Celecoxib Targeted Therapy Attenuates Mouse Colon Carcinogenesis through Modulation of Expression Patterns of Cancer...

This study was designated to explore the role of cancer stem cells (CSCs) during chemically induced mouse colon carcinogenesis (by 1,2- dimethylhydrazine dihydrochloride, DMH) with/or without the treatment with a targeted (anti-COX-2) therapeutic drug, celecoxib. Two experiments were conducted. The first, a short-term, 16-week mouse colon carcinogenesis bioassay, demonstrates the early stages of colon carcinogenesis. The other is a medium-term, 32-week mouse colon cancer experiment that mimics an end point of colon malignancy. Colon tumors were detected in animals after 32 weeks; histopathologically, they varied from benign hyperplastic polyps and adenomas to dysplastic polyps, adenocarcinomas, and invasive carcinomas. The overall colon tumor incidences, multiplicities, and volumes were obviously reduced when treated with celecoxib after DMH initiation. The immunohistochemical (IHC) labeling indexes (L1%) of the proliferating cell nuclear antigen (PCNA) were lower in the colonic epithelium in both experiments after treatment with celecoxib. Also, the IHC expression patterns of CD133 and CD44, known to associate CSCs, showed differential changes depending on the end-point stage of carcinogenesis and celecoxib treatment. Moreover, the biochemical aldehyde dehydrogenase-1 (ALDH-1) activity levels, a known CSC marker in colonic epithelia, were downregulated after 16 weeks but were upregulated after 32 weeks. Flow cytometric analysis showed that numbers of CD133 cells increased in the colonic epithelia of mice after 16 weeks, while the numbers of CD44 but not CD133 cells increased after 32 weeks. Treatment with celecoxib after DMH induced significant increase in apoptotic cell numbers by 47% after 16 weeks, but these numbers had not changed after 32 weeks compared with the corresponding group treated DMH only. Thus, the specific markers and CSC populations targeted by this drug may vary depending on the genetic and phenotypic stages of carcinogenesis. This drug could be useful during targeted therapy for colon cancer patients.