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Ibrahim et al ALDHs and prostate cancer

Early studies first demonstrated a chemo-resistant to the multidrug resistance (MDR) and enhanced
role for ALDHs in a CPA resistant L1210 leukaemia tumourigenicity of CSCs [214] . Within the proposed
cell line [206] . This study showed that high levels of hypoxic CSC niche, the cells are surrounded
ALDH activity were found in L1210 cells and that by an acidic microenvironment that activates a
treatment with disulfiram (ALDH inhibitor) reversed subset of metastasis promoting proteases such as
the resistance phenotype of the cells to CPA. A MMPs and cathepsins [215] . As a consequence of
subsequent study confirmed the role of ALDH- poor angiogenesis and the inaccessible location,
mediated CPA resistance in medulloblastoma [207] . hypoxic cells are exposed to insufficient drug
Similar studies demonstrated that high ALDH activity concentrations, which promote the survival of a drug-
indicates CPA resistance in cancer and CSCs [208] . resistant sub-population of cells. The lower oxygen
Accordingly, inhibition of ALDH activity can in tension increases resistance to radiotherapy and as
principle serve to sensitise CSCs to drugs such as discussed above, also enriches CSC niche within
CPA [209] . More specifically, ALDH1A1 and ALDH3A1 the TME. Hypoxia-activated prodrugs (HAPs) have
were both shown to inactivate CPA analogues [210,211] . been investigated for several decades and have
shown considerable promise in combination with
The sphere forming cells (a common property of chemotherapy or radiotherapy, but no HAPs have
CSCs), from the sarcoma cell line MG63 were yet been approved for clinical use. Unravelling the
significantly insensitive to doxorubicin and cisplatin PCa microenvironment is likely to offer new insight
treatment compared with monolayer adherent and opportunities to molecularly stratify patients for
counterparts. The sarcosphere cells with high treatment, based on their tumours’ hypoxic signature,
ALDH1 activity were proposed as candidate sarcoma including analysis of enzymes with oxidase and/
SCs, in which efficient drug detoxification is likely to or reductase functionality. Prostate tumours are
have contributed to generation of a chemo-resistant considerably hypoxic as discussed in this thematic
CSC phenotype [191] . Furthermore, high ALDH issue [216] and enzymes such as ALDHs are likely to
expression in CSCs has shown chemo-resistance be expressed differentially within the TME due to
in both breast CSCs [190,212] and head and neck different pressures including hypoxic stress and types
squamous cell carcinoma (HNSCC) SCs [213] , where of cells such as MDR and CSCs.
ALDH expression was associated with high Snail
expression, a marker of EMT. Knockdown of Snail The limited sensitivity of hypoxic tumours to
expression significantly decreased the expression radiotherapy may in part be related to CSCs residing
of ALDH1 whilst blocking the tumorigenic abilities in the hypoxic niche. Primary human PCa samples
of CD44+ CD24- ALDH1+ cells [213] . Although many express both elevated levels of ALDH1A1+ and
chemotherapeutic drugs are less effective in ALDH- hypoxia inducible factor 1 alpha (HIF-1α), which
expressing cancer cells, the underlying mechanisms have been linked to radioresistance [217,218] . A recent
are poorly understood. None of the drugs contain study [219] demonstrated that irradiation enriched
aldehyde functional groups that are direct substrates the CSC population of DU145 and PC-3 cells. The
for biochemical reactions with ALDHs, but esterase irradiated cells were shown to possess elevated
activity has been shown for some of these enzymes, ALDH functional activity as well as DNA damage
which potentially provides an ALDH mediated response activity, and in vivo the irradiated ALDH+
resistance mechanism for drugs such as the cells were shown to maintain their tumorigenic
taxanes. Phase 1 metabolism resulting in short lived properties, suggesting these might be radioresistant
aldehydes as illustrated for CPA are direct substrates in vivo. Furthermore, in primary human prostate
for ALDH detoxification, providing a potential tumours, IHC analysis revealed co-localisation of
resistance mechanism in ALDH+ expression cells ALDH1A1 and HIF-1α expression, implying that
including CSC population within the TME [Figure 2]. a subset of ALDH+ cells resides in the hypoxic
Drug resistance can be reversed by co-treatment niche and emphasising the need to target these to
with an ALDH inhibitor such as DEAB. For example, effectively eradicate heterogeneous prostate tumours.
doxorubicin, paclitaxel and radiotherapy resistance in
breast cancer cell lines has been reversed following In other tumours, for example radiation resistant
treatment with DEAB or RA [190] . mesenchymal glioma, the SCs (MGSCs) possess
elevated glycolytic activity and ALDH activity, in
contrast to benign proneural SCs. Expression of
ALDH, HYPOXIA AND TME ALDH1A3 was increased in clinical high-grade
glioma compared with low-grade glioma or normal
Hypoxia is not only a major feature of the tumour brain tissue [220] . Encouragingly, although the MGSCs
microenvironment but is also a potential contributor were very aggressive in vitro and in vivo, the pan-
8 Journal of Cancer Metastasis and Treatment ¦ Volume 4 ¦ Aug 21, 2018