Overt Increase of Oxidative Stress and DNA Damage in Murine and Human Colitis and Colitis-Associated Neoplasia

Frick, Adrian; Khare, Vineeta; Paul, Gregor; Lang, Michaela; Ferk, Franziska; Knasmüller, Siegfried; Beer, Andrea; Oberhuber, Georg; Gasché, Christoph

doi:10.1158/1541-7786.mcr-17-0451

Cited by 46 publications

(41 citation statements)

References 56 publications

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“…As expected, MSH2 loxP/loxP Vil‐cre mice did not develop intestinal inflammation. As previously observed, intestinal inflammation in IL‐10 −/− mice is dependent on housing conditions 11 ; however, in DKO mice, large bowel inflammation occurs independent of housing conditions and to a higher degree as compared to IL‐10 −/− mice.…”

Section: Resultssupporting

confidence: 71%

Crypt residing bacteria and proximal colonic carcinogenesis in a mouse model of Lynch syndrome

Lang

Baumgartner

Rożalska

et al. 2020

Intl Journal of Cancer

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Colorectal cancer is a multifactorial disease involving inherited DNA mutations, environmental factors, gut inflammation and intestinal microbiota. Certain germline mutations within the DNA mismatch repair system are associated with Lynch syndrome tumors including right‐sided colorectal cancer with mucinous phenotype and presence of an inflammatory infiltrate. Such tumors are more often associated with bacterial biofilms, which may contribute to disease onset and progression. Inflammatory bowel diseases are also associated with colorectal cancer and intestinal dysbiosis. Herein we addressed the question, whether inflammation can aggravate colorectal cancer development under mismatch repair deficiency. MSH2loxP/loxP Vill‐cre mice were crossed into the IL‐10−/− background to study the importance of inflammation and mucosal bacteria as a driver of tumorigenesis in a Lynch syndrome mouse model. An increase in large bowel tumorigenesis was found in double knockout mice both under conventional housing and under specific pathogen‐free conditions. This increase was mostly due to the development of proximal tumors, a hotspot for tumorigenesis in Lynch syndrome, and was associated with a higher degree of inflammation. Additionally, bacterial invasion into the mucus of tumor crypts was observed in the proximal tumors. Inflammation shifted fecal and mucosal microbiota composition and was associated with enrichment in Escherichia‐Shigella as well as Akkermansia, Bacteroides and Parabacteroides genera in fecal samples. Tumor‐bearing double knockout mice showed a similar enrichment for Escherichia‐Shigella and Parabacteroides. Lactobacilli, Lachnospiraceae and Muribaculaceae family members were depleted upon inflammation. In summary, chronic inflammation aggravates colonic tumorigenesis under mismatch repair deficiency and is associated with a shift in microbiota composition.

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Section: Resultssupporting

confidence: 71%

Crypt residing bacteria and proximal colonic carcinogenesis in a mouse model of Lynch syndrome

Lang

Baumgartner

Rożalska

et al. 2020

Intl Journal of Cancer

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“…ROS and RNI have been implicated as one of the mediators that facilitate cancer initiation during inflammatory processes. ROS and/or RNI can potentially potentiate tumorigenesis by affecting the activity of the ERK, Wnt, and Notch pathways 27,28 , by transiently oxidizing thiol groups on sensor proteins that regulate MAPK and NF-κβ pathways 28 , or by directly inducing DNA damage 4,17,29,30 . However, formal proof that the mutagenic effects of ROS and/or RNI lead to CAC and CRC is lacking.…”

Section: Discussionmentioning

confidence: 99%

Limiting oxidative DNA damage reduces microbe-induced colitis-associated colorectal cancer

et al. 2020

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Inflammatory bowel disease patients have a greatly increased risk of developing colitisassociated colon cancer (CAC); however, the basis for inflammation-induced genetic damage requisite for neoplasia is unclear. Using three models of CAC, we find that sustained inflammation triggers 8-oxoguanine DNA lesions. Strikingly, antioxidants or iNOS inhibitors reduce 8-oxoguanine and polyps in CAC models. Because the mismatch repair (MMR) system repairs 8-oxoguanine and is frequently defective in colorectal cancer (CRC), we test whether 8-oxoguanine mediates oncogenesis in a Lynch syndrome (MMR-deficient) model. We show that microbiota generates an accumulation of 8-oxoguanine lesions in MMRdeficient colons. Accordingly, we find that 8-oxoguanine is elevated in neoplastic tissue of Lynch syndrome patients compared to matched untransformed tissue or non-Lynch syndrome neoplastic tissue. While antioxidants reduce 8-oxoguanine, they do not reduce CRC in Lynch syndrome models. Hence, microbe-induced oxidative/nitrosative DNA damage play causative roles in inflammatory CRC models, but not in Lynch syndrome models.

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“…As for DNA double-stranded breaks as determined by p-H2A.X levels, it appears that sulforaphane has been studied mostly for its cytotoxic properties of inducing apoptosis in cancer cell lines resulting in increased p-H2A.X levels ( Singh et al, 2004 ). However, in large bowel organoids, sulforaphane was determined to have no effect on DNA double-stranded breaks due to oxidative stress ( Frick et al, 2018 ). Altogether, our data indicate that MBITC and MPACN have a unique activity in reducing DNA damage when compared to sulforaphane.…”

Section: Discussionmentioning

confidence: 99%

Photoprotective Properties of Isothiocyanate and Nitrile Glucosinolate Derivatives From Meadowfoam (Limnanthes alba) Against UVB Irradiation in Human Skin Equivalent

Carpenter

Miranda

et al. 2018

Front. Pharmacol.

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Exposure to ultraviolet B (UVB) irradiation of the skin leads to numerous dermatological concerns including skin cancer and accelerated aging. Natural product glucosinolate derivatives, like sulforaphane, have been shown to exhibit chemopreventive and photoprotective properties. In this study, we examined meadowfoam (Limnanthes alba) glucosinolate derivatives, 3-methoxybenzyl isothiocyanate (MBITC) and 3-methoxyphenyl acetonitrile (MPACN), for their activity in protecting against the consequences of UV exposure. To that end, we have exposed human primary epidermal keratinocytes (HPEKs) and 3D human skin reconstructed in vitro (EpiDermTM FT-400) to UVB insult and investigated whether MBITC and MPACN treatment ameliorated the harmful effects of UVB damage. Activity was determined by the compounds’ efficacy in counteracting UVB-induced DNA damage, matrix-metalloproteinase (MMP) expression, and proliferation. We found that in monolayer cultures of HPEK, MBITC and MPACN did not protect against a UVB-induced loss in proliferation and MBITC itself inhibited cell proliferation. However, in human reconstructed skin-equivalents, MBITC and MPACN decrease epidermal cyclobutane pyrimidine dimers (CPDs) and significantly reduce total phosphorylated γH2A.X levels. Both MBITC and MPACN inhibit UVB-induced MMP-1 and MMP-3 expression indicating their role to prevent photoaging. Both compounds, and MPACN in particular, showed activity against UVB-induced proliferation as indicated by fewer epidermal PCNA+ cells and prevented UVB-induced hyperplasia as determined by a reduction in reconstructed skin epidermal thickness (ET). These data demonstrate that MBITC and MPACN exhibit promising anti-photocarcinogenic and anti-photoaging properties in the skin microenvironment and could be used for therapeutic interventions.

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Overt Increase of Oxidative Stress and DNA Damage in Murine and Human Colitis and Colitis-Associated Neoplasia

Cited by 46 publications

References 56 publications

Crypt residing bacteria and proximal colonic carcinogenesis in a mouse model of Lynch syndrome

Crypt residing bacteria and proximal colonic carcinogenesis in a mouse model of Lynch syndrome

Limiting oxidative DNA damage reduces microbe-induced colitis-associated colorectal cancer

Photoprotective Properties of Isothiocyanate and Nitrile Glucosinolate Derivatives From Meadowfoam (Limnanthes alba) Against UVB Irradiation in Human Skin Equivalent

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