prostaglandin e1 Cancer stem cells CSCs may

Cancer stem cells (CSCs) may have been first identified in teratocarcinomas [11], [12], with its initial clues date back to the 19th century [13]. Kleinsmith and Pierce [12] established the immortal pluripotent teratocarcinoma lines from a single transplanted multi-potent malignant cell, strongly suggesting the existence of CSCs. Further data demonstrated the existence of CSCs in leukaemia and multiple solid tumours [14], [15], [16]. CSCs, also called tumour-initiating cells, comprise a small distinct subpopulation of tumour cells which possess high self-renewal properties, multiple differentiation capacity, tumourigenesis and drug resistance. The theory of cancer stem cell proposes an attractive cellular mechanism for the current unsatisfactory treatments. However, since the first discovery, challenges have arisen on how to effectively target CSCs. Recent studies have exhibited the importance of metabolic reprogramming as the hallmark of cancer and a growing number of results have established a link between material metabolisms and CSCs. For instance, the metabolic enzyme glycine decarboxylase, which functions in glycine metabolism, drive the tumorigenicity of CSCs in non-small cell lung cancer (NSCLC) [17]. Mutations in metabolic enzymes such as isocitrate dehydrogenase-2 play multiple roles in leukaemia initiation and maintenance [18]. As important metabolic enzymes in CSCs, ALDHs and their metabolic substrates retinoic prostaglandin e1 (RA), reactive oxygen species (ROS) and reactive aldehydes directly and indirectly influence the various cellular processes in CSCs; these processes include target gene expression, protein translation and signal transduction. Moreover, ALDHs are being widely used to isolate and identify various CSCs and are regarded as consistent CSC markers [19], compared with other CSC surface markers, such as CD24, CD44, CD133, CD166 and epithelial cell adhesion molecule, which are limited to specific types of tumours [20], [21].
ALDH family The following 19 ALDH subtypes with various chromosome locations have been detected in humans: 1A1, 1A2, 1A3, 1B1, 1L1, 1L2, 2, 3A1, 3A2, 3B1, 3B2, 4A1, 5A1, 6A1, 7A1, 8A1, 9A1, 16A1 and 18A1[22], [23]. Information on ALDHs is also available online (http://www.aldh.org). Alternatively spliced transcriptional variants exist in most of the 19 human ALDH genes enumerated above; however, their function and significance remain to be established. ALDHs have 11 families and 4 subfamilies, which are distributed in various cellular compartments, including cytoplasm, nucleus, mitochondria and endoplasmic reticulum [24]. Most ALDH isoforms are widely distributed in the body, with the highest concentrations in the liver and kidney [24]. Various ALDHs are considered to have specific biological roles aside from acting as enzymes which eliminate toxic biogenic and xenobiotic aldehydes. For instance, the ALDH1 family plays a vital role in RA signalling, which is essential for embryogenesis and development [25]. ALDH2 takes part in acetaldehyde detoxification and is significantly correlated with alcohol-mediated tumours [26]. ALDH1A1 and ALDH3A1 are lens and corneal crystallins which protect against ultraviolet (UV) radiation-induced damage [27]. ALDH7A1 involves in the pipecolic acid pathway of lysine catabolism, which can regulate osmotic pressure and has been recently implicated in prostate cancer metastasis [28].
ALDHs and cancer ALDHs have been recently regarded as potential novel cancer prognostic markers. Studies on gastric cancer have found that ALDH1A1 overexpression was closely related to poor prognosis in patient subgroups stratified by tumour size, depth invasion and lymph node metastasis. Patients with ALDH1A1 overexpression have poor overall survival and short recurrence-free survival [29], [30]. Similar studies have associated ALDH1-positive tumours with poor clinical prognosis in breast, lung, pancreatic and prostate cancers, as well as in head and neck squamous cell carcinomas [31], [32], [33], [34], [35], [36].