S100A4 as a Potential Target - Therapeutic Strategies in Cancer Biology and Pathology - page 60

translocation of p65, and expression of NF-κB responsive genes (Jin et al., 2010).
Highly powerful cytotoxicity of Niclosamide on multiple myeloma cells has been
attributed to both NF-κB inhibition and STAT3 signalling (Khanim et al., 2011).
A novel approach has been advocated by the Rudland/Barraclough group which
has shown specific mutations that inhibit self-association of S100A4 markedly
reduce its metastasis promoting effects measured by in vivo metastasis assays and in
vitro motility assays. The mutations reduce self-association and reduce the affinity
of S100A4 to two target proteins, namely p53 and non-muscle myosin heavy chain
isoform A (Ismail et al., 2010). An apparent contradiction might be construed in that
Malashkevich et al. (2010) found that trifluoperazine (TFP) promoted S100A4 oli-
gomerisation and in this way interfered with the interaction of S100A4 with myo-
sin-IIA interaction. Inhibition of S100A4 function occurs at concentrations that
promoted its oligomerisation. But here the disruption of interaction between S100A4
and myosin-IIA seems to be due to the packaging of S100A4/TFP dimers into the
formation of pentameric rings leading to the sequestration of the S100A4 dimers.
Osteopontin an Intermediary Target of S100A4
Many strands of evidence have reflected strongly the possibility of taking advantage of
osteopontin being an intermediary in a S100A4 signalling pathway. Osteopontin was
identified as a metastasis-associated protein some time ago. Oates et al. (1996) demon-
strated quite convincingly that progression of a murine cell line Rama37 to the metastatic
line Ca2-5-LT1 was accompanied by marked expression of osteopontin mRNA. Rama37
with forced expression of osteopontin produced tumours that were capable of metastasis.
An early study of breast cancer has shown expression of osteopontin generally correlated
with poor patient survival. The median survival time of osteopontin negative patients was
>228 months and 68 months of the osteopontin positive group (Rudland et al., 2002).
The prognosis for S100A4+ group was less favourable than for S100A4− group; the
median survival time was >204 months for S100A4− and 186 months for S100A4+
patients over an 18-year follow-up. The detection of both S100A4 and osteopontin
seemed to presage shorter survival time (Rudland et al., 2006), but there is no clear iden-
tification of difference in survival of S100A4+/osteopontin+ and S100A4+/osteopontin−
groups. Recently Lin et al. (2011a) found markedly enhanced expression of osteopontin
in metastasising hepatocellular carcinoma than in non-metastasising tumours.
NF-κB are a family of transcription factors that activate many genes closely con-
cerned with inflammation, cell survival, cell proliferation and apoptosis, angiogene-
sis, cell adhesion, invasion and metastasis ( Table 9.2 ). The association of osteopontin
with several activated NF-κB pathways gives osteopontin a predominant position in
the search for therapeutic intervention in the biology of cancer. Berge et al. (2011)
showed recently that S100A4 induced the expression and secretion of osteopontin
in some osteosarcoma cell lines in an NF-κB-dependent fashion. Inhibition of osteo-
pontin using siRNA at least partially counteracted the effects of S100A4 on uPA and
MMP13, suggesting that osteopontin could be a downstream effector of S100A4.
Equally, one ought to consider that S100A4 can activate NF-κB via the classical