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Ibrahim et al                                                                                                                                                                                        ALDHs and prostate cancer

           CONCLUDING REMARKS                                 DECLARATIONS

           The number of papers that report ALDH expression   Acknowledgments
           in the context of cancer is largely attributable to the   We wish to acknowledge Prostate Cancer UK (RIA15-
           use of the Aldefluor assay as a means to identify and   ST2-022 & PhD grant S12-027) for financial support
           isolate subpopulations with particularly stemness   and sponsorship, and Yaqeen Sawalha for producing
           characteristics. However, selected ALDH isoforms   figures for this manuscript.
           are also emerging as critical players in chemo-
           and radioresistance and a signature of tumour      Author’s contributions
           aggressiveness in conjunction with cells capable   Manuscript writting and revision: Ibrahim AIM, Sadiq
           of migration, invasion and metastasis. Still, as is
           clear from this review of ALDH expression and      M, Frame FM, Maitland NJ, Pors K
           function in PCa and other recent reviews [45,46,87,222] ,
           the ever increasing number of publications that    Availability of data and materials
           reveal inconsistent and sometimes contradictory    Not applicable.
           information is not helpful in clarifying ALDHs as
           potential biomarkers of specific cancer types or CSC   Financial support and sponsorship
           population; e.g., many early studies that reported on   None.
           ALDHs, utilised antibodies that only stained for e.g.
           ALDH1 but were not selective for 1A1, 1A2, 1A3,    Conflicts of interest
           1B1, 1L1 or 1L2. Equally the Aldefluor assay is not   The authors declare there are no conflicts of interest.
           isoform-selective and has contributed to inefficient
           validation of these enzymes. Furthermore, previous   Ethical approval and consent to participate
           studies were carried out when the understanding of   Not applicable.
           cancer cell subtypes, and the involvement of TME
           was limited, resulting in incomplete ALDH profiling.   Consent for publication
           Bearing this in mind, currently emerging evidence in   Not applicable.
           PCa suggests the dominant isoforms are ALDH1A1,
           1A2, 1A3, 3A1 and 7A1.  The expression and         Copyright
           function have been demonstrated using a number     © The Author(s) 2018.
           of different 2D and 3D cancer models as well as
           clinical samples. Further investigations of these
           isoforms are required in order to fully validate their   REFERENCES
           potential as biomarkers or targets for therapeutic
           intervention. Such investigations should take better   1.   Ramalingam S, Ramamurthy VP, Njar VC. Dissecting major
           account on our choices of models as argued by         signaling pathways in prostate cancer development and progression:
           Maitland in accompanying review [224]  in this thematic   mechanisms and novel therapeutic targets. J Steroid Biochem Mol
           issue. As discussed in this review, ALDH enzymes   2.   Biol 2017;166:16-27.
                                                                 Loblaw DA, Virgo KS, Nam R, Somerfield MR, Ben-Josef E,
           also play a functional role in CSC populations,       Mendelson DS, Middleton R, Sharp SA, Smith TJ, Talcott J, Taplin
           in the context of the TME. This synergy will be       M, Vogelzang NJ, Wade JL 3rd, Bennett CL, Scher HI. Initial
           important in future studies to dissect whether ALDH   hormonal management of androgen-sensitive metastatic, recurrent,
           expression leads to drug resistance via direct or     or progressive prostate cancer: 2006 update of an American
           indirect mechanisms. Underpinning the role of the RA   Society of Clinical Oncology practice guideline. J Clin Oncol
           signalling pathways, and the glycolytic biochemical   2007;25:1596-605.
           pathways associated with the Warburg effect form   3.   Pienta KJ, Bradley D. Mechanisms underlying the development
           part of both a regulatory network and a vicious cycle   of androgen-independent prostate cancer.  Clin Cancer Res
           of tumour aggressiveness. The TME no doubt plays      2006;12:1665-71.
           a critical role in exerting this selective pressure on   4.   Vermeulen L, Melo FDSE, van der Heijden M, Cameron K, de
           ALDH expression and function, and hence should be     Jong JH, Borovski T, Tuynman JB, Todaro M, Merz C, Rodermond
           more carefully considered in unravelling the cellular   H, Sprick MR, Kemper K, Richel DJ, Stassi G, Medema JP. Wnt
                                                                 activity defines colon cancer stem cells and is regulated by the
           roles for specific ALDH isoforms. In this regard, use   microenvironment. Nat Cell Biol 2010;12:468-76.
           of siRNA, CRISPR and the development of highly     5.   Morrissey C, Vessella RL. The role of tumor microenvironment in
           specific small molecules to probe ALDH function will   prostate cancer bone metastasis. J Cell Biochem 2007;101:873-86.
           enable us more quickly ascertain the importance of   6.   Barron DA, Rowley DR. The reactive stroma microenvironment and
           specific ALDHs.                                       prostate cancer progression. Endocr Relat Cancer 2012;19:R187-

             10                                                                     Journal of Cancer Metastasis and Treatment ¦ Volume 4 ¦ Aug 21, 2018
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