Expression of stem cell factor (SCF), a KIT ligand, in gastrointestinal stromal tumors (GISTs): a potential marker for tumor proliferation.
Gastrointestinal stromal tumors (GISTs) show a high incidence of gain-of-function mutations of the c-kit gene, which encodes a receptor tyrosine kinase KIT. This mutation is seen independently of metastasis and/or recurrence of tumors; thus, the factors involved in tumor proliferation rate and malignancy are still not known. Some mesenchymal and epithelial tumors have been reported to co-express KIT and its ligand, stem cell factor (SCF), for autonomous proliferation by the autocrine mechanism. The purpose of this study is to clarify whether GIST cells produce SCF, despite mutated KIT with constitutive activation. Immunohistochemically, we examined the co-expression of KIT and SCF in 36 GIST cases. All cases were found to be KIT-positive, and of these, 21 cases, including four recurrent or metastatic GISTs, showed co-expression of SCF. MIB-1 labeling index was significantly higher, and the average tumor size was larger in SCF-positive cases. By confocal microscopy, KIT was expressed on the cellular membrane, around which SCF was distributed less densely. Western blot analysis revealed that the membrane-bound SCF of 31 kDa was found to be approximately 10 times more abundant than the soluble SCF of 18.5 kDa, suggesting continuous KIT activation. These results indicate that proliferation of GIST cells can be caused not only by the gain-of-function mutation of c-kit, but also by the autocrine mechanism of the SCF/KIT system. Thus, SCF expression would be a useful marker for tumor proliferation.
Hirano
Kazuhiko
K
Department of Pathology, Kyorin University School of Medicine, Mitaka, Tokyo, Japan.
Shishido-Hara
Yukiko
Y
Kitazawa
Akiko
A
Kojima
Kaoruko
K
Sumiishi
Ayumi
A
Umino
Michiru
M
Kikuchi
Fumihito
F
Sakamoto
Atsuhiko
A
Fujioka
Yasunori
Y
Kamma
Hiroshi
H
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis*; D015153:Blotting, Western; D049109:Cell Proliferation; D005260:Female; D005455:Fluorescent Antibody Technique; D046152:Gastrointestinal Stromal Tumors / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D018613:Microscopy, Confocal; D008875:Middle Aged; D019009:Proto-Oncogene Proteins c-kit / Q000096:biosynthesis*; D019089:Stem Cell Factor / Q000096:biosynthesis*
D014408:Biomarkers, Tumor; D019089:Stem Cell Factor; D019009:Proto-Oncogene Proteins c-kit