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and silencing of SFRP2 occurs before the carcinomatous foci appear. Rawson et al.
(2011) have confirmed SFRP silencing by methylation in colon carcinomas. They
also noted Dkk1 suppression in a much smaller proportion of patients. The SFRP1
methylation status inversely related to MSI (microsatellite instability), but Dkk1
methylation was found in tumours with MSI. Although conceptually there is a causal
relationship between methylation and MSI statuses, the significance of this differ-
ence needs further elucidation, since less than 20% of colon cancers show MSI.
At the phenotypic levels, SFRPs have been implicated in angiogenesis. SFRP2 is
expressed in the microvasculature associated with breast cancers and has demon-
strable angiogenic properties
in vitro
(Bhati et al., 2008; Courtwright et al., 2009).
SFRP2 induces endothelial cell migration and tube formation
in vitro
. The Ca
2+
-
regulated transcription factor NFAT (nuclear factor of activated T cells) seems to
control gene expression required for SFRP2 stimulated angiogenesis (Courtwright
et al., 2009). In contrast, SFRP4 has been found to inhibit endothelial cell migra-
tion and the development of endothelial sprouts
in vitro
. It is also able to block the
effects of VEGF. There was also inhibition of tumour growth of xenografted SKOV-3
cells implanted subcutaneously into BALB/c nude mice (Muley et al., 2010).
Unfortunately vascular density associated with tumours was not been determined.
Previously He et al. (2005) reported silencing of SFRP4 gene in mesothelioma cells.
Indeed some tumours show uniform methylation of SFRPs. Some native molecules
possessing Fzd motifs actively inhibit Wnt signalling. Lavergne et al. (2011) have
described such a molecule which they call V3Nter. The latter is an SFRP-like mol-
ecule that seems to inhibit canonical Wnt/β-catenin signalling and the β-catenin
responsive genes. V3Nter inhibits cell proliferation
in vitro
as well as
in vivo
tumour
growth.
A secreted protein called the Tsukushi (TSK) protein binds to the cysteine-rich
domain and serves as a competitive inhibitor of Wnt ligands (Ohta et al., 2011).
While most of these studied focus on Wnt signalling, other pathways of signalling
might be involved in some of the phenotypic effects such as migration. SFRP1 seems
able to activate ERK mediated increase of MMPs (Foronjy et al., 2010) that could
be conducive to significant changes in cell behaviour. Equally downregulation of
SFRP1 may promote Wnt mediated activation of EMT or by TGF-β mediation as
suggested by Gauger et al. (2011).
Fzd and DVL Interaction
Another site of intervention is the Fzd-DVL binding. This interaction occurs via the
PDZ domains of DVL. PDZ domains are protein-protein recognition and interaction
modules. The nomenclature PDZ is derived from three protein (PSD-95 a synaptic
signalling protein, DLG the Drosophila melanogaster Discs Large protein, and the
zonula occludens 1 protein ZO-1) (Harris and Lim, 2001). PDZ domains occur in
many signalling proteins and participate in the assembly of signalling complexes.
They can recognise specific C-terminal as well as internal sequences that resemble a
terminal sequence.
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