Angiogenin-1 and -4 Regulate Intestinal Homeostasis and Limit Tumor Growth in a Mouse Model of Colitis-Associated Cancer
Alex Hu, Cullen Roberts, Andrei Moscalu, James Yoo
Brigham and Women's Hospital, Boston, MA
Angiogenin-1 (Ang1) and -4 (Ang4) are 14-kDa ribonucleases that have potent angiogenic and antimicrobial properties and have been implicated in both colitis and cancer. We recently reported that in a mouse model of colitis-associated cancer, Ang1 knock-out (Ang1-/-) mice develop significantly fewer tumors compared to wild-type (WT) mice. The regulation of colitis and the role of Ang4 in this setting have not been previously studied.
WT (n=23) and Ang1-/- (n=23) C57BL/6 mice were given azoxymethane (AOM, 10mg/kg I.P.), a colon carcinogen followed by three cycles of 3.5% dextran sodium sulfate (DSS). Disease activity index (DAI) was recorded. Ang1, Ang4, COX-2, Il-1B, IL-6, IL-10, IL-23, IL-33 mRNA levels were analyzed by RT-PCR.
In WT mice, DSS colitis was associated with a 1.52x10^4-fold up-regulation of Ang1 and a 1.33x10^7-fold increase in Ang4. Though Ang4 remained upregulated in Ang1-/- mice, the absence of Ang1 was associated with a higher DAI (P<0.05) and increased colonic mRNA expression of IL1-?, IL10, and IL23. Despite the more severe inflammation, Ang1-/- mice developed significantly fewer tumors (P<0.05). While 73 tumors formed in WT mice (3.48 tumors/mouse), only 16 tumors formed in Ang1-/- mice ( 0.76 tumors/mice) in association with an 8.68x10^-8-fold decrease in Ang1 and a 6.89x10^5-fold increase in Ang4.
In a mouse model of colitis-associated cancer, the absence of Ang1 worsens colitis but limits tumor growth, while Ang4 appears to mitigate both colitis and cancer. Ang1 and Ang4 differentially regulate the response to colitis and the development of colitis-associated cancer.
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