S100A4 as a Potential Target - Therapeutic Strategies in Cancer Biology and Pathology - page 57

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S100A4 as a Potential Target

S100A4 is a member of the S100 family of calcium binding proteins. The 1q21 locus
harbours the epidermal differentiation complex (EDC) encompassing a 2.05 Mbp of
human genomic DNA. The S100 family genes except the S100beta are arranged in the
following order: 1 cen-S100A10-S100A11-THH (trychohyalin)-FLG (profilaggrin)-
IVL (involucrin)-LOR (loricrin)-S100A9-S100A12-S100A8-S100A7-S100A6-S100A5-
S100A4-S100A3-S100A2-S100A13-S100A1-1qtel.S100beta is located on 21q22.3
(Schäfer et al., 1995; Marenholz et al., 1996; Mischke et al., 1996).

The Spectrum of Biological Function of S100A4

S100A4 signalling can focus on factors associated with normal and aberrant pro-
liferation, apoptosis and growth, and differentiation. It is able to activate signalling
pathways leading to the remodelling of the cell membrane and the extracellular
matrix, modulation of cytoskeletal dynamics, acquisition of invasiveness and induc-
tion of angiogenesis. Thus S100A4 protein can promote metastasis. This has been
confirmed by gene transfer studies. Its expression strongly correlates with tumour
spread to lymph nodes and with prognosis. Significantly, S100A4 appears to act as a
counter point to metastasis suppressor nm23. The routes of signalling by S100A4 are
listed in Table 9.1 . S100A4 is arguably a molecular target of considerable potential
possessing a wide ranging biological activity that can alter and regulate the major
phenotypic features of cancer (Sherbet, 2009, 2011b).
The ideal therapeutic strategy would involve the identification of targets most
likely to be effective in the disease process with minimum side effects. The ability
of S100A4 to activate interacting and multi-functional signalling systems and induce
several biological activities highly relevant in the context of cancer would make it
an eminently valuable chemotherapeutic target. Some downstream effectors of the
S100A4 pathways might also lend themselves as targets of interest. It is now an
indisputable fact that S100A4 signalling is deregulated under certain circumstances
and that this leads to abnormal cell behaviour ( Table 9.1 ).

Influence of Wnt Signalling on S100A4 Expression

Despite the recognition of the wide ranging function of S100S4, there has been lit-
tle notable effort towards comprehending, let alone accepting, the potential value of
targeting S100A4 for therapy. Admittedly hitherto efforts have been concentrated on