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Loss of p53 in enterocytes facilitates an inflammatory microenvironment enabling invasion and metastasis of carcinogen-induced colorectal tumors

ABSTRACT: Here, we examined the role of intestinal epithelial specific tumor suppressive function of 53. We provide evidence that p53 plays a dual role during carcinogen-induced tumorigenesis. At the initiation stage, p53 controls DNA damage and survival of initiated epithelia. In contrast, at later stages, loss of p53 is associated with the formation of an inflammatory microenvironment that is linked to epithelial mesenchymal transition, invasion and metastasis and the activation of NF-kappaB and Stat3. Thus, we propose a novel p53 controlled tumor suppressive function during the progression stage of colorectal cancer that is independent of its well-established role in cell cycle regulation, apoptosis and senescence.

ORGANISM(S): Mus musculus

PROVIDER: GSE27868 | GEO | 2012/11/13

SECONDARY ACCESSION(S): PRJNA138017

REPOSITORIES: GEO

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Loss of p53 in enterocytes facilitates an inflammatory microenvironment enabling invasion and metastasis of carcinogen-induced colorectal tumors

Project description:Here, we examined the role of intestinal epithelial specific tumor suppressive function of 53. We provide evidence that p53 plays a dual role during carcinogen-induced tumorigenesis. At the initiation stage, p53 controls DNA damage and survival of initiated epithelia. In contrast, at later stages, loss of p53 is associated with the formation of an inflammatory microenvironment that is linked to epithelial mesenchymal transition, invasion and metastasis and the activation of NF-kappaB and Stat3. Thus, we propose a novel p53 controlled tumor suppressive function during the progression stage of colorectal cancer that is independent of its well-established role in cell cycle regulation, apoptosis and senescence. 6 samples were analyzed. We compared 3 wt colon tumor samples and 3 p53-knockout tumor samples.

2012-11-13 | E-GEOD-27868 | biostudies-arrayexpress

Loss of p53 in enterocytes generates an inflammatory microenvironment enabling invasion and metastasis of carcinogen-induced colorectal tumors

Project description:Loss of p53 is considered to allow progression of colorectal tumors from the adenoma to the carcinoma stage. Using mice with an intestinal epithelial cell (IEC) specific deletion of p53, we demonstrate that single loss of p53 is not sufficient to initiate intestinal tumorigenesis, but markedly enhances carcinogen-induced tumor incidence and leads to invasive cancer and lymph node metastasis. While during the initiation stage p53 controls DNA damage and IEC survival, during tumor progression, loss of p53 is associated with the formation of an inflammatory microenvironment and activation of NF-kB and Stat3. Thus, we propose a novel p53 controlled tumor suppressive function that is independent of its well-established role in cell cycle regulation, apoptosis and senescence.

2011-03-24 | GSE28129 | GEO

Loss of p53 in enterocytes generates an inflammatory microenvironment enabling invasion and metastasis of carcinogen-induced colorectal tumors

2011-03-23 | E-GEOD-28129 | biostudies-arrayexpress

Early anti-tumor activity of oral Langerhans cells is compromised by a carcinogen

Project description:Early diagnosis of oral squamous cell carcinoma (OSCC) remains an unmet clinical need. Therefore, elucidating the initial events of OSCC preceding tumor development could benefit OSCC prognosis. Here we define the Langerhans cells (LC) of the tongue and demonstrate that LC protect the epithelium from carcinogen-induced OSCC by rapidly priming αβT cells capable of eliminating γH2AX+ epithelial cells, whereas γδT and NK cells are dispensable. The carcinogen, however, dysregulates the epithelial resident mononuclear phagocytes, reducing LC frequencies while dendritic cells (DC), macrophages, and plasmacytoid DC (pDC) populate the epithelium. Single-cell RNAseq analysis indicates that these newly differentiated cells display an immunosuppressive phenotype accompanied by an expansion of T regulatory (Treg) cells. Accumulation of the Treg cells was regulated, in part, by pDC and precedes the formation of visible tumors. This suggests LC play an early protective role during OSCC, yet the capacity of the carcinogen to dysregulate the differentiation of mononuclear phagocytes facilitates oral carcinogenesis.

2022-01-26 | GSE192470 | GEO

UV-induced DNA lesion mapping reveals that carcinogen susceptibility is regulated by genome architecture and dictates cancer mutagenesis

Project description:In this study, we present the first quantitative human genome-wide map of DNA lesions induced by ultraviolet (UV) radiation, the ubiquitous carcinogen in sunlight that causes skin cancer. Remarkably, the pattern of carcinogen susceptibility across the genome of primary cells significantly reflects mutation frequency in malignant melanoma. Surprisingly, DNase-accessible euchromatin is protected from UV, while lamina-associated heterochromatin at the nuclear periphery is vulnerable. Many cancer driver genes have an intrinsic increase in carcinogen susceptibility, including the BRAF oncogene that has the highest mutation frequency in melanoma. These findings provide a genome-wide snapshot of DNA injuries in cells at the earliest stage of carcinogenesis. Furthermore, they identify carcinogen susceptibility as a previously unrecognized origin of mutagenesis that is regulated by nuclear architecture and dictates genome instability in cancer.

2017-08-12 | GSE94434 | GEO

Acute Effects Caused by the Rodent Non-Genotoxic Carcinogen Diethylhexylphthalate

Project description:Acute effects caused by the non-genotoxic carcinogen and peroxisome proliferator (PP) diethylhexylphthalate (DEHP) in the mouse liver

2014-03-17 | GSE55733 | GEO

Gut microbiota carcinogen metabolism causes distal tissue tumours

Project description:<p>Exposure to environmental pollutants and human microbiome composition are important predisposition factors for tumour development. Similar to drug molecules, pollutants are typically metabolised in the body, which can change their carcinogenic potential and impact tissue distribution through altered toxicokinetics. Although recent studies demonstrated that human-associated microbes can chemically convert a wide range of xenobiotics and influence the profile and tissue exposure of resulting metabolites, the effect of microbial biotransformation on chemical-induced tumour development remains unclear. Here we show that the depletion of the gut microbiota dramatically reduces the development and severity of nitrosamine-induced urinary bladder cancer in mice, which affects the toxicokinetics of nitrosamines. We causally linked this carcinogen biotransformation to specific gut bacterial isolates in vitro and in vivo using individualized bacterial culture collections and gnotobiotic mouse models, respectively. We tested gut communities from different human donors to demonstrate that microbial carcinogen metabolism varies between individuals and we showed that this metabolic activity applies to structurally related nitrosamine-carcinogens. Altogether, these results suggest gut microbiota carcinogen metabolism as a contributing factor for chemical-induced carcinogenesis, which could open avenues to target the microbiome for improved predisposition risk assessment and prevention of cancer.</p>

2024-06-05 | MTBLS3581 | MetaboLights

Acute Effects Caused by the Rodent Non-Genotoxic Carcinogen Diethylhexylphthalate

Project description:Acute effects caused by the non-genotoxic carcinogen and peroxisome proliferator (PP) diethylhexylphthalate (DEHP) in the mouse liver Mice (n = 6) were dosed by oral gavage (10 ml/kg body weight) with the non-genotoxic carcinogen diethylhexylphthalate (DEHP), every 24 h for 3 days (1150 mg/kg/day), or with an equivalent volume of vehicle control (corn oil).

2014-03-17 | E-GEOD-55733 | biostudies-arrayexpress

Lipopolysaccharide-mediated chronic inflammation promotes tobacco carcinogen-induced lung tumorigenesis

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2020-12-31 | GSE132661 | GEO

RNAseq carcinogen induced signatures in lung adenocarcinoma cell lines

Project description:FVB, Balb/c, and C57BL/6 mice received the tobacco carcinogens urethane (Sigma Aldrich, U2500) intraperitoneally (1g/Kg in 100 μl phosphate-buffered saline) or diethylnitrosamine (200 mg/kg) (Sigma Aldrich, N0756). Carcinogen induced lung adenocarcinoma murine cell lines generation| Ten months post first carcinogen (urethane, DEN) exposure mice were sacrificed, lung tumours were dissected from surrounding healthy lung parenchyma under sterile conditions, were halved, one half was processed for histology and the other half was chopped into 1 mm pieces and seeded to cell culture dishes. Cells were cultured under standard conditions outlined below. When adenocarcinoma was diagnosed for a given tumour, its corresponding culture was passaged in vitro over a period of 18 months and 60 passages, whichever occurred first. After gene expression and mutational signature extraction, the signature were compared with human lung adenocarcinoma RNAseq results.

2022-10-24 | GSE126119 | GEO

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