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    • ALDHs also act as opposite roles in the initiation

    2023-07-31

    ALDHs also act as opposite roles in the initiation and development of carcinoma. For example, ALDH2, as a key enzyme which oxidises acetaldehyde, participates in alcohol metabolism and is associated with alcohol-mediated carcinogenesis [37]. It has been reported that up to 8% of the world's population carries a dominant-negative mutation in ALDH2. Alcohol consumption in these individuals has showed a good correlation with the risk for developing upper gastrointestinal tumour, particularly oesophageal cancer [38], [39]. Another study found that the acetaldehyde-catabolising enzyme Aldh2 is essential for the development of Fancd2−/− embryos and that Aldh2−/−Fancd2−/− mice have a high risk for the spontaneous development of acute leukaemia [40]. Other isozymes such as ALDH1A2, a regulator of RA synthesis in developing tissues, were discovered as candidate tumour suppressors in prostate cancer [41]. However, ALDH1A1 was found as a transcription target of the leukaemogenic factor TLX1/HOX1 and may induce tumour growth in leukaemia [42].
    ALDHs and CSCs ALDHs play critical roles in normal stem cell functions during development [43]. Recent studies have linked potent ALDH activity, which was detected using a quantified commercial assay known as Aldefluor assay, to CSC isolation and identification [44]. van den Hoogen et al. [45] evaluated ALDH-high prostate cancer cells by using Aldefluor assay and found that this population of cells displays strongly elevated clonogenicity and migratory behaviour in vitro. Further studies discovered that this subpopulation of cells readily forms distant metastases with strongly enhanced tumour progression at both orthotopic and metastatic sites in a nude mouse model [45]. Shao et al. [46] reported that ALDH1A3 isozyme is a marker for a subpopulation of highly clonogenic and tumourigenic NSCLC cells and that STAT3 activation is essential to maintain the subpopulation of ALDH1-positive lung cancer cells. Other studies which used the same sorting methods demonstrated that isoquercitrin cancer cells and cervical cancer cells with high ALDH activity display CSC functions, including high tumourigenicity, enhanced self-renewal and differentiation potentials [10], [47]. ALDH1A1 and ALDH3A1 are not the only isozymes responsible for Aldefluor activity; other ALDH isoforms such as ALDH1B1, ALDH1A7 and ALDH7A1 also exhibit elevated expression in CSCs [48]. However, the role of these isozymes in CSCs remains unsupported by compelling evidence. Therefore, ALDH1A1 and ALDH3A1 are the commonly used markers for most CSCs. These markers also play important roles in regulating critical processes in CSCs.
    Functional roles of ALDHs in CSCs
    Regulation of ALDH in CSCs
    Conclusions CSCs are regarded as the main cause of the incidence and progression of cancer and the failure of clinical tumour treatment. Surface markers such as CD133 and CD44 exhibit conflicting results in isolating different types of CSCs. ALDHs, especially ALDH1A1 and ALDH3A1, are well regarded as consistent markers for CSCs. In addition to its positive marker role, the ALDH family and its regulated RA, ROS and reactive aldehydes metabolism are strongly related with various properties of CSCs. Recent data have suggested that several pathways such as RA, Notch, Wnt and TGF-β may regulate ALDHs in CSCs at the transcriptional and post-translational level. In summary, CSCs regulate ALDH levels through intracellular signal transduction (Fig. 3). Consequently, ALDHs affect the development and progression of CSCs (Fig. 3). A holistic understanding of the factors which associate ALDHs with CSCs is crucial to facilitate the development and implementation of novel classes of therapeutics which target CSCs to improve the current status of cancer treatment.
    Funding This work was supported by grants from the National Natural Science Foundation of China (No. 81472170), the Major Science and Technology Special Project of Zhejiang Province (No.2012C13022-1), the Health Department of Zhejiang Province (No. 201340772), the Provincial Foundation of the Science and Technology Department of Zhejiang Province (No. 2013C33130, 2014C33188), and the Zhejiang Provincial Natural Science Foundation (No. LY14H160028).