Maspin (SerpinB5): a Postulated Tumour Suppressor - Therapeutic Strategies in Cancer Biology and Pathology - page 111

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Maspin (SerpinB5): a Postulated
Tumour Suppressor

Maspin (SerpinB5) is a serine protease inhibitor, but uncharacteristic of the Serpin
group does not possess serine protease activity. It is putatively regarded as a tumour
suppressor since its expression is downregulated in many tumours. It was recognised
some time ago that the loss of its expression was a result of promoter hypermeth-
ylation of one or both alleles of the gene (Ogasawara et al., 2004; Akiyama et al.,
2003). Epigenetic silencing might involve promoter methylation and hypo-acetyla-
tion of associated histones H3 and H4 and conversely Maspin activation occurs with
promoter demethylation and hyper-acetylation of the histones (Futscher et al., 2002;
Fitzgerald et al., 2003).
Maspin is markedly downregulated in many tumours. An early report on breast
cancers claimed that Maspin expression progressively decreased with breast can-
cer progression from in situ ductal carcinoma to invasive carcinoma and associ-
ated nodal involvement. Loss of Maspin also correlated with reduced disease-free
survival (Maass et al., 2002). Reduced Maspin expression has been recorded in
many tumours and it was related to tumour progression (Zhang and Zhang, 2002).
Consistent with this is the finding that it inhibits angiogenesis. It effectively reduced
microvessel density associated with tumours. In vitro it inhibited migration of
endothelial cells towards bFGF and VEGF and blocked endothelial proliferation and
tubule formation (Nickoloff et al., 2004; Zhang et al., 2000). The RSL (reactive site
loop) is the major determinant of the function of Maspin of influencing cell adhe-
sion, migration and apoptosis.
But suppression of angiogenesis is not believed to be totally dependent upon
RSL. For, mutation of the RSL domain or its deletion does not fully prevent this
inhibition (Zhang et al., 2000). In hindsight one would recall a second domain span-
ning from amino acid 139 to amino acid 225 is able to mediate adhesion (Cella et al.,
2006). Whether this might be important for inhibition of angiogenesis is not known.
The RSL does mediate interaction with β1 integrins of the ECM. The expres-
sion of several β1 integrins is induced by angiogenic agents (see Avraamides et al.,
2008; also see further discussion below). Maspin binds to mammary carcinoma cells
and this is prevented by the RSL peptide, indicating that it participates in ECM-
mediated adhesion of mammary carcinoma and is capable of inhibiting invasion
(Ngamkitidechakul et al., 2003). It would appear that an intact RSL is required only
for the invasion inhibitory but not anti-angiogenesis function.
In a small number of laryngeal carcinomas, nuclear expression of Maspin
directly correlated with longer disease-free interval and good prognosis (Marioni
et al., 2005). It is highly expressed in high grade intraepithelial neoplasia precursors
and subsequently it is downregulated in low grade to high grade prostate cancers.