title: Association of stem-like cells in gender-specific chemoprevention against intestinal neoplasia in MIN mouse.
abstract: This study was undertaken to examine the gender-sensitivity and chemopreventive responsiveness of celecoxib on intestinal stem-like cells as a biomarker of colon carcino-genesis, using the MIN mouse model. Male and female MIN mice (6-7-weeks old) were randomized to either control diet or to a diet supplemented with celecoxib (1,500 ppm). The animals were euthanized ten weeks later and the intestines were flushed and opened longitudinally to assess tumor count. Small intestinal segments were formalin-fixed and tissue sections were subjected to immunohistochemical evaluation of DCAMKL1, a known marker of stem-like cells. We found that in animals receiving control (AIN 76A diet) alone, female MIN mice had a higher polyp count than males (52.32 ± 13.89 vs. 35.43 ± 16.05; p<0.0005). However, compared to control diet groups, celecoxib supplementation caused a larger reduction in the number of polyps in females than their male cohorts (6.38 ± 1.43 vs. 12.83 ± 6.74; a reduction of 88% in females to 64% in males). Significant differences (p=0.013) were observed in the number of DCAMKL1-stained cells in the crypts of the wild-type (WT) (10.01 ± 1.07 stem cells per high powered field; HPF) compared to the MIN mice (24.15 ± 8.08 stem cells per HPF), illustrating increased stem-like cells in animals that are more prone to neoplasia. DCAMKL1 labeled stem-like cells were equal in number in the male and female groups receiving the control AIN 76A diet alone (females, 25.73 stem-like cells/HPF); males, 24.15 stem-like cells/HPF). However, females showed a greater reduction in the number of DCAMKL1-labeled stem-like cells with celecoxib supplementation than the respective males (16.63 ± 4.23 vs. 21.56 ± 9.06; a reduction of 35.4% in females to 10.7% in males). We conclude that a higher number of stem-like cells in the uninvolved mucosa paralleled tumorigenesis and mirrored greater chemopreventive responsiveness of female MIN mice compared to males.
authors.affiliation: Department of Internal Medicine, NorthShore University Healthsystem, Evanston, IL 60201, USA.
authors.forename: Seema R
authors.initials: SR
authors.lastname: Gandhi
authors.forename: Ashish K
authors.initials: AK
authors.lastname: Tiwari
authors.forename: Dhananjay P
authors.initials: DP
authors.lastname: Kunte
authors.forename: Mart Angelo
authors.initials: MA
authors.lastname: De la Cruz
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Stypula
authors.forename: Tina
authors.initials: T
authors.lastname: Gibson
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Brasky
authors.forename: Vadim
authors.initials: V
authors.lastname: Backman
authors.forename: Ramesh K
authors.initials: RK
authors.lastname: Wali
authors.forename: Hemant K
authors.initials: HK
authors.lastname: Roy
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000068579:Celecoxib; D018890:Chemoprevention; D004195:Disease Models, Animal; D000089742:Doublecortin-Like Kinases; D005260:Female; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D007414:Intestinal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis; D011720:Pyrazoles / Q000494:pharmacology*; D012737:Sex Factors; D013234:Stem Cells / Q000187:drug effects / Q000473:pathology*; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D011720:Pyrazoles; D013449:Sulfonamides; D000089742:Doublecortin-Like Kinases; C485525:Dclk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D000068579:Celecoxib