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Ibrahim et al ALDHs and prostate cancer

reductions in proliferation rate and the invasive ability ALDH1A3 has been demonstrated to be an androgen
of PC-3 cells. However, the regulation of ALDH1A3 responsive gene [67] whose induction contributes
expression is likely to be multifactorial [87] . to the conversion of retinol to RA with potential for
supporting cellular proliferation [55] . Hypermethylation
Outside the ALDH1 family, strong association of of the ALDH1A3 promoter region in clinical tissues
ALDH3A1 with PCa progression has also been has also been detected [99] , but this study used a
demonstrated in both immortalised cancer cell relatively small sample size (n = 24) and did not
lines and tumour xenografts [61] . In clinical tissues distinguish between methylation of basal and luminal
ALDH3A1 was detected in intra-epithelial neoplasia, PCa cells. Although larger studies are required, it is
with elevated levels in carcinomas in the absence possible that methylation of the promoter regions of
of expression in normal prostate glands. Finally, ALDH1A2 and ALDH1A3 could be used as a marker
in comparison with the paired local carcinomas, for PCa detection [55] .
ALDH3A1 was upregulated in both lymph node
metastatic tumours and was detectable in bone ALDH EXPRESSION IN CSC
metastatic PCa. MICROENVIRONMENT

ALDH7A1, which has also been related to the
stemness of CSCs [88] , is mainly localised in the Growing evidence strongly supports initiation of PCa
[100-105]
cytosol, but it has also been found expressed to a from CSCs residing within a basal niche . In
lesser degree in the mitochondria and nucleus [32,45] . xenotransplantation experiments, less than 100 TICs
In addition to catalysing aldehyde metabolism, are needed to generate a new tumour in mice and
[106]
ALDH7A1 also plays a role in protecting tissues from these cells exhibit a basal phenotype . Furthermore,
the damaging effects of osmotic stress while mutation using human tissue biopsies the prostate SC markers
[89]
of the ALDH7A1 gene has been related to pyridoxine- CD44+, α2β1-integrinhigh and CD133+ have been
dependent epilepsy [90,91] . In cancer, ALDH7A1 is used to identify and isolate prostate CSCs with self-
[100]
expressed in nodular melanoma (NM) [92] , ovarian [93] renewal capacity in vitro . Additionally, there are
and lung cancers [94] while in PCa the isoform has other important markers that have been used to
been shown to be involved in intra-bone growth and identify and isolate PCa SCs. ATP binding cassette
induced bone metastasis [64] as well as zoledronic (ABC) transporters which are proteins that play a
acid resistance [95] . Gene expression profiling vital role in the efflux of drugs have also been used
supports the involvement of ALDH7A1 in multiple to enrich CSCs. However, CD44+, α2β1-integrin high
molecular pathways related to the metastatic process and CD133+ ABC transporters are also expressed
[107,108]
in PCa [96] . in normal SCs which emphasises the need to
employ at least two markers to avoid cross reacting
populations of cells [107] . A growing body of evidence
EVIDENCE FOR EPIGENETIC CONTROL OF suggests that the functional activity of ALDHs can be
ALDHS used to identify and purify CSCs from e.g. breast [109] ,
ovary [110] , lung [111] , colon [112] , pancreas [113] and
PCa can be initiated by genetic or epigenetic prostate cancer [114] . At present it is unclear if ALDH
alterations, including DNA methylation in the expression is significantly different between normal
promoter region of genes, normally linked to SCs and CSCs, hence more research is required to
transcriptional silencing [55] . Epigenetic changes understand if any isoforms could be more predictive
including DNA methylation and histone modifications than e.g. CD44+, α2β1-integrin high and CD133+
of tumour suppressor genes (TSGs) preferentially used as a PCa SC gene-expression signature [115] .
occur in the early stages of cancer progression [55] .
The promoter region of ALDH1A2 in primary ALDHs expressed in SCs are members of the ALDH1
PCa specimens has been shown to be densely family (1A1, 1A2, 1A3, 1L1, 1L2), ALDH2, ALDH3A1,
hypermethylated in comparison to normal prostate ALDH4A1 and ALDH7A1, which have all been linked
tissues [97] . This observation is supported by another with various critical roles including chemo-protection,
study that showed a low/absent expression of DNA damage and regulation of the cell cycle [24] .
ALDH1A2 in PCa in formalin-fixed paraffin embedded The Aldefluor assay has frequently been used to
sections compared to elevated levels of expression identify and isolate CSCs, but as this assay does not
in normal prostate tissue [98] . On this basis it was distinguish between different isoforms many studies
suggested that ALDH1A2 act as a TSG in PCa, suffer from a lack of knowledge of the contributing
and that its epigenetic regulation could differentiate ALDHs to the stemness of the isolated subpopulations
normal prostate cells from malignancy. In contrast, with tumourigenic properties. However, some
4 Journal of Cancer Metastasis and Treatment ¦ Volume 4 ¦ Aug 21, 2018