Novel diet-related mouse model of colon cancer parallels human colon cancer  

作　　者：Anil R Prasad Shilpa Prasad Huy Nguyen Alexaner Facista Cristy Lewis Beryl Zaitlin Harris Bernstein Carol Bernstein 

机构地区：[1]Department of Pathology, Northwest Medical Center, Tucson, AZ 85741, United States [2]Department of Pathology, College of Medicine, University of Arizona, Tucson, AZ 85724, United States [3]College of Arts and Sciences, Boston University, Boston, MA 2215, United States [4]Department of Cellular and Molecular Medicine, College of Medicine, University of Arizona, Tucson, AZ 85724, United States [5]Matrix Solutions Inc., Alberta T2R 0V2, Canada

出　　处：《World Journal of Gastrointestinal Oncology》2014年第7期225-243,共19页世界胃肠肿瘤学杂志（英文版）（电子版）

基　　金：Supported by National Institutes of Health,No.5 R01 CA119087;Arizona Biomedical Research Commission,No.0803;Veterans Affairs Merit Review,No.0142;administered by the Southern Arizona Veterans Affairs Health Care System

摘　　要：AIM:To investigate the close parallels between our novel diet-related mouse model of colon cancer and human colon cancer.METHODS:Twenty-two wild-type female mice(ages 6-8 wk)were fed the standard control diet(AIN-93G)and an additional 22 female mice(ages 6-8 wk)were fed the control diet supplemented with 0.2%deoxycho-lic acid[diet+deoxycholic acid(DOC)]for 10 mo.Tu-mors occurred in the colons of mice fed diet+DOC and showed progression to colon cancer[adenocarcinoma(AC)].This progression is through the stages of tubular adenoma(TA),TA with high grade dysplasia or ad-enoma with sessile serrated morphology,intramucosal AC,AC stage T1,and AC stage T2.The mouse tumors were compared to human tumors at the same stages by histopathological analysis.Sections of the small and large intestines of mice and humans were evaluated for glandular architecture,cellular and nuclear morphology including cellular orientation,cellular and nuclear atyp-ia,pleomorphism,mitotic activity,frequency of goblet cells,crypt architecture,ulceration,penetration of crypts through the muscularis mucosa and presence of malignant crypts in the muscularis propria.In addition,preserved colonic tissues from genetically similar male mice,obtained from a prior experiment,were analyzed by immunohistochemistry.The male mice had been fed the control diet or diet+DOC.Four molecular markers were evaluated:8-OH-dG,DNA repair protein ERCC1,autophagy protein beclin-1 and the nuclear location of beta-catenin in the stem cell region of crypts.Also,male mice fed diet+DOC plus 0.007%chlorogenic acid(diet+DOC+CGA)were evaluated for ERCC1,beclin-1 and nuclear location of beta-catenin.RESULTS:Humans with high levels of diet-relatedDOC in their colons are at a substantially increased riskof developing colon cancer.The mice fed diet+DOChad levels of DOC in their colons comparable to that ofhumans on a high fat diet.The 22 mice without addedDOC in their diet had no colonic tumors while 20 ofthe 22 mice(91%)fed diet+DOC developed colonictumors.Furthermore,the tumors in 10AIM: To investigate the close parallels between our novel diet-related mouse model of colon cancer and human colon cancer.METHODS: Twenty-two wild-type female mice(ages 6-8 wk) were fed the standard control diet(AIN-93G) and an additional 22 female mice(ages 6-8 wk) were fed the control diet supplemented with 0.2% deoxycho-lic acid [diet + deoxycholic acid(DOC)] for 10 mo. Tu-mors occurred in the colons of mice fed diet + DOC and showed progression to colon cancer [adenocarcinoma(AC)]. This progression is through the stages of tubular adenoma(TA), TA with high grade dysplasia or ad-enoma with sessile serrated morphology, intramucosal AC, AC stage T1, and AC stage T2. The mouse tumors were compared to human tumors at the same stages by histopathological analysis. Sections of the small and large intestines of mice and humans were evaluated for glandular architecture, cellular and nuclear morphology including cellular orientation, cellular and nuclear atyp-ia, pleomorphism, mitotic activity, frequency of goblet cells, crypt architecture, ulceration, penetration of crypts through the muscularis mucosa and presence of malignant crypts in the muscularis propria. In addition, preserved colonic tissues from genetically similar male mice, obtained from a prior experiment, were analyzed by immunohistochemistry. The male mice had been fed the control diet or diet + DOC. Four molecular markers were evaluated: 8-OH-dG, DNA repair protein ERCC1, autophagy protein beclin-1 and the nuclear location of beta-catenin in the stem cell region of crypts. Also, male mice fed diet + DOC plus 0.007% chlorogenic acid(diet + DOC + CGA) were evaluated for ERCC1, beclin-1 and nuclear location of beta-catenin.RESULTS: Humans with high levels of diet-related DOC in their colons are at a substantially increased risk of developing colon cancer. The mice fed diet + DOC had levels of DOC in their colons comparable to that of humans on a high fat diet. The 22 mice without added DOC in their diet had no colonic tumors while 20 of the 22 mice(91%) fe

关 键 词：DIET DEOXYCHOLATE Mouse model Colon cancer Histology Chlorogenic acid 8-OH-DG Beclin 1 BETA-CATENIN 

分 类 号：R735.35[医药卫生—肿瘤]