S100A4 as a Potential Target - Therapeutic Strategies in Cancer Biology and Pathology - page 58

Table 9.l S100A4 Signalling Pathways in Cancer

Phenotypic Feature Signalling Pathway

Cell proliferation,
tumour growth

Binds to and forms complexes with P53, now confirmed as
target of S100A4; stabilises; binds to C-terminal regulatory
region of p53; p53 binding sites occur in S100A4 promoter;
Rb/stathmin/p53 downstream effectors, for example p21 waf ,
p16, etc.; bind to N-terminal domain of mdm2; P53/stathmin/
microtubule dynamics/cell division; p53, apoptosis family
genes; caspases; calpain/Fas (?)
EGFR expression correlates with S100A4 expression;
postulated interaction with HER2
S100A4 stimulates EGFR/HER2
Signalling; an HER2 response element occurs on human
S100A4 promoter

Invasion, intercellular
adhesion, EMT

Interacts with the TGF-β system via Smad; postulated S100A4
binding to the N-terminal region of Smad3; postulated to lead
to EMT; influenced by Wnt signalling; targeted by β-catenin
Modulation of cytoskeletal dynamics; Cadherin/catenin
complex cytoskeletal linkage; CD44/cytoskeletal linkage
ECM-associated proteolytic enzyme system/ECM remodelling

Tumour
vascularisation

Activation of MMP/TIMP
Activation of angiogenic factors
VEGF/endothelial cell proliferation
MetAP2/p53-mediated inhibition of endothelial cell
proliferation

Source : Based on Sherbet (2009, 2011b).

the biological manifestations and molecular mechanism of S100A4 function. The
patently obvious involvement of S100A4 in EMT has spurred much activity towards
elucidating the influence of Wnt signalling on its expression together with its rela-
tionship to the expression of downstream effectors of Wnt signalling and to that of
standard EMT markers.
It has emerged from early work that S100A4 expression inversely correlated with
E-cadherin in NSCLC specimens. S100A4 was expressed in a majority of speci-
mens and its expression correlated with metastasis to the lymph nodes and with
poor patient survival (Kimura et al., 2000). Transfection of E-cadherin into gallblad-
der carcinoma G-415 cells increased cell adhesion and inhibited motility and cell
proliferation and in vitro . These changes were paralleled by markedly reduced the
expression of S100A4, although comparatively minor increases of c-myc and mem-
brane type 1-MMP also occurred (Kohya et al., 2003). In oral squamous cell car-
cinoma cell lines with different invasive abilities, forced overexpression of S100A4
suppressed the expression of E-cadherin (Moriyama-Kita et al., 2005). High levels
of expression of E-cadherin coupled with S100A4 negative state correlated with
enhanced disease-free survival in melanoma patients (Andersen et al., 2004).