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Elevated D‐2‐Hydroxyglutarate during colitis drives progression to colorectal cancer
Author(s) -
Theiss Arianne,
Han Jie,
Genta Robert,
Sweetman Lawrence
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1023.2
Subject(s) - colitis , azoxymethane , medicine , colorectal cancer , gastroenterology , dysplasia , diarrhea , inflammatory bowel disease , ulcerative colitis , cancer , disease
Although the association between inflammatory bowel diseases (IBD) and an increased risk of developing colorectal cancer is well‐established, the pathogenesis of colitis‐associated cancer is poorly understood. Our previous study of quantitative metabolic profiling of urine serially collected from mice during azoxymethane (AOM)‐dextran sodium sulfate (DSS)‐induced colitis‐associated cancer identified that urine D‐2‐hydroxyglutarate (D2HG) levels during colitis directly correlated with severity of polyp formation. Levels of D2HG are normally low and accumulation of D2HG has been linked to oncogenesis in glioma and acute myeloid leukemia. Here, we determined whether elevated D2HG during colitis drives progression to colorectal cancer. Wild‐type C57BL/6 male mice were i.p. injected with 7.6 mg/kg AOM followed by 2 cycles of 3% DSS (1 week DSS and 3 weeks recovery). During DSS, mice were i.p. injected with 25 mg/kg D2HG or vehicle once daily. Body weight, severity of diarrhea, and presence of blood in the stool were monitored daily during DSS administration and twice per week during recovery phases. Excised colons were observed for polyp number/size and embedded for dysplasia scoring. Mice injected with D2HG exhibited similar body weight loss, severity of diarrhea, and presence of blood in the stool during DSS as vehicle‐injected mice. However, mice injected with D2HG during colitis exhibited delayed recovery of body weight and significantly more and larger (>6mm in diameter) colonic polyps with the majority of polyps being high‐grade dysplasia or intramucosal adenocarcinoma. These results suggest that elevated D2HG during colitis enhances progression to colon cancer. Support or Funding Information Cancer Prevention Research Institute of Texas (CPRIT) RP150638