Key result
Human tissue kallikrein was detected in 19 of 22 human GIST samples and was demonstrated to participate in tumour invasion and angiogenesis in vitro and in vivo.
Human tissue kallikrein is produced by gastrointestinal stromal tumors and promotes tumor invasion and angiogenesis, highlighting its potential as a therapeutic target.
May support kallikrein as a GIST therapeutic target; leaves open clinical translation from preclinical models.
BACKGROUND: Human tissue kallikrein (hK1) generates vasodilator kinins from kininogen and promotes angiogenesis by kinin-dependent and kinin-independent mechanisms. Here, we investigate the expression and functional relevance of hK1 in human gastrointestinal stromal tumour (GIST). METHODS: Vascularisation and hK1 expression of GIST samples were assessed by immunohistochemistry. In two GIST cell lines, hK1 expression was assessed by PCR, and hK1 protein levels and activity were measured by ELISA and an amidolytic assay, respectively. The effect of hK1 silencing, inhibition or overexpression on GIST cell proliferation, migration and paracrine induction of angiogenesis was studied. Finally, local and systemic levels of hK1 were assessed in mice injected with GIST cells. RESULTS: Human tissue kallikrein was detected in 19 out of 22 human GIST samples. Moreover, GIST cells express and secrete active hK1. Titration of hK1 demonstrated its involvement in GIST invasive behaviour, but not proliferation. Furthermore, hK1 released by GIST cells promoted endothelial cell migration and network formation through kinin-dependent mechanisms. Gastrointestinal stromal tumour implantation in nude mice resulted in local and systemic hK1 expression proportional to tumour dimension. CONCLUSIONS: Human tissue kallikrein is produced and released by GIST and participates in tumour invasion. Further studies are needed to validate hK1 as a diagnostic biomarker and therapeutic target in GIST.
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Dominek et al. (2010) studied Gastrointestinal stromal tumour (GIST) (n=22). Human tissue kallikrein (hK1) expression vs. Normal gastrointestinal tissue / hK1 negative cells was evaluated on hK1 expression in GIST samples and its functional role in tumour invasion. Human tissue kallikrein was detected in 19 of 22 human GIST samples and was demonstrated to participate in tumour invasion and angiogenesis in vitro and in vivo.
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