Finding cancer stem cells: are aldehyde dehydrogenases fit for purpose?

Abstract

Despite many years of intensive effort, there is surprisingly little consensus on the most suitable markers with which to locate and isolate stem cells from adult tissues. By comparison, the study of cancer stem cells is still in its infancy; so, unsurprisingly, there is great uncertainty as to the identity of these cells. Stem cell markers can be broadly categorized into molecular determinants of self-renewal, clonogenicity, multipotentiality, adherence to the niche, and longevity. This review assesses the utility of recognizing cancer stem cells by virtue of high expression of aldehyde dehydrogenases (ALDHs), probably significant determinants of cell survival through their ability to detoxify many potentially cytotoxic molecules, and contributing to drug resistance. Antibodies are available against the ALDH enzyme family, but the vast majority of studies have used cell sorting techniques to enrich for cells expressing these enzymes. Live cells expressing high ALDH activity are usually identified by the ALDEFLUOR kit and sorted by fluorescence activated cell sorting (FACS). For many human tumours, but notably breast cancer, cell selection based upon ALDH activity appears to be a useful marker for enriching for cells with tumour-initiating activity (presumed cancer stem cells) in immunodeficient mice, and indeed the frequency of so-called ALDH(bri) cells in many tumours can be an independent prognostic indicator.

The BMP2/7 heterodimer inhibits the human breast cancer stem cell subpopulation and bone metastases formation

“…ALDH activity is probably a determinant of cell survival through their ability to detoxify many potentially cytotoxic molecules, contributing to drug resistance (Alison et al, 2010). To date, it has remained unclear which of the 19 ALDH isoforms contribute to the observed high ALDEFLUOR activity.…”

Understanding cancer stem cell heterogeneity and plasticity

“…CSCs, now reported in most human tumors, are commonly identified and enriched using strategies for identifying normal stem cells, which include flow cytometrybased sorting using cell surface markers, such as CD44 and CD133, and functional approaches, including SP analysis [7], Aldefluor assay [8,48], and sphere formation coupled with serial sphere passaging [49]. The CSCenriched populations prospectively purified using these strategies are then implanted, at various cell doses, in immune-deficient mice to assay their tumor-regenerating capacity, an in vivo assay often called limiting dilution assay.…”

Concise Review: Aldehyde Dehydrogenase Bright Stem and Progenitor Cell Populations from Normal Tissues: Characteristics, Activities, and Emerging Uses in Regenerative Medicine

“…The individual members of the superfamily show substrate preferences for different aldehydes and some also have other functions unrelated to aldehyde oxidation [7]. A variety of compounds that inhibit ALDH activity is available; these compounds may inhibit the activities of several different ALDH gene products [4]. One inhibitor diethylaminobenzaldehyde (DEAB) is routinely used as an inhibitor of the Aldefluor reaction [2].…”

“…The length limitation of a review precludes detailed discussion of other aspects of roles of ALDH in cells or the literature on expression of ALDH by tumor cells. However, several recent reviews of these topics are available [3][4][5][6].…”