Role of human tissue kallikrein in gastrointestinal stromal tumour invasion.
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.
Dominek
P
P
Experimental Cardiovascular Medicine, Bristol Heart Institute, University of Bristol, Level 7, Bristol Royal Infirmary, Upper Maudlin Street, Bristol, UK.
Campagnolo
P
P
H-Zadeh
M
M
Kränkel
N
N
Chilosi
M
M
Sharman
J A
JA
Caporali
A
A
Mangialardi
G
G
Spinetti
G
G
Emanueli
C
C
Pignatelli
M
M
Madeddu
P
P
D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D020840:Tissue Kallikreins / Q000097:blood / Q000378:metabolism / Q000502:physiology*
D020840:Tissue Kallikreins