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Introduction
The Wnt signaling pathway plays an important role in embryonic development, carcinogenesis, and neurodegenerative
disease. Human cancer is the most extensively studied disease related to dysregulation of Wnt signaling. In recent years,
aberrant activation of the Wnt signaling pathway has been well documented in various human cancers including colorectal
cancer [1], melanoma [2], non-small cell lung cancer (NSCLC)
[3], leukemia [4], and mesothelioma
[5]. Wnt signaling consists of canonical and non-canonical pathways. In the canonical Wnt signaling
pathway, β-catenin is a key mediator. In the resting
state (Figure 1), no Wnt ligand binds to the frizzled/low density lipoprotein receptor-related protein
(LRP) receptor complex. Thus, cytosolic β-catenin is recruited to a multi-protein "destruction
complex" consisting of adenomatous polyposis coli
(APC), Axin, and glycogen synthase kinase-3β
(GSK-3β) [6_9]. β-catenin is phosphorylated by
GSK-3β and subsequently targeted for degradation via the ubiquitin proteosome
pathway [10_12]. In the activated state (Figure 2), Wnt protein binds
to the Frizzled/LRP receptor complex and transduces a
signal to Dishevelled (Dvl) [13_15]. Increased activity of Dvl
alters the composition of the "destruction complex," and the
degradation of β-catenin is inhibited.
Consequently, β-catenin accumulates in the cytoplasm and subsequently translocates
to the nucleus. In the nucleus, β-catenin interacts with T-cell
factor/lymphoid enhancer factor (TCF/LEF) transcription
factors and turns on the TCF target
genes[16,17]. In the non-canonical Wnt pathway, however,
β-catenin is dispensable. This pathway is not as well defined as the canonical Wnt
pathway but is interesting to many researchers as well. The
non-canonical pathway may proceed through calcium flux,
G proteins, and JNK [18].
For a long time, constitutive activation of the Wnt
pathway was thought to result from gain-of-function mutations
in CTNNB1/β-catenin or loss-of-function mutations in
tumor suppressor genes, for example APC and AXIN1.
However, recent studies have shown that expression of
secreted Wnt antagonist genes is silenced due to promoter
hypermethylation in
carcinogenesis[19_22]. These studies
imply that silencing of Wnt antagonists stimulates Wnt
signaling at the cell surface level and acts as a tumor suppressor.
Wnt antagonists can be divided into 2 classes based on
their mechanisms of action. The first class includes the
secreted frizzled related proteins (sFRPs) family, Wnt
inhibitory factor (WIF)-1, and
Cerberus[23]. This class of Wnt
antagonists binds to Wnt proteins directly and possibly
blocks all Wnt signaling pathways. The second class
consists of members of the Dickkopfs (Dkks) family that bind to
Wnt co-receptors and are thought to inhibit only the
canonical β-catenin pathway [23]. In this review, we focus on the
sFRP family, and discuss the evidence linking its
dysfunction to cancer.
sFRPs family
sFRPs contain a frizzled (FRZ) -type cysteine-rich
domain (CRD) that has Wnt-binding
properties[24,25]. There are 5 sFRPs existing in mammals. They were simultaneously
discovered and named by different groups but are now
uniformly designated as sFRP1-5. In 1996, sFRP3 was the first
identified member of the sFRP family and was isolated as a
chondrogenic factor in bovine cartilage extracts. It was
originally named Frzb because its N-terminal domain contains a
characteristic CRD that shares homology with the
Drosophila Fz CRD[26]. The CRD in Frzb led to the prediction that
the protein regulates the Wnt signaling pathway. Indeed,
further studies showed that Frzb interacts with Xwnt-8 and
antagonizes Xwnt-8 signaling in Xenopus
embryos[27,28]. Moreover, Frzb was reported to interact with Wnt-1 and
inhibit Wnt-1 induced accumulation of β-catenin in human
embryonic kidney cells[29,30], thereby blocking the Wnt
signaling pathway. Following the discovery of Frzb, 4 members
of the sFRP family including Frzb were identified in a 1997
study that searched expressed sequence tag (EST) databases
for sequences homologous to Fz
receptors[24]. The newly discovered proteins were then named sFRP1-4. sFRP1 and
sFRP4 were first identified in this manner. sFRP3 was found
to be identical to Frzb, and sFRP2 happened to be identical
to a previously cloned but incompletely characterized protein,
SDF5[31]. At the same time, another lab isolated a novel
protein during purification of hepatocyte growth factor/scatter
factor in a conditioned medium from a human embryonic lung
fibroblast line [32]. This protein was called frizzled-related
protein (FRP) and later proved to be identical to sFRP1. Soon
thereafter, 3 members of the sFRP family were isolated in
another study aimed at identifying human genes associated
with apoptosis[33]. These sFRPs were initially named secreted
apoptosis-related proteins (SARP) 1_3, but turned out to be
identical to sFRP2, 1, and 5, respectively. Moreover, sFRP5
was further characterized by Chang et al in 1999 and was
found to act by modulating Wnt signal
transduction[34].
Molecular structure of sFRPs
The CRD of sFRPs is one of the most important
characteristics of the sFRP molecular structure. The CRD includes
10 conserved cysteine residues and some additional
conserved residues. It is located in the N-terminal of the protein
and shares 30%_50% sequence similarity with the CRD
domains of Fz proteins[33]. CRD is not restricted to Fz proteins
and sFRPs. An Ensemble search revealed 46 genes in the
human genome incorporating the CRD domain (InterPro
domain IPR000024) including receptor tyrosine kinase,
receptor tyrosine kinase-like orphan receptor 1 and 2, type XVIII
collagen, serine peptidase, and others. Through their CRD
domain, sFRPs may interact with Wnt ligands, thus
antagonizing Wnt signaling[30]. It is also possible that the CRD of
sFRPs interacts with Fz to form nonfunctional complexes,
thereby interfering with the Wnt signaling
pathway[35]. In addition to CRD, the C-terminal of sFRPs contains a netrin
(NTR) domain, which is defined by 6 cysteine residues and
several conserved segments of hydrophobic residues. The
NTR domain has also been found in tissue inhibitors of
metalloproteases, type I procollagen C-proteinase enhancer
proteins, and complement proteins C3, C4, and
C5[36]. However, the function of the NTR domain in sFRPs is not
yet well defined.
sFRPs suppress tumor growth
Chromosomal deletion and loss of heterozygosity in
cancers Frequent allele loss at chromosomal regions is strong
evidence for the possibility that tumor suppressor genes are
present in these regions. The chromosomal location of sFRP1
at 8p11-12 provided the early prediction that it might be a
tumor suppressor because in various cancers, deletion and
loss of heterozygosity (LOH) are frequently observed in this
region[32,37,38]. Indeed, a study in surgically removed lung
cancer specimens found that 15 of 40 cases (38%) had LOH
in the sFRP1 gene locus[39]. Likewise, the chromosomal
location of SFRP3 at 2q31-33 is also an area often associated
with LOH in lung cancers, colorectal carcinomas, prostate
carcinomas, and
neuroblastomas[28,40,41] . One study in
prostate cancer reported LOH at 2q32-36 in 6 of 14 cases
(42%)[41]. However, 2q32-36 is the chromosomal region that partially
harbors the sFRP3 gene and partially harbors the inhibin
alpha-subunit gene. To our knowledge, there is no evidence
demonstrating that deletion and/or LOH have occurred
precisely within the sFRP3 gene locus.
Transcriptional inactivation of sFRPs in
cancer Transcriptional inactivation of sFRPs has been reported in
various cancers[19,39,42_50]. Epigenetic silencing due to hypermethylation of the promoter region of genes is a common
mechanism for transcriptional inactivation of tumor
suppressor genes in cancer[51,52]. The observation that sFRPs are
transcriptionally inactivated in tumors by hypermethylation
supports the hypothesis that sFRPs are tumor suppressors.
In a genomic screen for genes hypermethylated in colorectal
cancer, 4 genes in the sFRP family (sFRP1, 2, 4 and 5) were
found to be frequently hypermethylated in colorectal cancer
cell lines and in primary colorectal tumor
samples[19]. This hypermethylation is associated with a lack of basal
expression that is restored by a demethylation agent,
5-aza-2'-deoxycytidine. In an analysis of 124 primary colorectal
cancer samples, gene silencing due to hypermethylation was
found in 118 cases (95.1%) for SFRP1, 111 cases (89.5%) for
SFRP2, 73 cases (58.9%) for SFRP5, and to a lesser extent, 36
cases (29.0%) for SFRP4. Subsequent studies from the same
lab further demonstrated that exogenous overexpression of
sFRP1, sFRP2, and sFRP5 attenuated Wnt signaling in
colorectal cancer cells with downstream mutations, as did
overexpression of sFRP4, but to a lesser
degree[20]. Originally, downstream APC or
β-catenin mutations in colorectal cancer were thought to lead to accumulation of free
β-catenin and activation of downstream target genes independent of
upstream signals. However, the high frequency of sFRP
silencing suggests that upstream Wnt signals at the cell
surface level may play important roles in colorectal
tumorigenesis.
Besides colorectal cancer, sFRP epigenetic silencing by
hypermethylation has been reported in several other cancers.
Our lab has demonstrated that sFRP1, 4 and 5 gene
promoters are frequently methylated in more than 80% of malignant
mesothelioma primary tissues, and we have shown that the
restoration of sFRP4 results in growth suppression and
apoptosis in cell lines[44]. In lung cancer, hypermethylation
of sFRP1 was found in 15 of 29 (52%) non-small cell lung
cancer (NSCLC) cell lines, 2 of 25 (8%) small cell lung cancer
(SCLC) cell lines, and 44 of 80 (55%) primary lung
tumors[39]. In other labs, promoter methylation of sFRP1 was detected
in 29% of bladder cancer cases[46]. In ovarian cancer, SFRP1
was found inactivated by promoter methylation in 4 of 13
(13%) ovarian cancer cell lines, and 2 of 17 (12%) primary
ovarian cancers[45]. In esophageal carcinoma and its
precur-sor, Barrett's esophagus, hypermethylation of sFRP1, 4, and
5 was also observed[47,48]. In summary, epigenetic silencing
due to hypermethylation of the promoter regions of sFRP1,
2, 4, and 5 has been found in different cancers, suggesting
tumor suppressor function of these sFRPs.
Downregulation of sFRP3 has been found in malignant
mesothelioma and osteogenic
sarcoma[44,50]. Unlike other sFRPs, sFRP3 does not have CpG-islands in its promoter
region[19]. Therefore, the mechanism underlying
downregulation of sFRP3 remains unclear. sFRP3 was
hypothesized to be a tumor suppressor gene because sFRP3 binds
both Wnt-8 and Wnt-1 and inhibits Wnt signaling in
Xenopus embryos[27,28,53]. Furthermore, the sFRP3 gene is located
at 2q where frequent deletion and LOH are observed in many
cancers, which further evinces sFRP3's role as a tumor
suppressor[28,40,41]. Recently, it was reported that expression of
sFRP3 in human prostate cancer PC-3 cells suppresses
tumor growth and cellular
invasiveness[54]. This result,
together with the loss of sFRP3 expression in mesothelioma
and osteogenic sarcoma, provides strong evidence that
sFRP3 is a tumor suppressor gene.
sFRPs stimulate cell growth
Overexpression of the sFRP genes in cancers sFRP4
overexpression was first reported in the stroma of
endometrial carcinomas and in invasive breast carcinomas by
differential display techniques[55]. Later on, sFRP4 overexpression
was found in primary prostate
carcinomas[56], endometrial stromal
sarcomas[49] and colorectal
carcinomas[57]. The
molecular mechanisms responsible for the overexpression
of sFRP4 and the effect of this overexpression on tumors are
not well studied. However, increased levels of sFRP4 in
tumor samples are evidence against the hypothesis that
sFRP4 functions as a tumor suppressor in these tumor models.
Like sFRP4, sFRP1 overexpression has also been reported in
uterine leiomyomas, where it appears to have stimulated cell
growth[58].
sFRPs promote Wnt signaling In addition to the
observed sFRP overexpression in cancer, there are examples
in both tumor and non-tumor settings where sFRP1 does not
antagonize Wnt signaling, but instead potentiates it. It was
reported that sFRP1 has a biphasic effect on Wnt
signaling [59] in which high concentrations of recombinant sFRP-1 block
Wnt signaling, whereas lower concentrations of sFRP-1
enhance Wnt signaling. sFRP1 was also found highly
upregulated in cultured human periodontal ligament
fibroblasts during ceramide-induced
apoptosis[60]. Moreover,
silencing of sFRP1 by RNA interference in cultured
periodontal ligament fibroblasts increased apoptosis, while
ectopic overexpression of sFRP1 in gingival fibroblasts
decreased cell death[60]. Overall, these studies suggest that
sFRP1 may contribute to stimulating cell growth under
specific circumstances.
Like sFRP1, sFRP2 was also reported to promote cell
growth by enabling MCF-7 breast cells to resist TNF-induced apoptosis[33]. Expression of sFRP2 appears to
increase the intracellular levels of β-catenin, suggesting an
activation of the Wnt signaling pathway. In this work, the
function of sFRP1 was also studied. Unlike the behavior
observed with sFRP2, expression of sFRP1 decreases the
intracellular levels of β-catenin, suggesting an inhibition of
the Wnt signaling pathway[33]. The inconsistent function of
sFRP1 and sFRP2 in different settings complicates our
understanding of their function. Additionally, there is other
evidence indicating that sFRP-2 stimulates cell growth. For
example, in malignant glioma cells, ectopic expression of
sFRP-2 strongly promotes the growth of intracranial glioma
xenografts in nude mice[61]. Also, in canine mammary tumor
samples, sFRP2 was upregulated in tumor tissue compared
to normal tissue. Considered together, these results
suggested that sFRP2 might stimulate cell growth by activating
Wnt signaling.
Conclusions and Perspective
Recent studies have revealed that sFRPs are tumor
suppressor candidates. The expression of sFRPs is frequently
silenced by promoter hypermethylation in a variety of cancers.
Restored expression of sFRPs has been shown to inhibit cell
growth in vitro and tumor growth in
vivo. These lines of evidence suggest anti cancer potential in those compounds
that could reverse promoter hypermethylation. Also,
recombinant sFRP proteins developed to inhibit the activated Wnt
signaling pathway could be potential cancer therapeutics as
well. However, to our knowledge, the development of
therapeutics specifically targeting the aberrant Wnt pathway is
still in the preclinic stage. So far, there are no drug
candidates in clinical trials yet. Moreover, there is increasing
evidence showing that some sFRPs have oncogenic functions.
Under certain circumstances, some sFRPs are overexpressed
in cancer or have cell growth-promoting or anti-apoptotic
effects. The apparently contradictory roles of sFRPs in these
studies might be due to the different Wnt ligands present in
different cells, tissue-specific responses to different stimuli,
biphasic responses to different concentrations of sFRPs,
and the binding affinities and specificities of different sFRPs
for Wnts[23]. Better understanding of the specific
relationship between sFRPs and Wnt signaling will result from
further work _ particularly loss-of-function studies and the
availability of purified recombinant Wnt and sFRP
proteins[23]. We anticipate that within the next few years, further studies
of the roles of sFRPs in cancer will eventually lead to
successful therapeutic development targeting the Wnt
signaling pathway.
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