• Animal model
• Colorectal cancer
• Dimethylhydrazine
• Mouse species

• Animals
• 1,2-Dimethylhydrazine/toxicity
• Colorectal Neoplasms/chemically induced
• Colorectal Neoplasms/pathology
• Mice
• Mice, Inbred BALB C
• Disease Models, Animal
• Mice, Inbred C57BL
• Disease Susceptibility
• Species Specificity
• Carcinogens/toxicity
• Male
• Humans
• Female

• Animal models
• Carcinogenesis pathways
• Colorectal cancer

• Animals
• Colorectal Neoplasms/pathology
• Colorectal Neoplasms/etiology
• Disease Models, Animal
• Carcinogenesis/pathology
• Humans
• Mice
• Adenoma/pathology

• 82172983 National Natural Science Foundation of China

• Wnt signalling pathway
• cancer stem cells
• colitis-associated carcinoma
• colorectal cancer
• invasion and metastasis

• Humans
• Colorectal Neoplasms/pathology
• Wnt Signaling Pathway

• Colorectal cancer; Escherichia coli; colibactin; CNF-1; CoPEC

• Mice
• Humans
• Animals
• Escherichia coli/genetics
• Escherichia coli/metabolism
• Gastrointestinal Microbiome
• Escherichia coli Proteins/genetics
• Escherichia coli Proteins/metabolism
• Colon
• Carcinogenesis
• Cell Transformation, Neoplastic
• Escherichia coli Infections
• Inflammation

• colorectal cancer
• cancer microenvironment
• gastrointestinal diseases

• Animals
• Colonic Neoplasms/genetics
• Colonic Neoplasms/pathology
• DNA Damage
• Inflammation/genetics
• Mice
• Protein Isoforms/metabolism
• Sodium-Hydrogen Exchanger 3/genetics
• Sodium-Hydrogen Exchangers/genetics
• Sodium-Hydrogen Exchangers/metabolism

• R01 DK041274 NIDDK NIH HHS
• R01 DK113754 NIDDK NIH HHS
• R01 DK119198 NIDDK NIH HHS
• 5R01DK113754 NIH HHS
• National Institutes of Health
• Crohn's and Colitis Foundation
• PANDA Endowment in Autoimmune Diseases

• CAC
• IBD
• Inflammation
• Microbiota

• Animals
• Carcinogenesis
• Colorectal Neoplasms/pathology
• Humans
• Inflammation/complications
• Inflammatory Bowel Diseases/complications
• Inflammatory Bowel Diseases/genetics
• Inflammatory Bowel Diseases/pathology
• Intestines/pathology

• R01 DK119219 NIDDK NIH HHS

• Cimetidine
• Colorectal Cancer
• Histamine
• Inflammation

• cancer prevention
• chemoprevention
• colorectal cancer prevention
• cytokine signaling
• immunoprevention
• tumor initiation

• P30 CA006927 NCI NIH HHS
• T32 CA009035 NCI NIH HHS

Intestinal carcinogenesis is a multistep process that begins with epithelial hyperplasia, followed by a transition to an adenoma and then to a carcinoma. Many etiological factors, including KRAS mutations and inflammation, have been implicated in oncogenesis. However, the potential synergistic effects between KRAS mutations and inflammation as well as the potential mechanisms by which they promote intestinal carcinogenesis remain unclear. Thus, the objective of this study was to investigate the synergistic effects of kras^V12, lipopolysaccharides (LPS), and/or dextran sulfate sodium (DSS) on inflammation, tumor progression, and intestinal disorders using transgenic adults and larvae of zebrafish. Histopathology and pathological staining were used to examine the intestines of kras^V12 transgenic zebrafish treated with LPS and/or DSS. LPS and/or DSS treatment enhanced intestinal inflammation in kras^V12 transgenic larvae with concomitant increases in the number of neutrophils and macrophages in the intestines. The expression of kras^V12, combined with LPS treatment, also enhanced epithelial hyperplasia and tubular adenoma, demonstrated by histopathological examinations and by increases in cell apoptosis, cell proliferation, and downstream signaling of phosphorylated AKT serine/threonine kinase 1 (AKT), extracellular-signal-regulated kinase (ERK), and histone. We also found that kras^V12 expression, combined with LPS treatment, significantly enhanced changes in intestinal morphology, specifically (1) decreases in goblet cell number, goblet cell size, villi height, and intervilli space, as well as (2) increases in villi width and smooth muscle thickness. Moreover, kras^V12 transgenic larvae cotreated with DSS and LPS exhibited exacerbated intestinal inflammation. Cotreatment with DSS and LPS in kras^V12-expressing transgenic adult zebrafish also enhanced epithelial hyperplasia and tubular adenoma, compared with wild-type fish that received the same cotreatment. In conclusion, our data suggest that kras^V12 expression, combined with LPS and/or DSS treatment, can enhance intestinal tumor progression by activating the phosphatidylinositol-3-kinase (PI3K)/AKT signaling pathway and may provide a valuable in vivo platform to investigate tumor initiation and antitumor drugs for gastrointestinal cancers.

• colorectal cancer
• dextran sulfate sodium
• intestinal tumor
• krasV12
• lipopolysaccharides
• transgenic zebrafish

• Colorectal Cancer
• Epigenomics
• H4R3me2s
• PRMT1
• SMARCA4
• Transcription

• 2-photon tomography
• colorectal cancer
• inflammation
• mutagenesis
• somatic stem cells
• tumor promotion

• Animals
• Carcinogenesis/genetics
• Carcinogenesis/pathology
• Cell Movement/genetics
• Cell Proliferation/genetics
• Fluorescence
• Inflammation/genetics
• Inflammation/pathology
• Mice
• Mice, Inbred C57BL
• Mutation/genetics
• Neoplasms/genetics
• Neoplasms/pathology
• Reactive Nitrogen Species/genetics
• Reactive Oxygen Species/metabolism

• T32 GM008334 NIGMS NIH HHS
• T32 ES007020 NIEHS NIH HHS
• P30 ES002109 NIEHS NIH HHS
• P01 CA026731 NCI NIH HHS

• Colorectal cancer
• Gastrointestinal
• Inflammation
• Mouse model
• Tumor

Using mouse models that recapitulate key genetic abnormalities accumulating during colorectal cancer (CRC) tumorigenesis, we report that chemically induced colitis promoted development of colon tumors that were largely resistant to anti-VEGF antibody treatment. Serum G-CSF levels were markedly elevated after induction of colitis. Inhibition of G-CSF or Bv8/PROK2 increased the efficacy of anti-VEGF antibody and prevented onset of resistance. To verify the potential clinical relevance of these findings, we examined a series of CRC specimens and found that tumor-infiltrating neutrophils strongly expressed Bv8/PROK2. CRC patients had significantly higher plasma Bv8/PROK2 levels than healthy volunteers and high plasma Bv8/PROK2 levels were inversely correlated with overall survival. These findings establish Bv8/PROK2 as a translational target in CRC, in combination with anti-VEGF agents.

We tested cis-Apc^Δ716/Smad4^+/− and cis-Apc^Δ716/Smad4^+/−Kras^G12D mice, which recapitulate key genetic abnormalities accumulating during colorectal cancer (CRC) tumorigenesis in humans, for responsiveness to anti-VEGF therapy. We found that even tumors in cis-Apc^Δ716/Smad4^+/−Kras^G12D mice, although highly aggressive, were suppressed by anti-VEGF treatment. We tested the hypothesis that inflammation, a major risk factor and trigger for CRC, may affect responsiveness to anti-VEGF. Chemically induced colitis (CIC) in cis-Apc^Δ716/Smad4^+/− and cis-Apc^Δ716/Smad4^+/−Kras^G12D mice promoted development of colon tumors that were largely resistant to anti-VEGF treatment. The myeloid growth factor G-CSF was markedly increased in the serum after induction of colitis. Antibodies blocking G-CSF, or its target Bv8/PROK2, suppressed tumor progression and myeloid cell infiltration when combined with anti-VEGF in CIC-associated CRC and in anti-VEGF-resistant CRC liver metastasis models. In a series of CRC specimens, tumor-infiltrating neutrophils strongly expressed Bv8/PROK2. CRC patients had significantly higher plasma Bv8/PROK2 levels than healthy volunteers and high plasma Bv8/PROK2 levels were inversely correlated with overall survival. Our findings establish Bv8/PROK2 as a translational target in CRC, in combination with anti-VEGF agents.

• angiogenesis
• colorectal cancer
• drug resistance
• inflammation
• myeloid cells

• Carcinogen-induced models
• Colorectal cancer
• Genetically engineered mouse models
• Mouse models
• Patient-derived xenografts
• Preclinical drug development

• Animals
• Colorectal Neoplasms
• Disease Models, Animal
• Female
• Male
• Mice

• Colorectal cancer
• Drug therapy
• NF-kappaB
• Oncology
• Therapeutics

Colorectal cancer (CRC) is one of the most common cancers and a major cause of mortality. Mice with truncating Apc germline mutations have been used as a standard model of CRC, but most of the Apc-mutated lines develop multiple tumors in the proximal small intestine and rarely in the colon precluding detailed analysis of colon tumor microenvironment. Our aim was to develop a model with higher resemblance to human CRC and to characterize tumor infiltrating immune cells in spontaneously developing colon tumors compared to small intestinal tumors. Therefore, the Apc^1638N/+ line was treated repeatedly with azoxymethane (AOM) and 90% colon tumor incidence and 4 to 5 colon tumors per mouse were achieved. Of note, AOM treatment specifically increased the tumor burden in the colon, but not in the small intestine. Histological grading and WNT-signaling activity did not differ significantly between small intestinal and colon tumors with some lesions progressing to invasive adenocarcinoma in both locations. However, characterization of the intratumoral myeloid cell compartment revealed a massive infiltration of colon tumors with neutrophils − 6-fold higher than in small intestinal tumors. Moreover, CCL17-expressing macrophages and dendritic cells accumulated in the tumors indicating the establishment of a tumor-promoting immunosuppressive environment. Thus, Apc^1638N/+ mice treated with AOM are a suitable and straightforward model to study the influence of immune cells and chemokines on colon carcinogenesis.

• adenomatous polyposis coli
• azoxymethane
• colorectal cancer
• dendritic cells
• mouse model
• tumor immunology and microenvironment
• tumor-associated macrophages
• tumor-associated neutrophils

• MAP kinases
• histamine receptors
• inflammation-associated colon cancer
• macrophages

KRAS mutations are a major risk factor in colorectal cancers. In particular, a point mutation of KRAS of amino acid 12, such as KRAS^V12, renders it stable activity in oncogenesis. We found that kras^V12 promotes intestinal carcinogenesis by generating a transgenic zebrafish line with inducible kras^V12 expression in the intestine, Tg(ifabp:EGFP-kras^V12). The transgenic fish generated exhibited significant increases in the rates of intestinal epithelial outgrowth, proliferation, and cross talk in the active Ras signaling pathway involving in epithelial-mesenchymal transition (EMT). These results provide in vivo evidence of Ras pathway activation via kras^V12 overexpression. Long-term transgenic expression of kras^V12 resulted in enteritis, epithelial hyperplasia, and tubular adenoma in adult fish. This was accompanied by increased levels of the signaling proteins p-Erk and p-Akt and by downregulation of the EMT marker E-cadherin. Furthermore, we also observed a synergistic effect of kras^V12 expression and dextran sodium sulfate treatment to enhance intestinal tumor in zebrafish. Our results demonstrate that kras^V12 overexpression induces intestinal tumorigenesis in zebrafish, which mimics intestinal tumor formation in humans. Thus, our transgenic zebrafish may provide a valuable in vivo platform that can be used to investigate tumor initiation and anticancer drugs for gastrointestinal cancers.

• Animals
• Animals, Genetically Modified
• Biomarkers
• Cell Proliferation
• Cell Transformation, Neoplastic/genetics
• Cell Transformation, Neoplastic/metabolism
• DNA Transposable Elements
• Disease Models, Animal
• Gene Expression
• Gene Order
• Genes, Reporter
• Genetic Vectors/genetics
• Intestinal Mucosa/metabolism
• Intestinal Mucosa/pathology
• Mutation
• Phosphorylation
• Proto-Oncogene Proteins p21(ras)/genetics
• Signal Transduction
• Zebrafish

• CysLT1 receptor
• LTD4 signaling
• colitis-associated colon cancer (CAC)
• colon cancer
• inflammation

• Adenoma
• Apc min/+
• Bile acids
• Colorectal cancer
• Dextran sulfate sodium
• High fat

• Adenomatous Polyposis Coli Protein/genetics
• Animals
• Bile Acids and Salts/toxicity
• Colorectal Neoplasms/chemically induced
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/pathology
• Dextran Sulfate/toxicity
• Diet, High-Fat/adverse effects
• Disease Models, Animal
• Female
• Humans
• Male
• Mice
• Mice, Inbred C57BL

• P30 DK052574 NIDDK NIH HHS
• R01 DK056260 NIDDK NIH HHS
• R01 HL038180 NHLBI NIH HHS
• R37 HL038180 NHLBI NIH HHS

Intestinal tumorigenesis is promoted by myeloid differentiation primary response gene 88 (MyD88) activation in response to the components of microbiota in Apc^Min/+ mice. Microbiota also contains double-stranded RNA (dsRNA), a ligand for TLR3, which activates the toll-like receptor adaptor molecule 1 (TICAM-1, also known as TRIF) pathway.

We established Apc^Min/+Ticam1^−/− mice and their survival was compared to survival of Apc^Min/+Myd88^−/− and wild-type (WT) mice. The properties of polyps were investigated using immunofluorescence staining and RT-PCR analysis.

We demonstrate that TICAM-1 is essential for suppression of polyp formation in Apc^Min/+ mice. TICAM-1 knockout resulted in shorter survival of mice compared to WT mice or mice with knockout of MyD88 in the Apc^Min/+ background. Polyps were more frequently formed in the distal intestine of Apc^Min/+Ticam1^−/− mice than in Apc^Min/+ mice. Infiltration of immune cells such as CD11b⁺ and CD8α⁺ cells into the polyps was detected histologically. CD11b and CD8α mRNAs were increased in polyps of Apc^Min/+Ticam1^−/− mice compared to Apc^Min/+ mice. Gene expression of inducible nitric oxide synthase (iNOS), interferon (IFN)-γ, CXCL9 and IL-12p40 was increased in polyps of Apc^Min/+Ticam1^−/− mice. mRNA and protein expression of c-Myc, a critical transcription factor for inflammation-associated polyposis, were increased in polyps of Apc^Min/+Ticam1^−/− mice. A Lactobacillus strain producing dsRNA was detected in feces of Apc^Min/+ mice.

These results imply that the TLR3/TICAM-1 pathway inhibits polyposis through suppression of c-Myc expression and supports long survival in Apc^Min/+ mice.

The online version of this article (10.1186/s12929-017-0387-z) contains supplementary material, which is available to authorized users.

• Intestinal polyposis
• TICAM-1 (TRIF)
• TLR3
• c-Myc

• ApcMin/+
• azoxymethane
• black raspberries
• colorectal cancer
• dextran sulfate sodium
• immune surveillance
• natural killer cells

Incidences of infection-related cancers are on the rise in developing countries where the prevalence of intestinal nematode worm infections are also high. Trichuris muris (T. muris) is a murine gut-dwelling nematode that is the direct model for human T. trichiura, one of the major soil-transmitted helminth infections of humans. In order to assess whether chronic infection with T. muris does indeed influence the development of cancer hallmarks, both wild type mice and colon cancer model (APC ^min/+) mice were infected with this parasite. Parasite infection in wild type mice led to the development of neoplastic change similar to that seen in mice that had been treated with the carcinogen azoxymethane. Additionally, both chronic and acute infection in the APC^min/+ mice led to an enhanced tumour development that was distinct to the site of infection suggesting systemic control. By blocking the parasite induced T regulatory response in these mice, the increase in the number of tumours following infection was abrogated. Thus T. muris infection alone causes an increase in gut pathologies that are known to be markers of cancer but also increases the incidence of tumour formation in a colon cancer model. The influence of parasitic worm infection on the development of cancer may therefore be significant.

It is estimated that now 2 billion people currently live with chronic parasitic worm infections. As the incidences of cancer increase worldwide, the importance of these chronic inflammatory conditions on the development of cancer becomes more important. Several bacterial, viral and parasitic infections are already known to influence cancer development but as colon cancer is particularly prevalent worldwide, we wanted to assess the effect of a large intestinal dwelling worm, Trichuris muris (T. muris) on its aetiology. This whipworm is a natural infection of mice and has significant homology to human whipworm. From our studies, we showed that chronic infection alone induced changes in the caecum of the mouse that were comparable to those seen with a well-known carcinogen. In addition to this, T. muris infection was also able to increase the development of adenomas in the small intestine of mutant mice that spontaneously develop tumours. This change was abrogated if a T regulatory cell type was blocked during infection. The T regulatory cell type that arises during infection has been shown to play an important role in protecting the host from damage caused by the parasite and the immune response to it. The present study using the mouse model however, suggests that regulatory T cells can have negative effects, at least in terms of the development of bowel cancer. As so many people live with chronic, regulated parasitic infections, the importance of the parasites in cancer development may therefore be significant.

• Cancer initiation
• Chromatin
• DNA methylation
• Epigenetics
• Immune cells
• Inflammation

• Apc
• Kras
• TNF-α
• azoxymethane (AOM)
• colitis-associated cancer mouse model
• dextran sulfate sodium (DSS)
• inflammation
• p53

• APC mutation
• Ulcerative colitis
• cancer stem cells
• carcinogenesis
• colorectal cancer
• miR-21

• NF-kappa B (NF-KB)
• Phospholipase C
• S6 kinase
• inflammation
• lysophosphatidic acid
• tumor necrosis factor (TNF)

Koliaraki et al. report that IKKβ deletion in ColVI-expressing intestinal mesenchymal cells protects mice against inflammation-induced intestinal carcinogenesis. In contrast, a companion study by Pallangyo et al. shows that deletion of IKKβ by the Col1a2CreER promoter in intestinal fibroblasts leads to increased colitis-induced tumorigenesis. The two studies suggest that targeting IKKβ in different fibroblast populations by using different promoters might have opposite outcomes in intestinal cancer.

The importance of mesenchymal cells in inflammation and/or neoplastic transformation is well recognized, but their role in the initiation of these processes, particularly in the intestine, remains elusive. Using mouse models of colorectal cancer, we show that IKKβ in intestinal mesenchymal cells (IMCs) is critically involved in colitis-associated, but not spontaneous tumorigenesis. We further demonstrate that IMC-specific IKKβ is involved in the initiation of colitis-associated cancer (CAC), as in its absence mice develop reduced immune cell infiltration, epithelial cell proliferation, and dysplasia at the early stages of the disease. At the molecular level, these effects are associated with decreased early production of proinflammatory and protumorigenic mediators, including IL-6, and reduced STAT3 activation. Ex vivo IKKβ-deficient IMCs show defective responses to innate immune stimuli such as LPS, as shown by decreased NF-κB signaling and reduced expression of important NF-κB target genes. Collectively, our results reveal a hitherto unknown role of mesenchymal IKKβ in driving inflammation and enabling carcinogenesis in the intestine.

• A/J Min/+ mouse
• carcinoma
• colorectal cancer
• intestinal tumorigenesis

• Animals
• Antigens, Surface/genetics
• Antigens, Surface/metabolism
• Antigens, Surface/pharmacology
• Antigens, Surface/physiology
• Azoxymethane
• Body Weight/physiology
• Cell Proliferation/drug effects
• Cell Transformation, Neoplastic/metabolism
• Cell Transformation, Neoplastic/pathology
• Colitis/chemically induced
• Colitis/metabolism
• Colitis/pathology
• Colitis/physiopathology
• Colonic Neoplasms/chemically induced
• Colonic Neoplasms/metabolism
• Colonic Neoplasms/pathology
• Colonic Neoplasms/physiopathology
• Dextran Sulfate
• Disease Models, Animal
• Epithelial Cells/pathology
• Humans
• Integrin alphaVbeta3/physiology
• Intestinal Mucosa/metabolism
• Mice, Knockout
• Milk Proteins/genetics
• Milk Proteins/metabolism
• Milk Proteins/pharmacology
• Neoplasm Proteins/metabolism
• Recombinant Proteins/pharmacology
• Tumor Cells, Cultured

Control of colorectal cancer needs to be tailored to its etiology. Tumor promotion mechanisms in colitis-associated colon cancer differ somewhat from the mechanisms involved in hereditary and sporadic colorectal cancer. Unlike sporadic or inherited tumors, some experimental models show that colitis-associated colon tumors do not require cyclooxygenase (COX) expression for progression, and non-steroidal anti-inflammatory drugs (NSAIDs) which prevent sporadic or inherited colon cancer do not prevent colitis-associated colon cancer. We report that myeloperoxidase (MPO), an ancestor of the COX isoenzymes, is a determinant of colitis-associated colon tumors in Apc^Min/+ mice. During experimentally induced colitis, inhibition of MPO by resorcinol dampened colon tumor development. Conversely, in the bowels of Apc^Min/+ mice without colitis, resorcinol administration or ‘knockout’ of MPO gene coincided with a slight, but discernible increase in colon tumor incidence. Acrolein, a by-product of MPO catalysis, formed a covalent adduct with the phosphatase tensin homolog (PTEN) tumor suppressor and enhanced the activity of the Akt kinase proto-oncogene in vitro and in vivo. Thus, MPO may be an important determinant of diet and inflammation on colon cancer risk via its effect on endogenous exposure to oxidants and acrolein. We propose a hypothetical model to explain an apparent dichotomy between colon tumor occurrence and MPO inhibition in inflamed versus non-inflamed colons.

•

Myeloperoxidase is a determinant of colitis-associated colon tumors in Apc^Min/+ mice.

• Colitis
• Colon cancer
• Inflammation
• Myeloperoxidase

• 5-aminosalicylic acid
• colonic neoplasms
• peroxisome proliferator-activated receptor-γ
• ulcerative colitis

• Colitis
• Cytosolic phosphlipase A(2)
• Intestine
• Microsomal prostaglandin E synthase-1
• Prostaglandins
• Tumorigenesis

• inflammatory bowel disease
• ulcerative colitis
• crohn’s disease
• colitis-associated cancer
• colorectal carcinoma
• endoscopy
• chemoprevention

• Chemoprevention
• Colorectal Neoplasms/complications
• Colorectal Neoplasms/pathology
• Colorectal Neoplasms/prevention & control
• Epigenesis, Genetic
• Humans
• Inflammatory Bowel Diseases/complications
• Inflammatory Bowel Diseases/pathology
• Intestines/microbiology
• Microbiota
• Risk Factors
• Signal Transduction
• Tumor Suppressor Protein p53/genetics

Vasohibin-2 (VASH2) has been identified as an endogenous and vascular endothelial growth factor (VEGF)-independent angiogenic factor that is highly expressed in tumor cells. In the present study, we aimed to determine whether pre-existing vascular changes can be used to predict tumor transformation as benign or malignant. We sought to characterize microvascular changes and tumor development in the intestinal tract of Apc^Min/+ mice and Apc^Min/+/Vash2^-/- mice.

Apc^Min/+ mice provide a unique orthotopic model for the development of spontaneous adenomatous polyposis and subsequent carcinomas, a phenomenon termed the adenoma-carcinoma sequence. Apc^Min/+ mice were mated with Vash2^-/- mice with a mixed C57BL/6 background and the resulting pups were screened for the Min mutation and for the Vash2^-/- gene by PCR. Intestinal tumors from Apc^Min/+ mice and Apc^Min/+/Vash2^-/- mice were removed and either frozen or epon-embedded for subsequent analyses. For 3-dimensional imaging using confocal laser-scanning microscopy and transmission electron microscopy, cryosections were made, and immunofluorescent staining for various markers was performed.

We found that structural abnormalities in tumor vessels from benign tumors resembled those in malignant tumors. In addition, a novel angiogenic factor, vasohibin-2 (VASH2) protein, was detected around tumor blood vessels in late-stage adenomas and adenocarcinomas, but was absent from early-stage adenomas in Apc^Min/+ mice. Tumors used to examine endogenous VASH2 (derived from CMT93 colon carcinomas) were less vascularized in Vash2^-/- mice and were more regular than those seen in wild-type (WT) mice. In addition, tumors in Vash2^-/- mice were smaller than those in WT mice. Furthermore, cross-breeding of mice homozygous for a deletion of Vash2 with mice heterozygous for the APC mutation resulted in animals that showed a significant decrease in the number of polyps in the small intestine.

We propose that VASH2 may modulate the onset of tumors in the gastrointestinal tract by regulating tumor angiogenesis.

• mouse
• aom
• dss
• colitis cancer
• apc