S100A4 as a Potential Target - Therapeutic Strategies in Cancer Biology and Pathology - page 61

Table 9.2 NF- κ B Target Genes Relevant in Cancer Biology

Cellular Feature Activators/Target Genes

Inflammation TNF, interleukins, chemokines

Cell survival, apoptosis Bcl family, 14-3-3σ

Cell proliferation Myc, cyclins, interleukins, PDGF, CSF

Angiogenesis VEGF, NOS,TNF, interleukins

Invasion, motility MMPs, uPA, vimentin

Adhesion phenomena ICAM, VCAM, CD44

ELAM-1

Metastasis S100A4, osteopontin, S100A6, S100P

Source : Collated from Pahl (1999), Nishikori (2005) Sherbet (2001, 2011a,b).

Wnt/ β -catenin

S100A4

Osteopontin

NF- κ B Runx/Cbf

Merlin

OPN receptors

Integrins, CD44

MMP/uPA

RAN GTPase

c-met MMPs NF- κ B
uPA

Cell

Invasion

proliferation Apoptosis

Figure 9.1 Osteopontin intermediary function in promoting cell proliferation and invasion with
potential onward progression of tumours. This figure focuses on how osteopontin co-ordinates
the signalling pathways involving S100A4, Wnt/β-catenin, NF-κB and Merlin in generating the
invasive and metastasising phenotype. This representation is based on references cited in the text.

the same phenotypic outcome. This can occur quite independently of osteopontin.
One would recall here that S100A6 and S100P also are capable of exerting pro-meta-
static effects by activating the NF-κB pathway ( Figure 9.1 ).
The activation of NF-κB can upregulate the expression of MMP and uPA and in
this way promote cell motility. NF-κB can inhibit apoptosis and so promote cell pop-
ulation expansion (Matusan-Ilijas et al., 2011). Equally, osteopontin has been shown
to promote the motility of SMMC-7721 hepatocellular carcinoma cells in vitro . This
occurs via the agency of CD44 v 6. Antibodies against CD44 v 6 inhibited the invasion.
In parallel the osteopontin overexpressing cells also showed enhanced MMP-2 and
uPA levels (Chen et al., 2011c).
Since inhibition of osteopontin is known to be able to inhibit tumour develop-
ment and angiogenesis, inhibition of both might result in synergistic suppression of
tumour progression. A conceivable strategy would be to suppress osteopontin expres-
sion, which is regulated by the transcription factor Runx2 and the co-factor Cbf. Not
only does Cbf expression correlate with cell motility but also that it is a necessary
ingredient of Runx2-mediated induction of osteopontin expression and that of MMPs
and osteocalcin (Mendoza-Villanueva et al., 2010).