Stem cell factor-mediated wild-type KIT receptor activation is critical for gastrointestinal stromal tumor cell growth.
OBJECTIVE
To clarify the biological role of stem cell factor (SCF)-mediated wild-type KIT receptor activation in gastrointestinal stromal tumor (GIST) growth.


METHODS
The co-expression of wild-type KIT receptor and SCF was evaluated in 51 GIST samples using mutation analysis and immunohistochemistry, and the results were correlated with clinicopathological parameters, including the mitotic count, proliferative index (Ki-67 immunohistochemical staining), mitotic index (phospho-histone H3 immunohistochemical staining) and apoptotic index (terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling). Using primary cultured GIST cells, the effect of SCF-mediated wild-type KIT receptor activation was determined by western blotting, methyl thiazolyl tetrazolium (MTT), and apoptosis assays.


RESULTS
We found that wild-type KIT receptor and SCF protein were expressed in 100% and 76.5% of the 51 GIST samples, respectively, and the co-expression of wild-type KIT receptor and SCF was associated with known indicators of poor prognosis, including larger tumor size (P = 0.0118), higher mitotic count (P = 0.0058), higher proliferative index (P = 0.0012), higher mitotic index (P = 0.0282), lower apoptosis index (P = 0.0484), and increased National Institutes of Health risk level (P = 0.0012). We also found that the introduction of exogenous SCF potently increased KIT kinase activity, stimulated cell proliferation (P < 0.01) and inhibited apoptosis (P < 0.01) induced by serum starvation, while a KIT immunoblocking antibody suppressed proliferation (P = 0.01) and promoted apoptosis (P < 0.01) in cultured GIST cells.


CONCLUSIONS
SCF-mediated wild-type KIT receptor activation plays an important role in GIST cell growth. The inhibition of SCF-mediated wild-type KIT receptor activation may prove to be particularly important for GIST therapy.
Department of Pathology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
Chen-Guang
CG
Bai
Xiao-Wei
XW
Hou
Feng
F
Wang
Cen
C
Qiu
Yan
Y
Zhu
Ling
L
Huang
Jing
J
Zhao
Jing-Jing
JJ
Xu
Da-Lie
DL
Ma
D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D008940:Mitotic Index; D009154:Mutation; D019009:Proto-Oncogene Proteins c-kit / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D019089:Stem Cell Factor / Q000378:metabolism* / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D019089:Stem Cell Factor; D019009:Proto-Oncogene Proteins c-kit