| Co-Investigator(Kenkyū-buntansha) |
KITAMURA Shinji Osaka University Hospital, Medical Staff, 医学部・附属病院, 医員
KIYOHARA Tatsuya Osaka University, Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (50322178)
MIYAZAKI Yoshiji Osaka University, Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (30303960)
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| Research Abstract |
A large proportion of gastrointestinal mesenchymal tumors, which do not show typical features of smooth muscle cells or Shwann cells, are presently designated as gastrointestinal stromal tumor (GIST).
We have found that most of GISTs have mutations in the juxtamembrane domain of c-kit, which cause constitutive activation of c-kit protein without the c-kit ligands. It is known that c-kit is expressed in interstitial cells of Cajal, which are pacemaker cells located in gastrointestinal stroma. We showed that stem cell factor, a ligand of c-kit, was needed for the survival of interstitial cells of Cajal isolated from the mouse intestine. We showed that hyperplasia of interstitial cells of Cajal was present in a case of familiar gastrointestinal stromal tumors associated with germ line mutation of c-kit gene. We established stromal cell lines originating from the small intestine of the mouse. The stromal cells were transfected with normal and mutated c-kit cDNA. In the stromal cells transfected with normal c-kit cDNA, the expression of marker molecules of smooth muscle cells disappeared and the expression of marker molecules of interstitial cells of Cajal or GISTs appeared. In the stromal cells transfected with mutated c-kit cDNA, proliferation increased and apoptosis decreased. These results suggest that gain-of-function mutations of c-kit gene play an important role for the genesis of GISTs from gastrointestinal stromal cells.
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