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

Abstract

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 À 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. [Cancer Res 2009;69(8):3382-9]

Aberrant Expression of Retinoic Acid Signaling Molecules Influences Patient Survival in Astrocytic Gliomas

“…36 -42 Moreover, several studies have described a clinical influence of ALDH1A1-expressing tumor cells in cancers of breast, colon, prostate, and head and neck, as well as in leukemia. 36,39,40,43,44 These findings raise the intriguing question of how ALDH1A1, in charge of activating the prodifferentiation factor RA, is associated with worsened clinical outcome and an undifferentiated phenotype in both healthy and neoplastic tissues. Taking into account possible mechanisms of alternative RA signaling, it could be of great interest to investigate whether stem and progenitor cells are capable of steering self-generated intracellular RA levels.…”

Comparative evaluation of cancer stem cell markers in normal pancreas and pancreatic ductal adenocarcinoma

“…ALDH1 activity identifies normal stem cells and tumor-initiating cells (i.e. CSC) in several human malignancies, where it seems to play an important role in drug resistance, cell proliferation, differentiation and response to oxidative stress (52)(53)(54). It is reported that ALDH1 is required for development of the pancreas during mouse embryogenesis, and is associated with tumorigenic pancreatic cancer cells both in vitro and in vivo.…”

Cancer-Initiating Cells from Colorectal Cancer Patients Escape from T Cell–Mediated Immunosurveillance In Vitro through Membrane-Bound IL-4

“…The IF and cytofluorimetric or confocal microscopy analyses of a panel of TAAs previously reported as expressed by CRC (e.g., MAGE, NY-ESO-1, Gp100, SVV-1, COA-1, and IL-13Ra2) (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26) revealed that all CICs and FBS tumor cells from patients 1076, 1247, 111011 and 14583 were negative for MAGE and Gp100 and expressed low levels (MRFI = 2-4) of NY-ESO-1 and IL-13Ra2 (data not shown). Sox2, Ep-CAM, and CEA, which in addition to their role as markers associated with CICs or CRC-derived CICs (Supplemental Fig.…”