Angiogenin Regulates Tumor Growth via PKD and COX-2 in a Mouse Model of Colitis-associated Cancer
James Luo, Tiegang Liu, James Yoo
Brigham and Women's Hospital, Boston MA
Background: The myofibroblast is the predominant stromal cell of the tumor microenvironment and a major reservoir of cyclo-oxygenase-2 (COX-2). The angiogenesis protein angiogenin (ANG) enhances cell growth and survival. We recently reported that ANG regulates inflammatory mediator signaling within the myofibroblast, directly regulating COX-2 via PKD signaling. However, the physiologic impact of ANG signaling within the myofibroblast on colitis-associated cancer (CAC) has not been studied.
Methods: Angiogenin knock-out (ANG-KO) C57BL/6 (n=8) and wild-type (WT) mice (n=8) were given azoxymethane (AOM, 5mg/kg I.P.), a colon carcinogen, followed by three cycles of 3% dextran sodium sulfate (DSS). Disease activity index (DAI) was recorded during the “colitis” phase of each cycle. A colonoscopy was performed 1 week after DSS, mice were euthanized 1 week after the 3rd cycle.
Results: Of the 16 mice, 1 ANG-KO mouse died. There were no differences between WT and ANG-KO C57BL/6 mice in terms of DAI or colon length. In 7 ANG-KO mice only 3 distal tumors formed (0.4 tumors/mice), all were <2mm in diameter. In comparison, 23 tumors formed in 8 WT mice (2.8 tumors/mouse). 11 tumors were >2mm and 12 were <2mm in diameter. 13 of the 23 tumors that formed in WT mice were in the mid-colon.
Conclusion: In a mouse model of CAC, AOM-DSS leads to significantly diminished tumor growth in ANG-KO mice with no apparent impact on the severity of colitis. This suggests that targeting stroma-mediated COX-2 expression via ANG may be a novel therapeutic approach for the treatment of CAC.
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