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Ibrahim et al ALDHs and prostate cancer

their corresponding acids. This catalytic oxidation is (EMT) and other signalling pathways within the TME
a fine-tuned reaction evolved to protect cells from support progression of the disease. Stromal cells
the harmful effects of highly reactive aldehydes and such as fibroblasts and myofibroblasts are involved in
maintains cellular homeostasis [24,25,31] . Vital functions hormone signalling, contributing to stromal-epithelial
include protection of cells from oxidative stress (e.g., interactions in the primary tumour setting [56-58] .
reactive oxygen species, ROS) and promotion of For example both stromal and epithelial ALDH1
retinoic acid (RA) metabolism and signalling [32] . expression, measured using IHC, have been shown
to be a potential biomarker for breast cancer [59] . The
Mutations and polymorphisms in ALDH genes epithelial and stromal ALDH1 expression (detected in
lead to a loss-of-function that are associated with 43% and 69% of benign breast biopsies, respectively)
various human pathologies [33-39] , which supports their was associated with a predicted increase in the risk
important biological function. Plentiful studies have of breast cancer. However, as with many earlier
described the expression of ALDHs in human tissues, studies [45] on profiling ALDHs in clinical specimens,
however their expression profile and functional no information is available to ascertain which ALDH
activity is poorly understood within the TME. As a was overexpressed from the subfamily (ALDH1A1,
consequence of high and abundant expression, 1A2, 1A3, 1B1, 1L1, 1L2).
ALDHs have been considered to be biomarkers of
specific tumour types [40-45] . Human ALDHs are among In PCa, several ALDH isoforms (1A1, 1A3, 3A1, 3A2,
the regulatory proteins that catalyse the retinoic acid 4A1, 7A1, 9A1 and 18A1) have been found to be
(RA) pathway, which has been linked with “stemness” overexpressed [15,60-68] , but only a few isoforms appear
characteristics [45] . The ALDH1A subfamily members to play critical roles in PCa. In a recent proteomic
have also been identified in a wide-range of human study [69] , ALDH1A3 expression was in part controlled
CSCs, and their expression has been associated with via miR-187, as downregulation of this microRNA
poor prognosis in patients with several cancer types led to induction of ALDH1A3, while re-introduction
including PCa [46-54] . decreased ALDH1A3 expression in PC-3, DU145
and LNCAP prostate cancer cells. Some ALDHs
ALDH EXPRESSION AND REGULATION IN may also contribute to regulation of AR pathways,
with implications for normal prostate development,
PROSTATE CANCER prostate carcinogenesis and progression to
androgen-independent disease [70-73] . AR is expressed
The rate and frequency of PCa progression varies in almost all primary PCas [74-76] and the transition
considerably between individuals, ranging from from a localised hormone-naïve to a castration-
relatively slow (indolent, non-invasive) in some resistant phenotype is based on a complex interplay
patients whilst in other cases the disease is more of signalling molecules attributed to aberrant AR
aggressive and results in rapid metastasis [55] . At signalling [73,77-79] . Raised PSA suggests that AR
present, PCa is diagnosed at first by monitoring function is still active but abnormal in CRPC [80] , due
levels of serum prostate-specific antigen (PSA) and to a number of different mechanisms including AR
digital rectal examination [55] . However there is a amplification [81] , AR gain-of-function mutations [82] ,
substantial overlap in PSA levels between patients intracrine androgen production [83] , elevated levels of
with benign prostatic hyperplasia (BPH) and patients AR cofactor that sensitises cancer cells to low levels
with PCa [55] . About 25% of cases with PCa display of androgens [84] , ligand-independent activation of AR
no increase in serum PSA levels and thus must be by growth factors and cytokines [85] and constitutively
detected by other methods [55] , such as diagnostic active messenger ribonucleic acid (mRNA) spliced
needle biopsies and MRI scans. Furthermore, it is variants of AR [86] . Consequently, AR remains a critical
crucial to determine indolent from aggressive forms factor in the progression of early-stage PCa to CRPC.
of PCa, to offer patients earlier diagnosis and better
treatment options. This is neither currently possible ALDH1A3 is androgen responsive in human epithelial
nor routine. In this regard, more detailed, in-depth LNCaP cells since its expression was 4-fold higher
understanding of the correlation between ALDHs and after treatment with dihydrotestosterone (DHT),
PCa progression may provide alternative biomarkers which indirectly affects both AR regulation and cell
for disease diagnosis and treatment. differentiation [59] . ALDH1A3 has also been correlated
with AR signalling pathway in primary PCa tissue
As indicated above, a complex interplay of PCa where expression was consistent with luminal layer
with the surrounding stroma, androgen receptor localisation [65] . Significantly, the study also showed
(AR) signalling, epithelial-to-mesenchymal transition that knockdown of ALDH1A3 led to substantial

Journal of Cancer Metastasis and Treatment ¦ Volume 4 ¦ Aug 21, 2018 3