Abstract
The purpose of this study was to investigate the role of colon cancer stem cells (CSCs) during chemicallyinduced rat multi-step colon carcinogenesis with or without the treatment with a specific cyclooxygenase-2 inhibitor drug (celecoxib). Two experiments were performed, the first, a short term 12 week colon carcinogenesis bioassay in which only surrogate markers for colon cancer, aberrant crypt foci (ACF) lesions, were formed. The other experiment was a medium term colon cancer rat assay in which tumors had developed after 32 weeks. Treatment with celecoxib lowered the numbers of ACF, as well as the tumor volumes and multiplicities after 32 weeks. Immunohistochemical proliferating cell nuclear antigen (PCNA) labeling indexes LI (%) were downregulated after treatment by celecoxib. Also different cell surface antigens known to associate with CSCs such as the epithelial cell adhesion molecule (EpCAM), CD44 and CD133 were compared between the two experiments and showed differential expression patterns depending on the stage of carcinogenesis and treatment with celecoxib. Flow cytometric analysis demonstrated that the numbers of CD133 cells were increased in the colonic epithelium after 12 weeks while those of CD44 but not CD133 cells were increased after 32 weeks. Moreover, aldehyde dehydrogenase-1 activity levels in the colonic epithelium (a known CSC marker) detected by ELISA assay were found down-regulated after 12 weeks, but were up-regulated after 32 weeks. The data have also shown that the protective effect of celecoxib on these specific markers and populations of CSCs and on other molecular processes such as apoptosis targeted by this drug may vary depending on the genetic and phenotypic stages of carcinogenesis. Therefore, uncovering these distinction roles of CSCs during different phases of carcinogenesis and during specific treatment could be useful for targeted therapy.
Highlights
Cancer stem cells (CSCs) have been recently evidenced in solid tumors from various origins including colon in both human and experimental animals (Wang et al, 2012)
Different cell surface antigens known to associate with cancer stem cells (CSCs) such as the epithelial cell adhesion molecule (EpCAM), CD44 and CD133 were compared between the two experiments and showed differential expression patterns depending on the stage of carcinogenesis and treatment with celecoxib
All animals treated with DMH showed 100% incidence of aberrant crypt foci (ACF) in both experiments (Figure 1), in contrast to almost complete lack of such lesions in the control animals except one focus with 2 aberrant crypts (ACs) were seen in the mucosa of Group (4) of experiment (I) and two with 1 AC in Group (3) of experiment (II)
Summary
Cancer stem cells (CSCs) have been recently evidenced in solid tumors from various origins including colon in both human and experimental animals (Wang et al, 2012). Several stem cell markers have been proposed in human, rat and mouse, that highlight the stem cell or stem cell-like populations in several tissues including breast, colon and pancreas (O’Brien et al, 2007). Most commonly cell surface antigens used as markers for colon cancer cells with CSC-like properties in rodents are CD44, EpCAM, CD133, CD166, Lgr, etc, depending on the animal species (Vitiani et al, 2007). Aldehyde dehydrogenase 1 (ALDH-1) has been recognized as a promising CSC marker in experimental animals including the rat (Skidan and Steiniger, 2014). In the last few years, ALDH+ is being evaluated as a potential novel cancer prognostic marker in human (Marcato et al, 2011)
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