• ICC
• dedifferentiation
• mIHC
• macrophage
• proteomic
• scRNA-seq

• Cholangiocarcinoma/immunology
• Cholangiocarcinoma/pathology
• Cholangiocarcinoma/metabolism
• Cholangiocarcinoma/genetics
• Humans
• Animals
• Tumor Microenvironment/immunology
• Tumor Microenvironment/genetics
• Mice
• Bile Duct Neoplasms/immunology
• Bile Duct Neoplasms/pathology
• Bile Duct Neoplasms/metabolism
• Bile Duct Neoplasms/genetics
• Tumor-Associated Macrophages/immunology
• Tumor-Associated Macrophages/metabolism
• Cell Dedifferentiation
• Mice, Transgenic
• Disease Models, Animal
• Macrophages/immunology
• Macrophages/metabolism
• Gene Expression Regulation, Neoplastic
• Proteomics/methods

• Methylation
• NF-kappa B
• translocation
• tumor necrosis factor-alpha

• Bacterial
• Cancer
• Immunotherapy

• Humans
• Colorectal Neoplasms/immunology
• Colorectal Neoplasms/therapy
• Colorectal Neoplasms/microbiology
• Gastrointestinal Microbiome/immunology
• Animals
• Dysbiosis/immunology
• Tumor Microenvironment/immunology
• Immunity, Innate
• Adaptive Immunity

• 81872419 National Natural Science Foundation of China
• 82102949 National Natural Science Foundation of China
• 82003167 National Natural Science Foundation of China

• Carcinogenesis
• Colorectal cancer
• Dysbiosis
• Intestinal microbiota
• Next-generation sequencing

• Humans
• Colorectal Neoplasms/microbiology
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/pathology
• Gastrointestinal Microbiome/genetics
• Middle Aged
• Female
• Male
• Metagenomics/methods
• Aged
• Turkey
• Bacteria/genetics
• Bacteria/classification
• Bacteria/isolation & purification
• RNA, Ribosomal, 16S/genetics

• 148-TGD-2022 Turkish Gastroenterology Association

• antimicrobials
• synthetic biology
• computer modelling
• microbial communities

• Bacteriocins/pharmacology
• Bacteriocins/metabolism
• Bacteriocins/biosynthesis
• Enterococcus faecalis/metabolism
• Enterococcus faecalis/drug effects
• Enterococcus faecalis/genetics
• Enterococcus faecium/metabolism
• Enterococcus faecium/genetics
• Enterococcus faecium/drug effects
• Escherichia coli/metabolism
• Escherichia coli/drug effects
• Escherichia coli/genetics
• Anti-Bacterial Agents/pharmacology
• Microbial Sensitivity Tests
• Coculture Techniques

• EP/W004674/1 RCUK | Engineering and Physical Sciences Research Council (EPSRC)
• EP/X026892/1 RCUK | Engineering and Physical Sciences Research Council (EPSRC)
• EP/W004674/1 RCUK | Engineering and Physical Sciences Research Council (EPSRC)
• EP/W004674/1 RCUK | Engineering and Physical Sciences Research Council (EPSRC)
• MR/W025655/1 RCUK | Medical Research Council (MRC)

• Microbiota
• bladder cancer
• mechanism
• microbial metabolites
• tumor microenvironment

• colorectal cancer
• gut homeostasis
• gut microbiota
• immune regulation
• outer membrane vesicles

• causal associations
• dyslipidemia
• gut microbiota
• mendelian randomization study

• Humans
• Gastrointestinal Microbiome/genetics
• Mendelian Randomization Analysis
• Causality
• Clostridiales
• Dyslipidemias/genetics
• Firmicutes
• Lipids
• Genome-Wide Association Study

• 2020A1515110543 Guangdong Basic and Applied Basic Research Foundation

Colorectal cancer (CRC) remains the third most prevalent cancer disease and involves a multi-step process in which intestinal cells acquire malignant characteristics. It is well established that the appearance of distal metastasis in CRC patients is the cause of a poor prognosis and treatment failure. Nevertheless, in the last decades, CRC aggressiveness and progression have been attributed to a specific cell population called CRC stem cells (CCSC) with features like tumor initiation capacity, self-renewal capacity, and acquired multidrug resistance. Emerging data highlight the concept of this cell subtype as a plastic entity that has a dynamic status and can be originated from different types of cells through genetic and epigenetic changes. These alterations are modulated by complex and dynamic crosstalk with environmental factors by paracrine signaling. It is known that in the tumor niche, different cell types, structures, and biomolecules coexist and interact with cancer cells favoring cancer growth and development. Together, these components constitute the tumor microenvironment (TME). Most recently, researchers have also deepened the influence of the complex variety of microorganisms that inhabit the intestinal mucosa, collectively known as gut microbiota, on CRC. Both TME and microorganisms participate in inflammatory processes that can drive the initiation and evolution of CRC. Since in the last decade, crucial advances have been made concerning to the synergistic interaction among the TME and gut microorganisms that condition the identity of CCSC, the data exposed in this review could provide valuable insights into the biology of CRC and the development of new targeted therapies.

• Colorectal cancer
• Colorectal cancer stem cells
• Tumor microenvironment factors
• Tumor stroma
• Gut microbiota
• Cancer progression

• Bacterial metabolites
• Colorectal cancer
• Colorectal polyp
• Epigenetic changes
• Gut microbiota
• Stem cells

• Colorectal cancer
• genotoxin
• immunotherapy
• inflammation
• microbiome
• probiotics

• Humans
• Colorectal Neoplasms/etiology
• Colorectal Neoplasms/therapy
• Escherichia coli
• Gastrointestinal Microbiome
• Fusobacterium nucleatum
• Bacterial Infections

• R01 CA215553 NCI NIH HHS
• R01 DK073338 NIDDK NIH HHS
• R01 AG073338 NIA NIH HHS

• cancer
• cancer therapy
• genotoxicity
• microbiota
• probiotics

• Antiapoptotic activity
• Cancerogenic compounds
• Carcinogenesis
• Inflammation
• Microbiota

• Humans
• Carcinogens
• Colorectal Neoplasms/etiology
• Colorectal Neoplasms/pathology
• Fusobacterium nucleatum
• Carcinogenesis
• Microbiota

Doublecortin-like kinase 1 (DCLK1), a protein molecule, has been identified as a tumor stem cell marker in the cancer cells of gastrointestinal, pancreas, and human colon. DCLK1 expression in cancers, such as breast carcinoma, lung carcinoma, hepatic cell carcinoma, tuft cells, and human cholangiocarcinoma, has shown a way to target the DCLK1 gene and downregulate its expression. Several studies have discussed the inhibition of tumor cell proliferation along with neoplastic cell arrest when the DCLK1 gene, which is expressed in both cancer and normal cells, was targeted successfully. In addition, previous studies have shown that DCLK1 plays a vital role in various cancer metastases. The correlation of DCLK1 with numerous stem cell receptors, signaling pathways, and genes suggests its direct or an indirect role in promoting tumorigenesis. Moreover, the impact of DCLK1 was found to be related to the functioning of an oncogene. The downregulation of DCLK1 expression by using targeted strategies, such as embracing the use of siRNA, miRNA, CRISPR/Cas9 technology, nanomolecules, specific monoclonal antibodies, and silencing the pathways regulated by DCLK1, has shown promising results in both in vitro and in vivo studies on gastrointestinal (GI) cancers. In this review, we will discuss about the present understanding of DCLK1 and its role in the progression of GI cancer and metastasis.

Conveyance of pathogens between organisms causes communicable diseases. On the other hand, a non-communicable disease (NCD) was always thought to have no causative transmissible infective agents. Today, this clear distinction is increasingly getting blurred and NCDs are found to be associated with some transmissible components. The human microbiota carries a congregation of microbes, the majority and the most widely studied being bacteria in the gut. The adult human gut harbors ginormous inhabitant microbes, and the microbiome accommodates 150-fold more genes than the host genome. Microbial communities share a mutually beneficial relationship with the host, especially with respect to host physiology including digestion, immune responses, and metabolism. This review delineates the connection between environmental factors such as infections leading to gut dysbiosis and NCDs and explores the evidence regarding possible causal link between them. We also discuss the evidence regarding the value of appropriate therapeutic immunomodulatory nutritional interventions to reduce the development of such diseases. We behold such immunomodulatory effects have the potential to influence in various NCDs and restore homeostasis. We believe that the beginning of the era of microbiota-oriented personalized treatment modalities is not far away.

• DNA methylation
• aging
• classification
• colorectal cancer
• consensus molecular subtypes
• epigenetics
• subtyping

• R01 CA229240 NCI NIH HHS
• R01 CA230995 NCI NIH HHS
• U01 AG066101 NIA NIH HHS
• National Cancer Institute and National Institute on Aging at the National Institutes of Health

Inflammation is a hallmark of many cancers. Macrophages are key participants in innate immunity and important drivers of inflammation. When chronically polarized beyond normal homeostatic responses to infection, injury, or aging, macrophages can express several pro-carcinogenic phenotypes. In this review, evidence supporting polarized macrophages as endogenous sources of carcinogenesis is discussed. In addition, the depletion or modulation of macrophages by small molecule inhibitors and probiotics are reviewed as emerging strategies in cancer prevention.

Inflammation is an essential hallmark of cancer. Macrophages are key innate immune effector cells in chronic inflammation, parainflammation, and inflammaging. Parainflammation is a form of subclinical inflammation associated with a persistent DNA damage response. Inflammaging represents low-grade inflammation due to the dysregulation of innate and adaptive immune responses that occur with aging. Whether induced by infection, injury, or aging, immune dysregulation and chronic macrophage polarization contributes to cancer initiation through the production of proinflammatory chemokines/cytokines and genotoxins and by modulating immune surveillance. This review presents pre-clinical and clinical evidence for polarized macrophages as endogenous cellular carcinogens in the context of chronic inflammation, parainflammation, and inflammaging. Emerging strategies for cancer prevention, including small molecule inhibitors and probiotic approaches, that target macrophage function and phenotype are also discussed.

• DNA damage
• carcinogenesis
• inflammaging
• macrophage activation
• macrophage modulation
• mutation
• parainflammation

Colorectal cancer (CRC) is the second cause of cancer death and the third most frequently diagnosed cancer. Besides the lifestyle, genetic and epigenetic alterations, and environmental factors, gut microbiota also plays a vital role in CRC development. The interruption of the commensal relationship between gut microbiota and the host could lead to an imbalance in the bacteria population, in which the pathogenic bacteria become the predominant population in the gut. Different therapeutic strategies have been developed to modify the gut immune system, prevent pathogen colonization, and alter the activity and composition of gut microbiota, such as prebiotics, probiotics, postbiotics, antibiotics, and fecal microbiota transplantation (FMT). Even though the employed strategies exhibit promising results, their translation into the clinic requires evaluating potential implications and risks, as well as assessment of their long-term effects. This study was set to review the gut microbiota imbalances and their relationship with CRC and their effects on CRC therapy, including chemotherapy and immunotherapy. More importantly, we reviewed the strategies that have been used to modulate gut microbiota, their impact on the treatment of CRC, and the challenges of each strategy.

• Colorectal cancer
• Fecal microbiota transplantation
• Gut microbiota
• Probiotics

• bacterial infection
• carcinogenesis
• colorectal carcinoma
• epithelial–mesenchymal transition
• gastrointestinal neoplasm
• infectious disease
• malignancy
• metastasis

• association analysis
• colorectal cancer
• gut microbiota
• metabolites
• metabolomics

• King Saud University

• immune
• intestinal microbiota
• tumour microenvironment
• tumour therapy

• Animals
• B7-H1 Antigen/antagonists & inhibitors
• Disease Models, Animal
• Disease Progression
• Dysbiosis/immunology
• Dysbiosis/microbiology
• Dysbiosis/pathology
• Fusobacterium nucleatum/immunology
• Gastrointestinal Microbiome/drug effects
• Gastrointestinal Microbiome/immunology
• Helicobacter hepaticus/immunology
• Humans
• Immune Checkpoint Inhibitors/pharmacology
• Immune Checkpoint Inhibitors/therapeutic use
• Killer Cells, Natural/immunology
• Macrophages/immunology
• Neoplasms/drug therapy
• Neoplasms/immunology
• Neoplasms/microbiology
• Neoplasms/pathology
• T-Lymphocytes/immunology
• Tumor Microenvironment/drug effects
• Tumor Microenvironment/immunology

• National Natural Science Foundation of China

Epidemiological evidence reveal a very close association of malignancies with chronic inflammation as a result of persistent bacterial infection. Recently, more studies have provided experimental evidence for an etiological role of bacterial factors disposing infected tissue towards carcinoma. When healthy cells accumulate genomic insults resulting in DNA damage, they may sustain proliferative signalling, resist apoptotic signals, evade growth suppressors, enable replicative immortality, and induce angiogenesis, thus boosting active invasion and metastasis. Moreover, these cells must be able to deregulate cellular energetics and have the ability to evade immune destruction. How bacterial infection leads to mutations and enriches a tumour-promoting inflammatory response or micro-environment is still not clear. In this review we showcase well-studied bacteria and their virulence factors that are tightly associated with carcinoma and the various mechanisms and pathways that could have carcinogenic properties.

• DNA damage
• bacteria
• cancer hallmarks
• epithelial mesenchymal transition
• inflammation

• Bacteria
• Cancer stem cells
• Carcinogenesis
• Cell dedifferentiation
• Cell-of-origin
• Chromosomal instability
• Colorectal neoplasms
• DNA damage
• Doublecortin-like kinase 1
• Gut microbiome
• Mutation
• Neoplastic cell transformation
• Paligenosis
• Radiation-induced bystander effect

• Animals
• Bystander Effect
• Carcinogenesis/pathology
• Colorectal Neoplasms/complications
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/microbiology
• Dysbiosis/complications
• Dysbiosis/microbiology
• Gastrointestinal Microbiome
• Humans
• Inflammation/complications
• Inflammation/pathology

• P20 GM103447 NIGMS NIH HHS
• R01 CA230641 NCI NIH HHS
• National Cancer Institute
• National Natural Science Foundation of China
• National Institutes of Health

Obesity affects the gut microbiome, which in turn increases the risk for colorectal cancer. Several studies have shown the mechanisms by which some bacteria may influence the development of colorectal cancer; however, gut microbiome characteristics in obese patients with colorectal cancer remain unclear. Therefore, this study evaluated their gut microbiome profile and its relationship with metabolic markers.

The study assessed fecal samples from 36 consecutive patients with colorectal cancer and 38 controls without colorectal cancer. To identify microbiotic variations between patients with colorectal cancer and controls, as well as between nonobese and obese individuals, 16S rRNA gene amplicon sequencing was performed.

Principal coordinate analysis showed significant differences in the overall structure of the microbiome among the study groups. The α‐diversity, assessed by the Chao1 index or Shannon index, was higher in patients with colorectal cancer versus controls. The relative abundance of the genera Enterococcus, Capnocytophaga, and Polaribacter was significantly altered in obese patients with colorectal cancer, whose serum low‐density lipoprotein concentrations were positively correlated with the abundance of the genus Enterococcus; among the most abundant species was Enterococcus faecalis, observed at lower levels in obese versus nonobese patients.

This study demonstrated several compositional alterations of the gut microbiome in patients with colorectal cancer and showed that a reduced presence of E. faecalis may be associated with obesity‐related colorectal cancer development. The gut microbiome may provide novel insights into the potential mechanisms in obesity‐related colorectal carcinogenesis.

• Capnocytophaga
• colorectal neoplasms
• enterococcus
• gastrointestinal microbiome
• obesity

• bacteria
• colorectal adenoma
• colorectal cancer
• gut microbiota
• polyps

• cancer immunotherapy
• colitis-associated cancer (CAC)
• colorectal cancer (CRC)
• microbiota
• predictive biomarkers
• prognostic biomarkers
• tumor microenvironment (TME)
• tumor-associated macrophages (TAMs)

Colorectal cancer (CRC) is a global public health issue which poses a substantial humanistic and economic burden on patients, healthcare systems and society. In recent years, intestinal dysbiosis has been suggested to be involved in the pathogenesis of CRC, with specific pathogens exhibiting oncogenic potentials such as Fusobacterium nucleatum, Escherichia coli and enterotoxigenic Bacteroides fragilis having been found to contribute to CRC development. More recently, it has been shown that initiation of CRC development by these microorganisms requires the formation of biofilms. Gut microbial biofilm forms in the inner colonic mucus layer and is composed of polymicrobial communities. Biofilm results in the redistribution of colonic epithelial cell E-cadherin, increases permeability of the gut and causes a loss of function of the intestinal barrier, all of which enhance intestinal dysbiosis. This literature review aims to compile the various strategies that target these pathogenic biofilms and could potentially play a role in the prevention of CRC. We explore the potential use of natural products, silver nanoparticles, upconverting nanoparticles, thiosalicylate complexes, anti-rheumatic agent (Auranofin), probiotics and quorum-sensing inhibitors as strategies to hinder colon carcinogenesis via targeting colon-associated biofilms.

• chemoprevention
• colorectal cancer
• gut biofilm
• microbiota
• quorum-sensing

• Chemosensitivity
• Doublecortin-like kinase 1
• Esophageal squamous cell carcinoma
• Invasion
• Migration
• β-Catenin

• Adenoma/genetics
• Adenoma/pathology
• Adenomatous Polyps/genetics
• Adenomatous Polyps/pathology
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/pathology
• DNA Repair/genetics
• Genetic Predisposition to Disease
• Humans
• Oxidative Stress/genetics
• Reactive Oxygen Species/metabolism
• Tumor Microenvironment/genetics
• Wnt Signaling Pathway/genetics

• CD44
• Klintrup-Mäkinen score
• colorectal carcinoma
• immunohistochemistry
• inflammation
• mismatch repair proteins

• 4-Hydroxy-7-oxo-5-heptenoic acid lactone
• 4-Hydroxynon-2-enal
• Brain cancer
• Cancer stem cells
• Glioblastoma multiforme
• Hypoxia
• Matrix metalloprotease
• NF-κβ p65
• NOX4
• Oxidative stress
• PAR1
• Proneural to mesenchymal transition
• SOD
• Vimentin

• Brain
• Brain Neoplasms/genetics
• Cell Line, Tumor
• Cell Movement
• Endothelial Cells
• Glioblastoma/drug therapy
• Glioblastoma/genetics
• Humans
• Lactones/pharmacology
• Neoplasm Invasiveness
• Neoplasm Recurrence, Local

• R01 GM021249 NIGMS NIH HHS
• R01 EY016813 NEI NIH HHS

•

Genes from stools have molecular significance with CRC tumorgenesis.

Tumor metastasis or recurrence often occurs in patients with curative resection of colorectal cancer (CRC). Placental-specific 8 (PLAC8), which has increased expression in stool, may be associated with CRC recurrence. Insights into the role of PLAC8 in CRC recurrence and its clinical significance may support to develop strategies for preventing CRC recurrence and deterioration. Clinical tissues, cell and animal models were used to clarify the roles of PLAC8 in CRC tumorigenesis, invasion, and migration. Next-generation sequencing of 16S ribosomal DNA has been used to assess the gut microbiota in stool of CRC patients. We found that PLAC8 was upregulated in tissues from patients with late-stage CRC. In our in vitro studies, PLAC8 was dynamically regulated in mitotic cells. Overexpressed PLAC8 was nucleated at the centrosome during mitosis, and therefore, PLAC8 overexpression might increase cell growth and migration (all p < 0.05). The tumorigenic and invasive effects of PLAC8 on CRC cells were also confirmed in a xenograft mouse model. We further identified reduced levels of two butyrate-producing organisms, Butyricicoccus and Prevotella spp., in stools from CRC patients. We found that butyrate downregulated PLAC8 expression and induced apoptosis in PLAC8-overexpressing cells. Our data suggests that PLAC8 gene and protein expression and dysbiosis of gut microflora, especially in butyrate-producing microorganisms, may be indicators of CRC progression.

• Butyrate
• Butyricicoccus
• Colorectal cancer progression
• Gut microbiota
• Placenta Specific 8

• bone formation
• bone resorption
• intestinal microbiota
• osteoporosis

• Bone Resorption
• Bone and Bones/metabolism
• Gastrointestinal Microbiome
• Host Microbial Interactions
• Humans
• Osteoporosis/physiopathology

• Bacterial infections
• Colorectal cancer
• Microbiology
• Mouse models
• Oncology

• Animals
• Biofilms
• Carcinogenesis
• Colon/metabolism
• Colon/microbiology
• Colonic Neoplasms/genetics
• Colonic Neoplasms/metabolism
• Colonic Neoplasms/microbiology
• Colonic Neoplasms/pathology
• Gastrointestinal Microbiome
• Humans
• Mice
• Mice, Knockout
• Neoplasms, Experimental/genetics
• Neoplasms, Experimental/metabolism
• Neoplasms, Experimental/microbiology
• Neoplasms, Experimental/pathology

• R01 DK073338 NIDDK NIH HHS
• R01 DK047700 NIDDK NIH HHS
• R21 CA195226 NCI NIH HHS
• K99 CA230192 NCI NIH HHS
• R01 CA203891 NCI NIH HHS
• R01 CA196845 NCI NIH HHS
• S10 OD016374 NIH HHS
• P50 CA062924 NCI NIH HHS
• P30 CA006973 NCI NIH HHS
• P30 DK089502 NIDDK NIH HHS
• R01 CA151393 NCI NIH HHS
• Crohn’s and Colitis Foundation

In recent years, the number of studies investigating the impact of the gut microbiome in colorectal cancer (CRC) has risen sharply. As a result, we now know that various microbes (and microbial communities) are found more frequently in the stool and mucosa of individuals with CRC than healthy controls, including in the primary tumors themselves, and even in distant metastases. We also know that these microbes induce tumors in various mouse models, but we know little about how they impact colon epithelial cells (CECs) directly, or about how these interactions might lead to modifications at the genetic and epigenetic levels that trigger and propagate tumor growth. Rates of CRC are increasing in younger individuals, and CRC remains the second most frequent cause of cancer-related deaths globally. Hence, a more in-depth understanding of the role that gut microbes play in CRC is needed. Here, we review recent advances in understanding the impact of gut microbes on the genome and epigenome of CECs, as it relates to CRC. Overall, numerous studies in the past few years have definitively shown that gut microbes exert distinct impacts on DNA damage, DNA methylation, chromatin structure and non-coding RNA expression in CECs. Some of the genes and pathways that are altered by gut microbes relate to CRC development, particularly those involved in cell proliferation and WNT signaling. We need to implement more standardized analysis strategies, collate data from multiple studies, and utilize CRC mouse models to better assess these effects, understand their functional relevance, and leverage this information to improve patient care.

• Enterococcus faecalis
• chronic inflammation
• colorectal cancer
• gastrointestinal cancer
• gut microbiota

• Ente Cassa di Risparmio di Firenze