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Ibrahim et al ALDHs and prostate cancer

RA receptors was 47-fold up-regulated in the UGE, activity while the activity could be inhibited with a
as confirmed by qPCR analysis, and may indicate the TGF-β signalling antagonist [88] . Overexpression of the
potential of these cells to differentiate. In the context TGF-β signalling pathway correlates with poor clinical
of PCa, ALDH1A3 might play a significant role in outcomes in PCa. TGF-β promotes tumour progression
the CSC niche of the TME, thereby contributing to a by stimulating the metastasis and angiogenesis [180] .
survival mechanism.
As with many other studies, investigation of ALDH+
THE CSC NICHE, SIGNALLING PATHWAYS cells isolated from both PCa cell lines and primary
AND POTENTIAL FOR THERAPEUTIC cells have shown self-renewal, colony forming capacity
and tumourigenicity. ALDH expression correlated
INTERVENTION with CD44 and α2β1-integrin expression as well as
phosphorylation of the transcription factor STAT3.
Cancer cells acquire a more invasive and migratory Galiellalactone, a potent and specific inhibitor of
phenotype through EMT [165-168] . Cell adhesion is STAT3 signalling, reduced ALDH1A1 expression and
reduced in early metastatic PCa by downregulation subpopulation of ALDH+ cells following treatment of
of expression of E-cadherin and β-catenin DU145 PCa xenografts. This study highlighted the role
(characteristically expressed in normal epithelial of the STAT3 signalling pathway in putative prostate
cells) [169] . In contrast, the expression of N-cadherin CSCs and further supports STAT3 as a potential
(characteristically expressed in mesenchymal cells) therapeutic target [181] . In a separate study using
is upregulated [170] . In clinical specimens there is primary tumour cells, STAT3 inhibition resulted in both
lower E-cadherin and β-catenin expression and cell death and CSC differentiation, resulting in a loss of
higher N-cadherin expression in higher grade PCa both colony forming and tumour initiating capacity [182] .
compared to lower grade PCa [171-174] . However
restoration of elevated E-cadherin expression and ALDH ASSOCIATED DRUG RESISTANCE IN
β-catenin was seen in metastatic cells deposited in
the bone [175] , implicating expression control rather THE TME
than total E-cadherin gene loss.
A number of studies have linked ALDH expression
The Wnt/β-catenin signalling pathway plays a with chemotherapy resistance, although the
significant role in maintaining the stemness of underlying mechanisms are not well understood.
PCa [176,177] . In radioresistant ALDH+ (identified by Whilst chemotherapy reduces the bulk of a tumour,
Aldefluor assay) prostate progenitor cells, activation it also enriches the previously described CSC
of EMT and the Wnt/β-catenin signalling pathways population [183-185] which are not susceptible to
has been demonstrated. In this study, ALDH1A1 anti-mitotic drugs currently approved for clinical
gene expression was regulated by the Wnt signalling use. Although evidence is not available in PCa,
pathway and correlated with simultaneous expression CSCs have been shown to be highly resistant to
of β-catenin in whole prostate tumour specimens [178] . both radiotherapy and chemotherapies including
Encouragingly, inhibition of the Wnt pathway (by temozolomide, gemcitabine, etoposide, carboplatin,
siRNA knockdown or the tankyrase inhibitor XAV939) paclitaxel, fluorouracil, mitoxantrone, daunorubicin
resulted in reduced ALDH+ tumour progenitor and cyclophosphamide (CPA) [186-200] , contributing to
population and radio-sensitisation of cancer cells [178] . tumour recurrence and metastasis. There are several
The link between ALDH1A1 and β-catenin has also possible mechanisms for CSC resistance to cancer
been demonstrated using spheroidal aggregates therapy. Firstly, CSCs are slow-proliferating cells
in a xenograft model comprised of ovarian cancer in a quiescent state and thus resist drugs primarily
cells with stem cell characteristics [179] . In this designed to target rapidly dividing cells [201] . Secondly,
study, β-catenin knockdown decreased ALDH1A1 CSCs resist irradiation because of increased
expression, which subsequently led to inhibition of activation of the DNA damage checkpoint response,
tumour growth and metastasis. as exemplified in a recent study of glioblastoma
CSCs [202] . Thirdly, increased expression of ABC
As described above, ALDH7A1 is highly expressed transporters protects CSCs from high concentrations
in primary PCa tissue [15,88] . ALDH7A1 knockdown of drugs [203] , as demonstrated by removal of Hoechst
decreased the stem/progenitor cell subpopulation in stain in analysis of side populations [204,205] . Lastly, high
the human PCa cells and tumour migration ability in ALDH expression is likely linked to metabolic and
vitro [88] . The activity was correlated with increased detoxifying mechanisms, supporting a role as chemo-
TGF-β signalling, which strongly induced ALDH7A1 protecting enzymes [201] .

Journal of Cancer Metastasis and Treatment ¦ Volume 4 ¦ Aug 21, 2018 7