c-Ski, originally identified as a proto-oncogene product, is an important negative regulator of
transforming growth factor (
TGF)-beta family signaling through interaction with Smad2, Smad3, and Smad4. High expression of c-Ski has been found in some
cancers, including
gastric cancer. We previously showed that disruption of
TGF-beta signaling by dominant-negative
TGF-beta type II receptor in a diffuse-type gastric
carcinoma model accelerated
tumor growth through induction of
tumor angiogenesis by decreased expression of the anti-
angiogenic factor thrombospondin (TSP)-1. Here, we examined the function of c-Ski in human diffuse-type gastric
carcinoma OCUM-2MLN cells. Overexpression of c-Ski inhibited
TGF-beta signaling in OCUM-2MLN cells. Interestingly, c-Ski overexpression resulted in extensive acceleration of the growth of subcutaneous xenografts in BALB/c nu/nu female mice (6 weeks of age). Similar to
tumors expressing dominant-negative
TGF-beta type II receptor, histochemical studies revealed less
fibrosis and increased angiogenesis in xenografted
tumors expressing c-Ski compared to control
tumors. Induction of
TSP-1 mRNA by
TGF-beta was attenuated by c-Ski in vitro, and expression of
TSP-1 mRNA was decreased in
tumors expressing c-Ski in vivo. These findings suggest that c-Ski overexpression promotes the growth of diffuse-type gastric
carcinoma through induction of angiogenesis.