DCAMKL-1 Expression Identifies Tuft Cells Rather Than Stem Cells in the Adult Mouse Intestinal Epithelium

Gerbe, François; Brulin, Bénédicte; Makrini, Leila; Legraverend, Catherine; Jay, Philippe

doi:10.1053/j.gastro.2009.06.072

Cited by 146 publications

(134 citation statements)

References 7 publications

Supporting

Mentioning

125

Contrasting

Unclassified

Order By: Relevance

“…In this study, DCLK1-positive epithelial cells were found in normal colon tissues but they were not located at the crypt bottoms, what we call intestinal stem cell niches. Our findings in the normal colon tissues are compatible with previous reports that implicated DCLK1 as a differentiation marker in normal tissue (27,28). In contrast, DCLK1-positive cancer cells were widely distributed not only in the primary colon cancer region, but also metastatic regional lymph nodes ( Supplementary Fig.…”

Section: Discussionsupporting

confidence: 82%

miR-137 Regulates the Tumorigenicity of Colon Cancer Stem Cells through the Inhibition of DCLK1

Sakaguchi

Hisamori

Oshima

et al. 2016

Molecular Cancer Research

View full text Add to dashboard Cite

miRNAs have important roles in regulating cancer stem cell (CSC) properties and are considered to be potential therapeutic targets. However, few studies have focused on miRNAs which are specifically related to colon CSCs. Here, a PCR-based miRNA profiling analysis of normal colon stem cells (NCSC) and colonÀ ) identified miRNAs which regulate colon CSC properties. Interestingly, miRNA-137 (miR-137) expression was downregulated in the colon CSCs compared with NCSCs, while doublecortin-like kinase 1 (DCLK1) mRNA was highly expressed in the colon CSCs but low in the NCSCs. In fact, DCLK1-positive cancer cells were widely distributed in clinically resected colon cancer specimens, while DCLK1-positve epithelial cells were rarely detected in normal colon tissues including the crypt bottoms. Luciferase assay and immunoblot analysis revealed that miR-137 regulated DCLK1 gene expression. Transduction of exogenous miR-137 suppressed the development of colon cancer organoids in vitro and the tumorigenicity of colon cancer cells in vivo without affecting the growth of normal intestinal organoids. Furthermore, the suppression of miR-137 enhanced the organoid development of normal colon cells. These data demonstrate that miR-137 has the capacity to suppress the tumorigenicity of colon CSCs and that maintained expression of miR-137 in NCSCs contributes to suppressing uncontrolled cell proliferation through the inhibition of DCLK1 expression.Implications: The miR-137/DCLK1 axis as an important regulator in NCSCs and colon CSCs; further understanding of this axis may foster the development of potential gene therapeutic strategies targeting colon CSCs.

show abstract

Section: Discussionsupporting

confidence: 82%

miR-137 Regulates the Tumorigenicity of Colon Cancer Stem Cells through the Inhibition of DCLK1

Sakaguchi

Hisamori

Oshima

et al. 2016

Molecular Cancer Research

View full text Add to dashboard Cite

show abstract

“…4D). Only positive cells in the crypt were scored in order to distinguish quiescent stem cells from the Dclk-1-positive differentiated Tuft cells, which reside in or near the villus Gerbe et al, 2009;Gagliardi et al, 2012). Unexpectedly, mice lacking Msi-1 showed higher numbers of Dclk-1-positive cells in all three sections of the small intestine when compared to wild-type mice (Fig.…”

Section: Msi-1mentioning

confidence: 99%

Suppression of intestinal tumorigenesis in Apc mutant mice upon Musashi-1 deletion

Wolfe

Ernlund

McGuinness

et al. 2017

Journal of Cell Science

View full text Add to dashboard Cite

Therapeutic strategies based on a specific oncogenic target are better justified when elimination of that particular oncogene reduces tumorigenesis in a model organism. One such oncogene, Musashi-1 (Msi-1), regulates translation of target mRNAs and is implicated in promoting tumorigenesis in the colon and other tissues. Msi-1 targets include the tumor suppressor adenomatous polyposis coli (Apc), a Wnt pathway antagonist lost in ∼80% of all colorectal cancers. Cell culture experiments have established that Msi-1 is a Wnt target, thus positioning Msi-1 and Apc as mutual antagonists in a mutually repressive feedback loop. Here, we report that intestines from mice lacking Msi-1 display aberrant Apc and Msi-1 mutually repressive feedback, reduced Wnt and Notch signaling, decreased proliferation, and changes in stem cell populations, features predicted to suppress tumorigenesis. Indeed, mice with germline Apc mutations (Apc Min ) or with the Apc 1322T truncation mutation have a dramatic reduction in intestinal polyp number when Msi-1 is deleted. Taken together, these results provide genetic evidence that Msi-1 contributes to intestinal tumorigenesis driven by Apc loss, and validate the pursuit of Msi-1 inhibitors as chemo-prevention agents to reduce tumor burden.

show abstract

“…Progastrin was shown to promote the proliferation of progenitor cells in the mouse colonic epithelium (16) and a link has been suggested between progastrin expression and populations of cells expressing CD133 (17), DCAMKL1 (18), or CD44 (19) in mouse colonic crypts and human cancer cell lines. Yet, expression of these markers is not restricted to CSCs (20)(21)(22)(23), and the functional role of progastrin on CSC self-renewal and tumor-initiating potential has not been documented.…”

Section: Introductionmentioning

confidence: 99%

Autocrine Secretion of Progastrin Promotes the Survival and Self-Renewal of Colon Cancer Stem–like Cells

et al. 2016

View full text Add to dashboard Cite

Subpopulations of cancer stem-like cells (CSC) are thought to drive tumor progression and posttreatment recurrence in multiple solid tumors. However, the mechanisms that maintain stable proportions of self-renewing CSC within heterogeneous tumors under homeostatic conditions remain poorly understood. Progastrin is a secreted peptide that exhibits tumorforming potential in colorectal cancer, where it regulates pathways known to modulate colon CSC behaviors. In this study, we investigated the role of progastrin in regulating CSC phenotype in advanced colorectal cancer. Progastrin expression and secretion were highly enriched in colon CSC isolated from human colorectal cancer cell lines and colon tumor biopsies.Progastrin expression promoted CSC self-renewal and survival, whereas its depletion by RNA interference-mediated or antibody-mediated strategies altered the homeostatic proportions of CSC cells within heterogeneous colorectal cancer tumors. Progastrin downregulation also decreased the frequency of ALDH high cells, impairing their tumor-initiating potential, and inhibited the high glycolytic activity of ALDH high CSC to limit their self-renewal capability. Taken together, our results show how colorectal CSC maintain their tumor-initiating and selfrenewal capabilities by secreting progastrin, thereby contributing to the tumor microenvironment to support malignancy.

show abstract

DCAMKL-1 Expression Identifies Tuft Cells Rather Than Stem Cells in the Adult Mouse Intestinal Epithelium

Cited by 146 publications

References 7 publications

miR-137 Regulates the Tumorigenicity of Colon Cancer Stem Cells through the Inhibition of DCLK1

miR-137 Regulates the Tumorigenicity of Colon Cancer Stem Cells through the Inhibition of DCLK1

Suppression of intestinal tumorigenesis in Apc mutant mice upon Musashi-1 deletion

Autocrine Secretion of Progastrin Promotes the Survival and Self-Renewal of Colon Cancer Stem–like Cells

Contact Info

Product

Resources

About