Approximately 85�C90% of GISTs harbour activating mutations

Approximately 85�C90% of GISTs harbour activating mutations selleck bio for the stem cell factor (SCF) receptor CD117 (c-Kit) or the alpha-type platelet-derived growth factor receptor (PDGFR��) (Heinrich et al, 2000; Hirota et al, 2000), which makes this tumour responsive to the tyrosine kinase inhibitor imatinib mesylate (Demetri et al, 2002). However, the mechanisms involved in the invasive capacity of GIST remain largely unknown. The kallikrein (hK) family has been recognised to have fundamental roles in cancer and vascular biology (Bhoola et al, 2001; Borgono and Diamandis, 2004; Clements et al, 2004; Madeddu et al, 2007). Individual members of the hK family have in the past been identified as biomarkers for cancer, such as prostate cancer-specific marker hK3 (Welch and Albertsen, 2009).

To date, no studies have investigated the involvement of hKs in the growth and development of GIST. Human tissue kallikrein (hK1) has a crucial role in postischaemic neovascularisation (Emanueli et al, 2000, 2001, 2004; Yao et al, 2008; Stone et al, 2009). Furthermore, hK1 has been implicated in the growth and invasiveness of pancreatic carcinoma (Wolf et al, 2001), oesophageal carcinoma (Dlamini et al, 1999; Dlamini and Bhoola, 2005), gastric malignancy (Sawant et al, 2001) and lung cancer (Chee et al, 2008). Although the exact molecular mechanisms by which hK1 promotes tumour growth and invasion have not been determined so far, two principal actions of hK1 may have a role: (1) promoting tumour cell invasion of extracellular matrix by its protease activity, directly or through the activation of metalloproteinases (MMPs) (Tschesche et al, 1989; Desrivieres et al, 1993; Menashi et al, 1994; Leeb-Lundberg et al, 2005; Stone et al, 2009) and (2) activating kinin receptors, either directly (Biyashev et al, 2006) or through the generation of kinins (Madeddu et al, 2007).

Autocrine activation of the kinin B2 receptor (B2R) on tumour cells may promote proliferation and motility, whereas paracrine action could induce endothelial cell (EC) proliferation and migration, thus increasing tumour vascularisation. In this study, we aimed to investigate whether hK1 is expressed and released by GIST and participates in tumour growth and expansion. Materials and methods Immunohistochemistry Formalin-fixed and paraffin-embedded GIST specimens were obtained from the Departments of Pathology of Bristol University (UK) and Verona Anacetrapib University (Italy), with the approval of the local ethics committee.

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