Aldehyde Dehydrogenase 1 Is a Marker for Normal and Malignant Human Colonic Stem Cells (SC) and Tracks SC Overpopulation during Colon Tumorigenesis

By E. Huang, Mark J. Hynes, Tao Zhang, Christophe Ginestier, G. Dontu, H. Appelman, J. Fields, M. Wicha, B. Boman. Cancer Research, 2009

1,082 citations recorded by the source corpus.

Although the concept that cancers originate from stem cells (SC) is becoming scientifically accepted, mechanisms by which SC contribute to tumor initiation and progression are largely unknown. For colorectal cancer (CRC), investigation of this problem has been hindered by a paucity of specific markers for identification and isolation of SC from normal and malignant colon. Accordingly, aldehyde dehydrogenase 1 (ALDH1) was investigated as a possible marker for identifying colonic SC and for tracking them during cancer progression. Immunostaining showed that ALDH1+ cells are sparse and limited to the normal crypt bottom, where SCs reside. During progression from normal epithelium to mutant (APC) epithelium to adenoma, ALDH1+ cells increased in number and became distributed farther up the crypt. CD133+ and CD44+ cells, which are more numerous and broadly distributed in normal crypts, showed similar changes during tumorigenesis. Flow cytometric isolation of cancer cells based on enzymatic activity of ALDH (Aldefluor assay) and implantation of these cells in nonobese diabetic–severe combined immunodeficient mice (a) generated xenograft tumors (Aldefluor− cells did not), (b) generated them after implanting as few as 25 cells, and (c) generated them dose dependently. Further isolation of cancer cells using a second marker (CD44+ or CD133+ serially) only modestly increased enrichment based on tumor-initiating ability. Thus, ALDH1 seems to be a specific marker for identifying, isolating, and tracking human colonic SC during CRC development. These findings also support our original hypothesis, derived previously from mathematical modeling of crypt dynamics, that progressive colonic SC overpopulation occurs during colon tumorigenesis and drives CRC development.

Subfields: Cancer Research, Oncology, Psychiatry and Mental health

View Paper: https://www.semanticscholar.org/paper/f9aff6a8545c944bdffd028741cf788615e5e2c7

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Citations in the corpus

• CD44v6 is a marker of constitutive and reprogrammed cancer stem cells driving colon cancer metastasis. (2014, background): “Several groups have identified tumorigenic populations with stem-like features in CRC (Barker et al., 2007; Dalerba et al., 2007; Huang et al., 2009; O’Brien et al., 2007; Ricci-Vitiani et al., 2007; Todaro et al., 2007; Vermeulen et al., 2008, 2010).”
• Targeting cancer stem cell pathways for cancer therapy (2020, background): “373 Activation of mTORC2 upregulates the expression of the hepatic CSC marker EpCAM (epithelial cellular adhesion molecule) and tumorigenicity in hepatocellular CSCs.”
• Mesenchymal glioma stem cells are maintained by activated glycolytic metabolism involving aldehyde dehydrogenase 1A3 (2013, background): “4), we examined whether ALDH1 is required for the putative PMT in these GSCs. Treatment with the ALDH1 inhibitor DEAB before radiation for PN GSCs (n = 3) blocked the shift of expression of Sox2 and CD44 in the treated PN GSCs (Fig.”
• Targeting cancer stem cells by inhibiting Wnt, Notch, and Hedgehog pathways (2011, background): “Alternatively, some CSCs can be identified using flow cytometry-based functional assays such as aldehyde dehydrogenase-1 (ALDH1) expression and side population assays to enrich the CSC population from patient tumor explants”