; Permeability; Tumor Cells, Cultured; Mice
PubMed: 34461052
DOI: 10.1053/j.gastro.2021.08.041 -
Nature May 2015Crypt stem cells represent the cells of origin for intestinal neoplasia. Both mouse and human intestinal stem cells can be cultured in medium containing the...
Crypt stem cells represent the cells of origin for intestinal neoplasia. Both mouse and human intestinal stem cells can be cultured in medium containing the stem-cell-niche factors WNT, R-spondin, epidermal growth factor (EGF) and noggin over long time periods as epithelial organoids that remain genetically and phenotypically stable. Here we utilize CRISPR/Cas9 technology for targeted gene modification of four of the most commonly mutated colorectal cancer genes (APC, P53 (also known as TP53), KRAS and SMAD4) in cultured human intestinal stem cells. Mutant organoids can be selected by removing individual growth factors from the culture medium. Quadruple mutants grow independently of all stem-cell-niche factors and tolerate the presence of the P53 stabilizer nutlin-3. Upon xenotransplantation into mice, quadruple mutants grow as tumours with features of invasive carcinoma. Finally, combined loss of APC and P53 is sufficient for the appearance of extensive aneuploidy, a hallmark of tumour progression.
Topics: Aneuploidy; Animals; CRISPR-Cas Systems; Child; Child, Preschool; Colorectal Neoplasms; Female; Genes, APC; Genes, p53; Heterografts; Humans; Imidazoles; Intercellular Signaling Peptides and Proteins; Intestinal Mucosa; Intestines; Mice; Middle Aged; Mutagenesis, Site-Directed; Mutation; Neoplasm Invasiveness; Neoplasm Transplantation; Organoids; Piperazines; Proto-Oncogene Proteins p21(ras); Smad4 Protein; Stem Cell Niche; Stem Cells
PubMed: 25924068
DOI: 10.1038/nature14415 -
Gut Feb 2019Gastric cancer is the second leading cause of cancer-related deaths and the fifth most common malignancy worldwide. In this study, human and mouse gastric cancer...
OBJECTIVE
Gastric cancer is the second leading cause of cancer-related deaths and the fifth most common malignancy worldwide. In this study, human and mouse gastric cancer organoids were generated to model the disease and perform drug testing to delineate treatment strategies.
DESIGN
Human gastric cancer organoid cultures were established, samples classified according to their molecular profile and their response to conventional chemotherapeutics tested. Targeted treatment was performed according to specific druggable mutations. Mouse gastric cancer organoid cultures were generated carrying molecular subtype-specific alterations.
RESULTS
Twenty human gastric cancer organoid cultures were established and four selected for a comprehensive in-depth analysis. Organoids demonstrated divergent growth characteristics and morphologies. Immunohistochemistry showed similar characteristics to the corresponding primary tissue. A divergent response to 5-fluoruracil, oxaliplatin, irinotecan, epirubicin and docetaxel treatment was observed. Whole genome sequencing revealed a mutational spectrum that corresponded to the previously identified microsatellite instable, genomic stable and chromosomal instable subtypes of gastric cancer. The mutational landscape allowed targeted therapy with trastuzumab for alterations and palbociclib for loss. Mouse cancer organoids carrying and or and mutations were characterised and serve as model system to study the signalling of induced pathways.
CONCLUSION
We generated human and mouse gastric cancer organoids modelling typical characteristics and altered pathways of human gastric cancer. Successful interference with activated pathways demonstrates their potential usefulness as living biomarkers for therapy response testing.
Topics: Animals; Cdh1 Proteins; Disease Models, Animal; Genes, APC; Humans; Immunohistochemistry; Mice; Mutation; Organ Culture Techniques; Organoids; Piperazines; Proto-Oncogene Proteins p21(ras); Pyridines; Stomach Neoplasms; Trastuzumab; Tumor Suppressor Protein p53
PubMed: 29703791
DOI: 10.1136/gutjnl-2017-314549 -
Journal of Cancer Research and Clinical... May 2019Apc mouse is an excellent animal model bearing multiple intestinal neoplasia, used to simulate human familial adenomatous polyposis and colorectal tumors. The key point... (Review)
Review
PURPOSE
Apc mouse is an excellent animal model bearing multiple intestinal neoplasia, used to simulate human familial adenomatous polyposis and colorectal tumors. The key point of this model is the mutation of Apc gene, which is a significant tumor-suppressor gene in the Wnt signaling pathway. There are also some other possible mechanisms responsible for the development of colorectal tumors in the Apc mouse model, such as tumor-associated signaling pathways activation, the changes of tumor-related genes, and the involvement of some related proteins or molecules.
METHODS
The relevant literatures about Apc mouse model from PUBMED databases are reviewed in this study.
RESULTS
In recent years, increasing studies have focused on the application of Apc mouse model in colorectal tumor, trying to find effective therapeutic targets for further use.
CONCLUSION
This article will give a brief review on the related molecular mechanisms of the Apc mouse model and its application in colorectal tumor researches.
Topics: Adenomatous Polyposis Coli Protein; Animals; Biomarkers, Tumor; Cell Transformation, Neoplastic; Colorectal Neoplasms; DNA Repair; Disease Models, Animal; Epigenesis, Genetic; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Humans; Mice; Mice, Transgenic; Mutation; Phenotype; Research; Signal Transduction
PubMed: 30887153
DOI: 10.1007/s00432-019-02883-6 -
Nature Mar 2016Little is known about how pro-obesity diets regulate tissue stem and progenitor cell function. Here we show that high-fat diet (HFD)-induced obesity augments the numbers...
Little is known about how pro-obesity diets regulate tissue stem and progenitor cell function. Here we show that high-fat diet (HFD)-induced obesity augments the numbers and function of Lgr5(+) intestinal stem cells of the mammalian intestine. Mechanistically, a HFD induces a robust peroxisome proliferator-activated receptor delta (PPAR-δ) signature in intestinal stem cells and progenitor cells (non-intestinal stem cells), and pharmacological activation of PPAR-δ recapitulates the effects of a HFD on these cells. Like a HFD, ex vivo treatment of intestinal organoid cultures with fatty acid constituents of the HFD enhances the self-renewal potential of these organoid bodies in a PPAR-δ-dependent manner. Notably, HFD- and agonist-activated PPAR-δ signalling endow organoid-initiating capacity to progenitors, and enforced PPAR-δ signalling permits these progenitors to form in vivo tumours after loss of the tumour suppressor Apc. These findings highlight how diet-modulated PPAR-δ activation alters not only the function of intestinal stem and progenitor cells, but also their capacity to initiate tumours.
Topics: Animals; Cell Count; Cell Self Renewal; Cell Transformation, Neoplastic; Colonic Neoplasms; Diet, High-Fat; Female; Genes, APC; Humans; Intestines; Male; Mice; Obesity; Organoids; PPAR delta; Signal Transduction; Stem Cell Niche; Stem Cells; beta Catenin
PubMed: 26935695
DOI: 10.1038/nature17173 -
CA: a Cancer Journal For Clinicians May 2018The current understanding of familial colorectal cancer was limited to descriptions of affected pedigrees until the early 1990s. A series of landscape-altering... (Review)
Review
The current understanding of familial colorectal cancer was limited to descriptions of affected pedigrees until the early 1990s. A series of landscape-altering discoveries revealed that there were distinct forms of familial cancer, and most were related to genes previously not known to be involved in human disease. This review largely focuses on advances in our understanding of Lynch syndrome because of the unique relationship of this disease to defective DNA mismatch repair and the clinical implications this has for diagnostics, prevention, and therapy. Recent advances have occurred in our understanding of the epidemiology of this disease, and the advent of broad genetic panels has altered the approach to germline and somatic diagnoses for all of the familial colorectal cancer syndromes. Important advances have been made toward a more complete mechanistic understanding of the pathogenesis of neoplasia in the setting of Lynch syndrome, and these advances have important implications for prevention. Finally, paradigm-shifting approaches to treatment of Lynch-syndrome and related tumors have occurred through the development of immune checkpoint therapies for hypermutated cancers. CA Cancer J Clin 2018;68:217-231. © 2018 American Cancer Society.
Topics: Adenoma; Cell Transformation, Neoplastic; Chemoprevention; Chemotherapy, Adjuvant; Colectomy; Colonoscopy; Colorectal Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Mutational Analysis; Genetic Testing; Germ-Line Mutation; Humans; Sequence Analysis, DNA
PubMed: 29485237
DOI: 10.3322/caac.21448 -
Nature Jun 2021The tumour suppressor APC is the most commonly mutated gene in colorectal cancer. Loss of Apc in intestinal stem cells drives the formation of adenomas in mice via...
The tumour suppressor APC is the most commonly mutated gene in colorectal cancer. Loss of Apc in intestinal stem cells drives the formation of adenomas in mice via increased WNT signalling, but reduced secretion of WNT ligands increases the ability of Apc-mutant intestinal stem cells to colonize a crypt (known as fixation). Here we investigated how Apc-mutant cells gain a clonal advantage over wild-type counterparts to achieve fixation. We found that Apc-mutant cells are enriched for transcripts that encode several secreted WNT antagonists, with Notum being the most highly expressed. Conditioned medium from Apc-mutant cells suppressed the growth of wild-type organoids in a NOTUM-dependent manner. Furthermore, NOTUM-secreting Apc-mutant clones actively inhibited the proliferation of surrounding wild-type crypt cells and drove their differentiation, thereby outcompeting crypt cells from the niche. Genetic or pharmacological inhibition of NOTUM abrogated the ability of Apc-mutant cells to expand and form intestinal adenomas. We identify NOTUM as a key mediator during the early stages of mutation fixation that can be targeted to restore wild-type cell competitiveness and provide preventative strategies for people at a high risk of developing colorectal cancer.
Topics: Adenoma; Adenomatous Polyposis Coli Protein; Animals; Cell Competition; Cell Differentiation; Cell Proliferation; Cell Transformation, Neoplastic; Colorectal Neoplasms; Culture Media, Conditioned; Disease Progression; Esterases; Female; Genes, APC; Humans; Ligands; Male; Mice; Mice, Inbred C57BL; Mutation; Organoids; Stem Cells; Wnt Proteins; Wnt Signaling Pathway
PubMed: 34079124
DOI: 10.1038/s41586-021-03525-z -
Circulation Aug 2018Heart failure (HF) survival has improved, and nowadays, many patients with HF die of noncardiac causes, including cancer. Our aim was to investigate whether a causal...
BACKGROUND
Heart failure (HF) survival has improved, and nowadays, many patients with HF die of noncardiac causes, including cancer. Our aim was to investigate whether a causal relationship exists between HF and the development of cancer.
METHODS
HF was induced by inflicting large anterior myocardial infarction in APC mice, which are prone to developing precancerous intestinal tumors, and tumor growth was measured. In addition, to rule out hemodynamic impairment, a heterotopic heart transplantation model was used in which an infarcted or sham-operated heart was transplanted into a recipient mouse while the native heart was left in situ. After 6 weeks, tumor number, volume, and proliferation were quantified. Candidate secreted proteins were selected because they were previously associated both with (colon) tumor growth and with myocardial production in post-myocardial infarction proteomic studies. Myocardial gene expression levels of these selected candidates were analyzed, as well as their proliferative effects on HT-29 (colon cancer) cells. We validated these candidates by measuring them in plasma of healthy subjects and patients with HF. Finally, we associated the relation between cardiac specific and inflammatory biomarkers and new-onset cancer in a large, prospective general population cohort.
RESULTS
The presence of failing hearts, both native and heterotopically transplanted, resulted in significantly increased intestinal tumor load of 2.4-fold in APC mice (all P<0.0001). The severity of left ventricular dysfunction and fibrotic scar strongly correlated with tumor growth ( P=0.002 and P=0.016, respectively). We identified several proteins (including serpinA3 and A1, fibronectin, ceruloplasmin, and paraoxonase 1) that were elevated in human patients with chronic HF (n=101) compared with healthy subjects (n=180; P<0.001). Functionally, serpinA3 resulted in marked proliferation effects in human colon cancer (HT-29) cells, associated with Akt-S6 phosphorylation. Finally, elevated cardiac and inflammation biomarkers in apparently healthy humans (n=8319) were predictive of new-onset cancer (n=1124) independently of risk factors for cancer (age, smoking status, and body mass index).
CONCLUSIONS
We demonstrate that the presence of HF is associated with enhanced tumor growth and that this is independent of hemodynamic impairment and could be caused by cardiac excreted factors. A diagnosis of HF may therefore be considered a risk factor for incident cancer.
Topics: Adenomatous Polyps; Adult; Aged; Animals; Anterior Wall Myocardial Infarction; Case-Control Studies; Cell Proliferation; Disease Models, Animal; Female; Genes, APC; HT29 Cells; Heart Failure; Humans; Inflammation Mediators; Intercellular Signaling Peptides and Proteins; Intestinal Neoplasms; Intestinal Polyps; Male; Mice, Inbred C57BL; Mice, Transgenic; Middle Aged; Prognosis; Risk Assessment; Risk Factors; Signal Transduction; Time Factors; Tumor Burden; Ventricular Remodeling
PubMed: 29459363
DOI: 10.1161/CIRCULATIONAHA.117.030816 -
Gastroenterology Sep 2021Lipidomic changes were causally linked to metabolic diseases, but the scenario for colorectal cancer (CRC) is less clear. We investigated the CRC lipidome for putative...
OBJECTIVE
Lipidomic changes were causally linked to metabolic diseases, but the scenario for colorectal cancer (CRC) is less clear. We investigated the CRC lipidome for putative tumor-specific alterations through analysis of 3 independent retrospective patient cohorts from 2 clinical centers, to derive a clinically useful signature.
DESIGN
Quantitative comprehensive lipidomic analysis was performed using direct infusion electrospray ionization coupled with tandem mass spectrometry (ESI-MS/MS) and high-resolution mass spectrometry (HR-MS) on matched nondiseased mucosa and tumor tissue in a discovery cohort (n = 106). Results were validated in 2 independent cohorts (n = 28, and n = 20), associated with genomic and clinical data, and lipidomic data from a genetic mouse tumor model (Apc).
RESULTS
Significant differences were found between tumor and normal tissue for glycero-, glycerophospho-, and sphingolipids in the discovery cohort. Comparison to the validation collectives unveiled that glycerophospholipids showed high interpatient variation and were strongly affected by preanalytical conditions, whereas glycero- and sphingolipids appeared more robust. Signatures of sphingomyelin and triacylglycerol (TG) species significantly differentiated cancerous from nondiseased tissue in both validation studies. Moreover, lipogenic enzymes were significantly up-regulated in CRC, and FASN gene expression was prognostically detrimental. The TG profile was significantly associated with postoperative disease-free survival and lymphovascular invasion, and was essentially conserved in murine digestive cancer, but not associated with microsatellite status, KRAS or BRAF mutations, or T-cell infiltration.
CONCLUSION
Analysis of the CRC lipidome revealed a robust TG-species signature with prognostic potential. A better understanding of the cancer-associated glycerolipid and sphingolipid metabolism may lead to novel therapeutic strategies.
Topics: Adult; Aged; Aged, 80 and over; Animals; Biomarkers, Tumor; Ceramides; Colectomy; Colorectal Neoplasms; Disease-Free Survival; Female; Genes, APC; Germany; Humans; Lipidomics; Lipids; Male; Metabolome; Mice, Inbred C57BL; Mice, Transgenic; Middle Aged; Neoplasm Invasiveness; Reproducibility of Results; Retrospective Studies; Spectrometry, Mass, Electrospray Ionization; Sphingolipids; Tandem Mass Spectrometry; Triglycerides; Mice
PubMed: 34000281
DOI: 10.1053/j.gastro.2021.05.009