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To cite this article: Paola Marcato, Cheryl A. Dean, Carman A. Giacomantonio & Patrick W.K. Lee (2011) Aldehyde
dehydrogenase: Its role as a cancer stem cell marker comes down to the specific isoform, Cell Cycle, 10:9, 1378-1384, DOI:
10.4161/cc.10.9.15486
To link to this article: http://dx.doi.org/10.4161/cc.10.9.15486
review
Aldehyde dehydrogenase
Key words: cancer stem cells, aldehyde dehydrogenase, aldefluor assay, isoforms, prognosis
Abbreviations: ALDH, aldehyde dehydrogenase; CSCs, cancer stem cells; EMT, epithelial mescenchymal transition; TICs, tumor
initiating cells; AML, acute myeloid leukemia; RA, retinoic acid; RAR, retinoic acid receptor; RXR, retinoid x receptor; RAREs,
retinoic acid response elements; DEAB, diethylaminobenzaldehyde; ATRA, all-trans-retinoic acid
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e.and thereby modulates a wide
RAB
induces
gene
transcription
variety of biological processes like cell proliferation, differentiao
no
di
s
t
r
i
b
ut
e
.and apoptosis. As generated by ALDHs,
Using the aldefluor assay, Cheung et al. wereD
the
first
to t
show
tion,
cell
cycle
arrest
ALDH Activity as a Universal CSC Marker
45-49
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the lipophilic RA can function in paracrine or endocrine manner by diffusing into neighbouring cells or the nucleus (Fig. 1).
Once inside the nucleus, RA binds to heterodimers of retinoic
acid receptor (RAR) and retinoid x receptor (RXR). Activated
receptor complexes then bind to retinoic acid response elements
(RAREs), which are regulatory sequences in target genes and
induce transcription. Lists of known RA target genes, including
the HOX and RAR genes, have been compiled.50,51
Retinoic acid production by ALDH can induce differentiation of hematopoietic and neural stem cells.52 Conversely, inhibition of ALDH by diethylaminobenzaldehyde (DEAB) expands
hematopoietic stem cells.53 Based on the ability of retinoic acid
to induce differentiation, all-trans-retinoic acid (ATRA) is used
to treat acute promyelocytic leukemia (APL).54-56 ATRA treatment of APL patients induces differentiation of immature leukemia blasts into terminally differentiated granulocytes, leading
to a clinical remission in approximately 90% of patients. Since
the successful application of ATRA in the treatment of APL,
its effects are being studied in other cancers. In general, ATRA
appears to induce apoptosis and differentiation in a number of
cancers.57-60 Ginestier et al. (2009) recently showed that addition
of ATRA to cultured breast cancer cells induced their differentiation in vitro (evidenced by reduced tumorsphere formation
frequency).44 Conversely, DEAB addition increased their tumorsphere formation frequency. Based on their results, the authors
suggested that ATRA could be a novel breast cancer therapeutic,
by inducing the differentiation of breast CSCs.
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Cancer
Prognostic correlation
Worse outcome/
More aggressive
cancer
*ALDH
Leukemia
ALDH1A1
Bladder
ALDH1A1
Breast
65
No correlation
Publication
Improved outcome/
Less aggressive
cancer
94
216
31
577
14
ALDH1A1
Breast
203
95
ALDH1A1
Breast
381
96
ALDH1A1
Breast
109
ALDH1A1
Breast
639
98
ALDH1A1
Breast
47
36
ALDH1A1
Colon
1420
99
ALDH1A1
Lung
60
ALDH1A1
Ovarian
442
ALDH1A1
Ovarian
439
22
ALDH1A1
Pancreatic
269
27
ALDH1A1
Prostate
40
ALDH1A1
Prostate
163
25
ALDH1A3
Breast
47
36
ALDH2
Breast
47
36
ALDH4A1
Breast
ALDH7A1
Prostate
97
24
X
100
29
47
36
40
29
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Table 2. Summary of immunohistological studies detecting ALDH+ cells in combination with other CSC markers
Prognostic correlation
Cancer
Patient
s ample size
Worse outcome/
More aggressive
cancer
Breast
ALDH1A1+CD44+ cytokeratin+
639
98
Breast
ALDH1A1 CD44
47
36
Breast
ALDH1A3+CD44+
47
36
Breast
ALDH2 CD44
47
36
Breast
ALDH6A1+CD44+
47
36
the use of cell surface markers for CSC identification has met
with varying degrees of success, intracellular ALDH activity is
emerging as an important and reliable universal CSC hallmark
applicable for most cancers. However, while measuring ALDH
activity may be an accepted method for the separation of CSC
and non-CSC populations of may cancers, at the protein level,
the ALDH isoform(s) responsible for ALDH activity is likely different and cancer-specific. Precise identification of active ALDH
isoforms for specific cancers would have major diagnostic and
prognostic implications.
Another unresolved puzzle pertains to the precise role(s) of
ALDH in CSCs. In view of the diversity of ALDHs various functions, particularly that of cellular differentiation control, it seems
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