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Angiogenin-1 Regulates Colorectal Cancer Growth in Orthotopic and Apc Mouse Models
Alexander Hu, Cullen Roberts, Andrei Moscalu, James Yoo
Surgery, Brigham and Women's Hospital, Boston, Massachusetts, United States

Introduction: Angiogenin-1 (Ang1) is a 14-kDa ribonuclease that was the first tumor-derived angiogenesis protein. The role of Ang1 on the development of colorectal cancer has not been well studied.

Methods: Experiments utilized Apc conditional knock-out (Apcfl/fl;Lgr5 eGFP-CreER/+) mice, an inducible colorectal cancer mouse model using tamoxifen-dependent Cre recombinase to block the expression of Apc in Lgr5-expressing intestinal stem cells. Apcfl/fl;Lgr5 eGFP-CreER/+ mice were crossed with Ang1 knock-out (Ang1-KO) mice, a whole-body homozygous knockout strain, to create Apcfl/fl;Lgr5 eGFP-CreER/+ mice that do not express Ang1. Apcfl/fl;Lgr5 eGFP-CreER/+ mice on both a wild-type (WT, n=6) and Ang1-KO (n=4) background were then injected with tamoxifen (75mg/kg, i.p.) to activate Cre recombinase. Three weeks after injection of tamoxifen, a mouse colonoscopy was performed using a Karl Storz Coloview miniendoscopic system. Small bowel and colon tissue was also evaluated grossly and by immunohistochemistry. A separate set of experiments utilized an orthotopic mouse model of colorectal cancer. Genetically defined (ApcΔ/Δ;KrasG12D/+;Trp53Δ/Δ) primary mouse colorectal cancer cells were endoscopically microinjected into the colon submucosa (20 L, 1-2x104 cells) of WT (n=5) and Ang1-KO (n=5) mice. A mouse colonoscopy was performed, and tissue was collected and evaluated grossly and by immunohistochemistry.

Results: WT Apcfl/fl;Lgr5 eGFP-CreER/+ mice developed significantly more tumors in the distal SB and a non-significant increase in colon tumors compared to Ang1-KO Apcfl/fl;Lgr5 eGFP-CreER/+ mice (Fig 1A). While a small number of SB tumors were seen in Ang1-KO Apcfl/fl;Lgr5 eGFP-CreER/+ mice, no colonic tumors were identified endoscopically, grossly, or by immunohistochemistry. In the orthotopic colorectal cancer model, injected primary colorectal cancer cells remained viable and grew over 4 weeks in WT mice, confirmed by endoscopy and histology (Fig 1B). Tumors were not seen at the injection site endoscopically or histologically (Fig 1C) in any of the Ang1-KO mice (0/5).

Conclusions: Angiogenin-1 appears to play an important role in colorectal cancer development and may serve as a novel therapeutic target.

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