Identification of a Novel Putative Gastrointestinal Stem Cell and Adenoma Stem Cell Marker, Doublecortin and CaM Kinase-Like-1, Following Radiation Injury and in Adenomatous Polyposis Coli/Multiple Intestinal Neoplasia Mice

Abstract

In the gut, tumorigenesis arises from intestinal or colonic crypt stem cells. Currently, no definitive markers exist that reliably identify gut stem cells. Here, we used the putative stem cell marker doublecortin and CaM kinase-like-1 (DCAMKL-1) to examine radiation-induced stem cell apoptosis and adenomatous polyposis coli (APC)/multiple intestinal neoplasia (min) mice to determine the effects of APC mutation on DCAMKL-1 expression. Immunoreactive DCAMKL-1 staining was demonstrated in the intestinal stem cell zone. Furthermore, we observed apoptosis of the cells negative for DCAMKL-1 at 6 hours. We found DNA damage in all the cells in the crypt region, including the DCAMKL-1-positive cells. We also observed stem cell apoptosis and mitotic DCAMKL-1-expressing cells 24 hours after irradiation. Moreover, in APC/min mice, DCAMKL-1-expressing cells were negative for proliferating cell nuclear antigen and nuclear ␤-catenin in normal-appearing intestine. However, ␤-catenin was nuclear in DCAMKL-1-positive cells in adenomas. Thus, nuclear translocation of ␤-catenin distinguishes normal and adenoma stem cells. Targeting DCAMKL-1 may represent a strategy for developing novel chemotherapeutic agents. STEM CELLS 2008;26:630 -637 Disclosure of potential conflicts of interest is found at the end of this article.

Attributes of adult stem cells

“…In the mouse small intestine, Msi-1 and Hes-1 are co-expressed in the cells just above the Paneth cell zone, although Hes-1 expression additionally extends to proliferative cells higher up the crypt [102]. Msi-1 also co-localizes with another putative stem cell marker, DCAMKL-1, at cell position 4 [103]. Potten et al [67] observed Msi-1 expression, not only at cell positions 4-5, where LRCs exist, but also in crypt base columnar cells (CBCs, Figure 6E).…”

Novel Double-negative Feedback Loop between Adenomatous Polyposis Coli and Musashi1 in Colon Epithelia

“…Two subpopulations of stem cells have recently been identified in the intestinal epithelium (1)(2)(3). It has been shown that loss of Apc in one of these stem cell subpopulations results in intestinal adenomas (4).…”

Characterization of Anoikis-Resistant Cells in Mouse Colonic Epithelium

“…As expected, the majority of the mouse colonic epithelium AR cells were positive for the stem or progenitor cell marker CD133. Further characterization revealed that mouse colonic AR cells express DCLK1 and Hopx, which have been reported as a +4 position cell marker [16,29], but negative for Lgr5, Msi1 and Bmi1.…”

“…It also mediates fiber tract decussation and neuronal migration during brain development [13]. Although DCLK1 has been considered to be a marker of putative quiescent stem cells [9,16,17], recent findings have revealed that it marks a subset of colorectal stem cells, and also a rare subset of epithelial cells called tuft cells [7,8]. In the present experiment, an immunohistochemical investigation of the mouse colon revealed that DCLK1/ CD133 double positive cells are located not only in basal crypt, but also in apical crypt.…”

“…Rather, Bmi1-expresssing cells were able to compensate for the lack of Lgr5-positive cells and generate all of the epithelial lineages. Bmi1-positive cells are thought to reside above the crypt base (+4 position) and are also suggested to express doublecortin and CaM kinase-like-1 (DCLK1) [16,24]. Both CBCs and +4 position cells express stem or progenitor cell markers, such as CD133 and Musashi1 (Msi1) [22,27].…”