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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 -
International Journal of Clinical... Oct 2021Pancreatic cancer is associated with both family and hereditary cancer syndromes. Multigene panel testing for pancreatic cancer detected the germline variants BRCA1/2,... (Review)
Review
Pancreatic cancer is associated with both family and hereditary cancer syndromes. Multigene panel testing for pancreatic cancer detected the germline variants BRCA1/2, PALB2, ATM, TP53, MLH1, STK11/LKB1, APC, CDKN2A, and SPINK1/PRSS1 as high-risk genes. A latest genome-wide association study revealed the common, but low-risk germline variants in pancreatic cancer patients. Active pancreatic surveillance using magnetic resonance imaging and endoscopic ultrasound is recommended for high-risk individuals who have a family history of pancreatic cancer or harbor these germline pathogenic variants to improve the detection rate and prognosis of pancreatic cancer. Since poly-ADP-ribose polymerase (PARP) inhibitor has been shown to be effective in improving the prognosis of BRCA-positive pancreatic cancer as well as hereditary breast and ovarian cancer syndrome, PARP inhibitor therapy is currently being applied as precision medicine to pancreatic cancer patients harboring the BRCA1/2 germline variant. This review highlights the importance of surveillance for germline pathogenic variants in pancreatic cancer and is expected to lead to improvements in the diagnosis and prevention of pancreatic cancer as well as facilitate the development of effective therapeutic strategies and precision medicine.
Topics: Genetic Predisposition to Disease; Genome-Wide Association Study; Germ-Line Mutation; Humans; Pancreatic Neoplasms; Prognosis
PubMed: 34476650
DOI: 10.1007/s10147-021-02015-6 -
Journal of Hepatology Feb 2023The heritability and actionability of variants in homologous recombination-related genes in biliary tract cancers (BTCs) are uncertain. Although associations between BTC...
BACKGROUND & AIMS
The heritability and actionability of variants in homologous recombination-related genes in biliary tract cancers (BTCs) are uncertain. Although associations between BTC and BRCA germline variants have been reported, homologous recombination deficiency has not been investigated in BTCs.
METHODS
We sequenced germline variants in 27 cancer-predisposing genes in 1,292 BTC cases and 37,583 controls without a personal nor family history of cancer. We compared pathogenic germline variant frequencies between cases and controls and documented the demographic and clinical characteristics of carriers. In addition, whole-genome sequencing of 45 BTC tissues was performed to evaluate homologous recombination deficiency status.
RESULTS
Targeted sequencing identified 5,018 germline variants, which were classified into 317 pathogenic, 3,611 variants of uncertain significance, and 1,090 benign variants. Seventy-one BTC cases (5.5%) had at least one pathogenic variant among 27 cancer-predisposing genes. Pathogenic germline variants enriched in BTCs were present in BRCA1, BRCA2, APC, and MSH6 (p <0.00185). PALB2 variants were marginally associated with BTC (p = 0.01). APC variants were predominantly found in ampulla of Vater carcinomas. Whole-genome sequencing demonstrated that three BTCs with pathogenic germline variants in BRCA2 and PALB2, accompanied by loss of heterozygosity, displayed homologous recombination deficiency. Conversely, pathogenic germline variants without a second hit or variants of other homologous recombination-related genes such as ATM and BRIP1 showed homologous recombination-proficient phenotypes.
CONCLUSIONS
In this study, we describe the heritability and actionability of variants in homologous recombination-related genes, which could be used to guide screening and therapeutic strategies for BTCs.
IMPACT AND IMPLICATIONS
We found that 5.5% of biliary tract cancers (BTCs) in a Japanese population possessed hereditary cancer-predisposing gene alterations, including in BRCA and genes associated with colorectal cancer. Two hits in homologous recombination-related genes were required to confer a homologous recombination-deficient phenotype. PARP inhibitors and DNA-damaging regimens may be effective strategies against BTCs exhibiting homologous recombination deficiency. Hence, in this study, genome-wide sequencing has revealed a potential new therapeutic strategy that could be applied to a subset of BTCs.
Topics: Humans; Genetic Predisposition to Disease; Germ-Line Mutation; Biliary Tract Neoplasms; Whole Genome Sequencing; Homologous Recombination
PubMed: 36243179
DOI: 10.1016/j.jhep.2022.09.025 -
Cells Sep 2020The Wnt/β-catenin signaling pathway exerts integral roles in embryogenesis and adult homeostasis. Aberrant activation of the pathway is implicated in growth-associated... (Review)
Review
The Wnt/β-catenin signaling pathway exerts integral roles in embryogenesis and adult homeostasis. Aberrant activation of the pathway is implicated in growth-associated diseases and cancers, especially as a key driver in the initiation and progression of colorectal cancer (CRC). Loss or inactivation of Adenomatous polyposis coli (APC) results in constitutive activation of Wnt/β-catenin signaling, which is considered as an initiating event in the development of CRC. Increased Wnt/β-catenin signaling is observed in virtually all CRC patients, underscoring the importance of this pathway for therapeutic intervention. Prior studies have deciphered the regulatory networks required for the cytoplasmic stabilisation or degradation of the Wnt pathway effector, β-catenin. However, the mechanism whereby nuclear β-catenin drives or inhibits expression of Wnt target genes is more diverse and less well characterised. Here, we describe a brief synopsis of the core canonical Wnt pathway components, set the spotlight on nuclear mediators and highlight the emerging role of chromatin regulators as modulators of β-catenin-dependent transcription activity and oncogenic output.
Topics: Adenomatous Polyposis Coli Protein; Carcinogenesis; Chromatin; Colorectal Neoplasms; Disease Progression; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Histones; Humans; Proteasome Endopeptidase Complex; Proteolysis; Signal Transduction; TCF Transcription Factors; Transcription, Genetic; Wnt Proteins; beta Catenin
PubMed: 32961708
DOI: 10.3390/cells9092125 -
Molecular Cancer Dec 2021Epigenetic mechanisms play vital roles not only in cancer initiation and progression, but also in the activation, differentiation and effector function(s) of immune... (Review)
Review
Epigenetic mechanisms play vital roles not only in cancer initiation and progression, but also in the activation, differentiation and effector function(s) of immune cells. In this review, we summarize current literature related to epigenomic dynamics in immune cells impacting immune cell fate and functionality, and the immunogenicity of cancer cells. Some important immune-associated genes, such as granzyme B, IFN-γ, IL-2, IL-12, FoxP3 and STING, are regulated via epigenetic mechanisms in immune or/and cancer cells, as are immune checkpoint molecules (PD-1, CTLA-4, TIM-3, LAG-3, TIGIT) expressed by immune cells and tumor-associated stromal cells. Thus, therapeutic strategies implementing epigenetic modulating drugs are expected to significantly impact the tumor microenvironment (TME) by promoting transcriptional and metabolic reprogramming in local immune cell populations, resulting in inhibition of immunosuppressive cells (MDSCs and Treg) and the activation of anti-tumor T effector cells, professional antigen presenting cells (APC), as well as cancer cells which can serve as non-professional APC. In the latter instance, epigenetic modulating agents may coordinately promote tumor immunogenicity by inducing de novo expression of transcriptionally repressed tumor-associated antigens, increasing expression of neoantigens and MHC processing/presentation machinery, and activating tumor immunogenic cell death (ICD). ICD provides a rich source of immunogens for anti-tumor T cell cross-priming and sensitizing cancer cells to interventional immunotherapy. In this way, epigenetic modulators may be envisioned as effective components in combination immunotherapy approaches capable of mediating superior therapeutic efficacy.
Topics: Animals; Antineoplastic Agents, Immunological; Biomarkers, Tumor; Clinical Trials as Topic; Combined Modality Therapy; Disease Management; Disease Susceptibility; Drug Development; Energy Metabolism; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Humans; Immunity; Immunomodulation; Immunotherapy; Neoplasms; Signal Transduction; Treatment Outcome; Tumor Microenvironment
PubMed: 34930302
DOI: 10.1186/s12943-021-01464-x -
Cell Stem Cell Mar 2020Forward genetic screens with genome-wide CRISPR libraries are powerful tools for resolving cellular circuits and signaling pathways. Applying this technology to...
Forward genetic screens with genome-wide CRISPR libraries are powerful tools for resolving cellular circuits and signaling pathways. Applying this technology to organoids, however, has been hampered by technical limitations. Here we report improved accuracy and robustness for pooled-library CRISPR screens by capturing sgRNA integrations in single organoids, substantially reducing required cell numbers for genome-scale screening. We applied our approach to wild-type and APC mutant human intestinal organoids to identify genes involved in resistance to TGF-β-mediated growth restriction, a key process during colorectal cancer progression, and validated hits including multiple subunits of the tumor-suppressive SWI/SNF chromatin remodeling complex. Mutations within these genes require concurrent inactivation of APC to promote TGF-β resistance and attenuate TGF-β target gene transcription. Our approach can be applied to a variety of assays and organoid types to facilitate biological discovery in primary 3D tissue models.
Topics: Clustered Regularly Interspaced Short Palindromic Repeats; Genetic Testing; Humans; Intestines; Organoids; Transforming Growth Factor beta
PubMed: 32142663
DOI: 10.1016/j.stem.2020.02.007 -
Cell Stem Cell May 2020Colorectal cancer (CRC) is characterized by prominent genetic and phenotypic heterogeneity between patients. To facilitate high-throughput genetic testing and functional...
Colorectal cancer (CRC) is characterized by prominent genetic and phenotypic heterogeneity between patients. To facilitate high-throughput genetic testing and functional identification of tumor drivers, we developed a platform for pooled CRISPR-Cas9 screening in human colon organoids. Using transforming growth factor β (TGF-β) resistance as a paradigm to establish sensitivity and scalability in vitro, we identified optimal conditions and strict guide RNA (gRNA) requirements for screening in 3D organoids. We then screened a pan-cancer tumor suppressor gene (TSG) library in pre-malignant organoids with APC;KRAS mutations, which were xenografted to study clonal advantages in context of a complex tumor microenvironment. We identified TGFBR2 as the most prevalent TSG, followed by known and previously uncharacterized mediators of CRC growth. gRNAs were validated in a secondary screen using unique molecular identifiers (UMIs) to adjust for clonal drift and to distinguish clone size and abundance. Together, these findings highlight a powerful organoid-based platform for pooled CRISPR-Cas9 screening for patient-specific functional genomics.
Topics: CRISPR-Cas Systems; Clustered Regularly Interspaced Short Palindromic Repeats; Colon; Genes, Tumor Suppressor; Humans; Organoids
PubMed: 32348727
DOI: 10.1016/j.stem.2020.04.003 -
Cancers Jul 2020Desmoid tumors represent a rare entity of monoclonal origin characterized by locally aggressive behavior and inability to metastasize. Most cases present in a sporadic... (Review)
Review
Desmoid tumors represent a rare entity of monoclonal origin characterized by locally aggressive behavior and inability to metastasize. Most cases present in a sporadic pattern and are characterized by a mutation in the CTNNB1 gene; while 5-15% show a hereditary pattern associated with APC gene mutation, both resulting in abnormal β-catenin accumulation within the cell. The most common sites of presentation are the extremities and the thoracic wall, whereas FAP associated cases present intra-abdominally or in the abdominal wall. Histopathological diagnosis is mandatory, and evaluation is guided with imaging studies ranging from ultrasound, computed tomography or magnetic resonance. Current approaches advocate for an initial active surveillance period due to the stabilization and even regression capacity of desmoid tumors. For progressive, symptomatic, or disabling cases, systemic treatment, radiotherapy or surgery may be used. This is a narrative review of this uncommon disease; we present current knowledge about molecular pathogenesis, diagnosis and treatment.
PubMed: 32660036
DOI: 10.3390/cancers12071851 -
Gastroenterology Research Feb 2020Colon cancer is a common preventable cancer. With the adoption of widespread colon cancer screening in the developed countries, the incidence and mortality of colon... (Review)
Review
Colon cancer is a common preventable cancer. With the adoption of widespread colon cancer screening in the developed countries, the incidence and mortality of colon cancer have decreased in the targeted population. But unfortunately, the incidence and mortality of colorectal cancer (CRC) have been increasing over the last 25 years in the young adults below the age of 50. There is disparity in benefit, i.e. reduction in risk of death between right-sided and left-sided colon cancer by screening colonoscopy. The reason could be multifactorial and various measures have been taken to decrease this disparity. Although most of the screened populations are average risk individuals, a minority of the population have various risk factors for developing colon cancer and need to follow specific colon cancer screening guidelines. Gene mutations (adenomatous polyposis coli (APC), deleted in colon cancer (DCC), K-ras, p53, B-Raf proto-oncogene serine/threonine kinase (BRAF), mismatch repair genes) and microsatellite instability lead to the development of colon cancer. Although various non-invasive methods of colon cancer screening are now available, colonoscopy remains the gold standard of colon cancer screening and adenoma detection rate is now being used as the quality metrics in screening colonoscopy. Although Multi-Society Task Force (MSTF) and American College of Physicians (ACP) recommend initiating screening colonoscopy at age 50 years in all individuals except African Americans who should begin screening colonoscopy at age 45 years, the American Cancer Society (ACS) recommends initiating screening colonoscopy at age 45 years in all individuals irrespective of race and ethnicity. Low-volume split-dose prep has been found to be as effective as high-volume split-dose prep and more tolerable to patients with increased compliance. Boston bowel preparation scale is recommended to measure the quality of colon cleansing. CRC is curative if it is diagnosed at an early stage but various palliative treatment options (endoscopic, oncologic and surgical) are available in advanced stages of this cancer. Adequate number of lymph node assessment during surgery is essential in accurate staging of CRC. Checkpoint inhibitors have been found to have dramatic response and durable clinical benefit in dMMR/MSI-H metastatic CRC. Different genetic and immune-oncologic research trials are ongoing for early detection and better management of CRC.
PubMed: 32095167
DOI: 10.14740/gr1239