Chute, J.P. et al. Inhibition of aldehyde dehydrogenase and retinoid signaling induces the expansion of human hematopoietic stem cells. Proc. Natl. Acad. Sci. USA 103, 11707-11712

Duke University, Durham, North Carolina, United States
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 09/2006; 103(31):11707-12. DOI: 10.1073/pnas.0603806103
Source: PubMed


Aldehyde dehydrogenase (ALDH) is an enzyme that is expressed in the liver and is required for the conversion of retinol (vitamin A) to retinoic acids. ALDH is also highly enriched in hematopoietic stem cells (HSCs) and is considered a selectable marker of human HSCs, although its contribution to stem cell fate remains unknown. In this study, we demonstrate that ALDH is a key regulator of HSC differentiation. Inhibition of ALDH with diethylaminobenzaldehyde (DEAB) delayed the differentiation of human HSCs that otherwise occurred in response to cytokines. Moreover, short-term culture with DEAB caused a 3.4-fold expansion in the most primitive assayable human cells, the nonobese diabetic/severe combined immunodeficiency mouse repopulating cells, compared with day 0 CD34(+)CD38(-)lin(-) cells. The effects of DEAB on HSC differentiation could be reversed by the coadministration of the retinoic acid receptor agonist, all-trans-retinoic acid, suggesting that the ability of ALDH to generate retinoic acids is important in determining HSC fate. DEAB treatment also caused a decrease in retinoic acid receptor-mediated signaling within human HSCs, suggesting directly that inhibition of ALDH promotes HSC self-renewal via reduction of retinoic acid activity. Modulation of ALDH activity and retinoid signaling is a previously unrecognized and effective strategy to amplify human HSCs.

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Available from: Rachid Safi, Aug 13, 2014
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    • "The functional role of ALDH has been studied, with specific inhibitor of ALDH, diethylaminobenzaldehyde (DEAB), which was able to alter the molecular and cellular mechanisms that control self-renewal capacity of human HSC (Chute et al., 2006). The evidence of ALDH involvement in the physiology of HSC was further highlighted by a series of studies devoted to purification/analysis of highly immature progenitor cells, particularly in human cord blood (CB) as well as in murine bone marrow (BM) (Christ et al., 2007; Juopperi et al., 2007; Hess et al., 2006). "

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    • "Paraffin blocks from 47 individual patients, four fresh specimens of malignant PT and their xenografted tumors, were examined by immunohistochemical staining for the following markers: CD44 (HCAM), CD29 (integrin β-1), CD106 (VCAM-1), CD166 (ALCAM), CD105 (Endoglin), CD90 (Thy-1) [17-20], GD2 (ganglioside) [11], CD117(c-kit receptor) [21], ALDH1 [15], embryonic stem cell marker Oct-4 (Octamer-4 in abbreviation), CD34 [22], CD10, p53, p63, Ki-67, Bcl-2 [23] and vimentin [24]. Mesenchymal progenitor cell-line HS-5 was chosen as a control. "
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    ABSTRACT: Although breast phyllodes tumors are rare, there is no effective therapy other than surgery. Little is known about their tumor biology. Malignant phyllodes tumor contains heterologous stromal elements, and can transform into rhabdomyosarcoma, liposarcoma and osteosarcoma. These versatile properties prompted us to explore their possible relationship to mesenchymal stem cells (MSCs) and search for the presence of cancer stem cells (CSCs) in phyllodes tumors. Paraffin sections of malignant phyllodes tumors were examined for various markers by immunohistochemical staining. Xenografts of human primary phyllodes tumors were established by injecting freshly isolated tumor cells into the mammary fat pad of nonobese diabetic/severe combined immunodeficient (NOD-SCID) mice. To search for CSCs, xenografted tumor cells were sorted into various subpopulations by flow cytometry and examined for their in vitro mammosphere forming capacity, in vivo tumorigenicity in NOD-CSID mice and their ability to undergo differentiation. Immunohistochemical analysis revealed the expression of the following 10 markers: CD44, CD29, CD106, CD166, CD105, CD90, disialoganglioside (GD2), CD117, Aldehyde dehydrogenase 1 (ALDH), and Oct4, and 7 clinically relevant markers (CD10, CD34, p53, p63, Ki-67, Bcl-2, vimentin, and Globo H) in all 51 malignant phyllodes tumors examined, albeit to different extents. Four xenografts were successfully established from human primary phyllodes tumors. In vitro, ALDH+ cells sorted from xenografts displayed approximately 10-fold greater mammosphere-forming capacity than ALDH- cells. GD2+ cells showed a 3.9-fold greater capacity than GD2- cells. ALDH+/GD2+cells displayed 12.8-fold greater mammosphere forming ability than ALDH-/ GD2- cells. In vivo, the tumor-initiating frequency of ALDH+/GD2+ cells were up to 33-fold higher than that of ALDH+ cells, with as few as 50 ALDH+/GD2+ cells being sufficient for engraftment . Moreover, we provided the first evidence for the induction of ALDH+/GD2+ cells to differentiate into neural cells of various lineages, along with the observation of neural differentiation in clinical specimens and xenografts of malignant phyllodes tumors. ALDH+ or ALDH+/GD2+ cells could also be induced to differentiate into adipocytes, osteocytes or chondrocytes. Our findings revealed that malignant phyllodes tumor possessed many characteristics of MSC, and their CSCs were enriched in ALDH+ and ALDH+/GD2+ subpopulations.
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    • "The aldehyde dehydrogenase family, of which ALDH1 is a member, is a family of cytosolic isoenzymes, which are highly expressed in many stem and progenitor cells [40]. Its known functions include the conversion of retinol to retinoic acids and the oxidation of toxic aldehyde metabolites, like those formed during alcohol metabolism and with certain chemotherapeutics such as cyclophosphamide and cisplatin [41, 42]. As with CD44, the lead for investigating ALDH as a marker for CSCs in HNSCC followed identification in other solid malignancies such as breast, colon, liver, and lung tumors [43–46]. "
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    ABSTRACT: There is increasing evidence that the growth and spread of cancers is driven by a small subpopulation of cancer stem cells (CSCs)-the only cells that are capable of long-term self-renewal and generation of the phenotypically diverse tumor cell population. CSCs have been identified and isolated in a variety of human cancers including head and neck squamous cell carcinoma (HNSCC). The concept of cancer stem cells may have profound implications for our understanding of tumor biology and for the design of novel treatments targeted toward these cells. The present review is an attempt to conceptualize the role of CSCs in HNSCC-its implication in tumorigenesis and the possible additional approach in current treatment strategies.
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