Therapeutic Targeting of TGF-B Signalling - Therapeutic Strategies in Cancer Biology and Pathology - page 46

7

Therapeutic Targeting of
TGF- β Signalling

Morphogenesis, neoplastic transformation and EMT are a phenotypic outcome of
a closely integrated network of growth factor, Wnt and Hh signal transduction. We
have seen how Hh signalling interacts with and interrelates to the Wnt pathway.
TGF-β also can activate Wnt signalling. Arguably TGF-β can do this by means of
the canonical Smad system or indirectly by the Smad/NF-κB route. Hh can function
in concert with growth factors such TGF-β, FGF and together with the trail of tran-
scription factors that can lead to the activation of Hh signalling and activation of the
EMT programme. TGF-β can augment the expression of some miRNAs and perform
a co-operative induction of EMT. Growth factor signalling by the activation of RTKs
can activate Gli and aid transcription of Hh responsive genes. Among key charac-
teristics of EMT are the loss of E-cadherin, acquisition of N-cadherin and vimen-
tin, together with the activation of Wnt/β-catenin, which highlight a major mode of
signalling. Finally, certain tumour promoters have been seen as potential activators
of EMT. This network of signalling with possible cross talk and synergistic as well
additive functioning provides a firm foundation on which to build a multifaceted
therapeutic edifice.
The targeting of TGF-β signalling may be regarded as a potentially rewarding
avenue to approach. Inhibition of canonical Smad signalling also inhibits the Wnt/β-
catenin pathway and in consequence modulates E-cadherin expression, thus provid-
ing a dual route to the inhibition of EMT. It is well known that TGF-β can act as
a tumour suppressor or switch to a promoter mode of function. Therefore detailed
information about the factors involved in the switch over and if this switch operates
at specific time points in tumour progression is crucially important in developing
strategies for therapeutic deployment of TGF-β inhibitors. One can see a spectrum
of effects following upon TGF-β inhibition. Modulation of the microenvironment
including the infiltration of inflammatory cells and fibroblasts into the tumour micro-
environment can quite conceivably modulate the signalling functions of regulatory
ligands such as TGF-β. The derepression of TGF-β induced suppression of immuno-
logical responses is another salient phenomenon. Neutralising TGF-β with antibod-
ies or RTK (receptor tyrosine kinase) inhibitors has led to a remarkable inhibition
of progression of triple negative mouse tumours to the metastatic state (Tan et al.,
2009). In this study by Tan et al. (2009), no effects were seen on cell proliferation
and apoptosis, which might suggest a stage dependent effect of inhibition possibly
reflecting the well-known switching of TGF-β function with disease progression.
The potential involvement of miRNA-128a in the suppression of the Smad signal-
ling pathway would deserve to be mentioned here. Masri et al. (2010) reported that
miRNA-128a bound to the 3′UTR region of the gene encoding the TGF-β RTK