Elevated Incidence of Polyp Formation in APCMin/+Msh2−/− Mice Is Independent of Nitric Oxide-Induced DNA Mutations

Belcheva, A.; Green, Blerta; Weiss, Ashley; Streutker, Catherine; Martín, Alberto

doi:10.1371/journal.pone.0065204

Cited by 6 publications

(6 citation statements)

References 51 publications

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“…It is worth noting that we previously found no role for RNI in tumor formation in homozygous null deficient Msh2 mice 26 , which is consistent with the notion that the Lynch syndrome model of CRC does not require inflammation. Notably, although VitC suppresses 8-oxoG, it did not have an effect on CRC in the Lynch syndrome model.…”

Section: Discussionsupporting

confidence: 89%

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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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Section: Discussionsupporting

confidence: 89%

“…Msh2 -/- cells, we tested whether antioxidants could affect CRC in Lynch syndrome models. We had previously tested the effects of L-NIL on CRC induction in MMR-mutant mice, and found no effect 26 . Hence, we focused our efforts on the antioxidants VitC and NAC.…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2020

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“…DNA-damaging effects of microbiota in CRC are thought to be induced by microbes that produce numerous genotoxic substances and are thus linked to CRC development. For example, microbial-derived nitric oxide has the capacity to damage DNA (18,19). Reactive oxygen species (ROS) are also powerful instigators of mutation and could contribute to chromosomal instability and risk of CRC (20,21).…”

Section: Comparison Of Human Gut Microbiota In Control Subjects and Pmentioning

confidence: 99%

Comparison of human gut microbiota in control subjects and patients with colorectal carcinoma in adenoma: Terminal restriction fragment length polymorphism and next-generation sequencing analyses

et al. 2015

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Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in Japan. The etiology of CRC has been linked to numerous factors including genetic mutation, diet, life style, inflammation, and recently, the gut microbiota. However, CRC-associated gut microbiota is still largely unexamined. This study used terminal restriction fragment length polymorphism (T-RFLP) and next-generation sequencing (NGS) to analyze and compare gut microbiota of Japanese control subjects and Japanese patients with carcinoma in adenoma. Stool samples were collected from 49 control subjects, 50 patients with colon adenoma, and 9 patients with colorectal cancer (3/9 with invasive cancer and 6/9 with carcinoma in adenoma) immediately before colonoscopy; DNA was extracted from each stool sample. Based on T-RFLP analysis, 12 subjects (six control and six carcinoma in adenoma subjects) were selected; their samples were used for NGS and species-level analysis. T-RFLP analysis showed no significant differences in bacterial population between control, adenoma and cancer groups. However, NGS revealed that i), control and carcinoma in adenoma subjects had different gut microbiota compositions, ii), one bacterial genus (Slackia) was significantly associated with the control group and four bacterial genera (Actinomyces, Atopobium, Fusobacterium, and Haemophilus) were significantly associated with the carcinoma-in-adenoma group, and iii), several bacterial species were significantly associated with each type (control: Eubacterium coprostanoligens; carcinoma in adenoma: Actinomyces odontolyticus, Bacteroides fragiles, Clostridium nexile, Fusobacterium varium, Haemophilus parainfluenzae, Prevotella stercorea, Streptococcus gordonii, and Veillonella dispar). Gut microbial properties differ between control subjects and carcinoma-in-adenoma patients in this Japanese population, suggesting that gut microbiota is related to CRC prevention and development.

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“…4). This striking increase in intestinal adenomas is a characteristic feature of MMR-deficient Apc Min/+ mice phenotypes (23-26). Our data suggests that when Apc is inactivated by intragenic mutation in this model, rather than by LOH, transgenic BLM has no significant effect on the outcome of intestinal adenoma development.…”

Section: Resultsmentioning

confidence: 96%

Genetic Manipulation of Homologous Recombination In Vivo Attenuates Intestinal Tumorigenesis

McIlhatton

Murnan

Carson

et al. 2015

Cancer Prevention Research

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Although disruption of DNA repair capacity is unquestionably associated with cancer susceptibility in humans and model organisms, it remains unclear if the inherent tumor phenotypes of DNA repair deficiency syndromes can be regulated by manipulating DNA repair pathways. Loss-of-function mutations in BLM, a member of the RecQ helicase family, cause Bloom's syndrome (BS), a rare, recessive genetic disorder that predisposes to many types of cancer. BLM functions in many aspects of DNA homeostasis, including the suppression of homologous recombination (HR) in somatic cells. We investigated whether BLM overexpression, in contrast to loss-of-function mutations, attenuated the intestinal tumor phenotypes of ApcMin/+ and ApcMin/+;Msh2-/- mice, animal models of familial adenomatous polyposis coli (FAP). We constructed a transgenic mouse line expressing human BLM (BLM-Tg) and crossed it onto both backgrounds. BLM-Tg decreased adenoma incidence in a dose-dependent manner in our ApcMin/+ model of FAP, although levels of GIN were unaffected, and concomitantly increased animal survival over 50%. It did not reduce intestinal tumorigenesis in ApcMin/+;Msh2-/- mice. We used the pink-eyed unstable (pun) mouse model to demonstrate that increasing BLM dosage in vivo lowered endogenous levels of HR by two-fold. Our data suggests that attenuation of the Min phenotype is achieved through a direct effect of BLM-Tg on the HR repair pathway. These findings demonstrate that HR can be manipulated in vivo to modulate tumor formation at the organismal level. Our data suggests that lowering HR frequencies may have positive therapeutic outcomes in the context of specific hereditary cancer predisposition syndromes, exemplified by FAP.

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Elevated Incidence of Polyp Formation in APCMin/+Msh2−/− Mice Is Independent of Nitric Oxide-Induced DNA Mutations

Cited by 6 publications

References 51 publications

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

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

Comparison of human gut microbiota in control subjects and patients with colorectal carcinoma in adenoma: Terminal restriction fragment length polymorphism and next-generation sequencing analyses

Genetic Manipulation of Homologous Recombination In Vivo Attenuates Intestinal Tumorigenesis

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