|Budget Amount *help
¥1,500,000 (Direct Cost : ¥1,500,000)
Fiscal Year 1991 : ¥800,000 (Direct Cost : ¥800,000)
Fiscal Year 1990 : ¥700,000 (Direct Cost : ¥700,000)
Scirrhous carcinoma of the stomach is characterized by extensive fibrosis with sparse tumor cell infiltration in desmoplastic stroma and clinically by the worst prognosis of any type of gastric cancer. The mechanisms of these phenomenon, however, are still not understood. We studied the possible pathogenic role of tumor derived transforming growth factor-beta (TGF-beta)in the progression of fibrosis and invasive capacity of scirrhous carcinoma of the stomach.
Human gastric cancer cell lines investigated showed the activity of TGF-beta in the conditioned medium, measured by the colony formation of NRK fibroblasts on soft agger cultures and radioreceptor assay using ^<125>I-TGF-beta, with the activity being particularly evident in scirrhous type, KATO III cells. The intracellular TGF-beta of this cell line was latent form with 50 KDa corresponded to the precursor form of TGF-beta. KATO III cells also secreted a heat and acid labile proteinase with 70KDa in the conditioned medium, which de
clines-latent TGF-beta to the acitve form. On the other hand, conditioned media from KATO III cells promoted the collagen synthesizing activity of fibroblasts. The increase in the activity was concentration dependent and inhibited by anti-TGF-beta antibody. These results suggest that scirrhous gastric cancer cells produce and secrete a latent form of TGF-beta and its activator simultaneously, and that activated TGF-beta form tumor cells stimulated collagen synthesis in stromal fibroblasts in a paracrine manner.
To examine the relationship between the expression of E-cadherin and invasive capacity of tumor cells in scirrhous gastric carcinoma, KATO III cells was transfected with E cadherin gene pBATEM2 and evaluated its adhesiveness and invasiveness. While KATO III cells were negative stained for E-cadherin by Western blot, KATO III cells trasnfected pBATEM2 were observed 124KDa of E-cadherin and increased intercellular adhesiveness. Further, in vitro invasive capacity of these transfectants was decreasedby invassion assay using double chamber system. These results indicate that depressed expression of E-cadherin on scirrhous gastric cacinoma cells facilitates their liberation from primary site to infiltrate freely into tissue or fluid. Less