Stem Cell Factor/c-kit Signaling Promotes the Survival, Migration, and Capillary Tube Formation of Human Umbilical Vein Endothelial Cells

Abstract

c-kit receptor tyrosine kinase is a marker of progenitor cells, which differentiate into blood and/or vascular endothelial cells, and has an important role in the amplification/mobilization of progenitor cells. c-kit is expressed in mature endothelial cells, but its role there is unclear. Stem cell factor, a c-kit ligand, dose-dependently promoted survival, migration, and capillary tube formation of human umbilical vein endothelial cells. These effects mimicked those of vascular endothelial growth factor, except that stem cell factor did not sufficiently support proliferation of these cells. After exposing cells to this factor, Akt, Erk1/2, and c-kit were immediately (<5 min) and dose-dependently tyrosinephosphorylated. STI-571, a c-kit inhibitor, dose-dependently attenuated these phosphorylations and inhibited stem cell factor-promoted survival and capillary tube formation over the same dose range. Wortmannin and LY294002, inhibitors of phosphoinositide 3-kinase, and PD98059, an inhibitor of MEK, abrogated survival and capillary tube formation, indicating that Akt and Erk1/2 should promote survival and capillary tube formation of these endothelial cells at a locus downstream to stem cell factor/c-kit signaling. Akt was more strongly phosphorylated, whereas Erk1/2 and p38 were more weakly phosphorylated with stem cell factor than with vascular endothelial growth factor. Phospholipase C␥ was phosphorylated only with the latter, indicating that stem cell factor/c-kit signaling is somewhat different.

The Wilms’ tumour suppressor Wt1 is a major regulator of tumour angiogenesis and progression

“…Activation of c-kit by Wt1 explains the lower c-kit expression in tumours of Wt1 KO animals. c-kit is expressed by human and rodent endothelial cells [36][37][38] , and it has been shown that stem cell factor, a c-kit ligand, stimulated migration and tube formation of human endothelial cells 46 . We demonstrate here that overexpression of c-kit increases migration and tube formation of mouse endothelial cells and partially rescues the disturbed proliferation, migration and tube formation in Wt1 knockdown cells.…”

In vivo efficacy of STI571 in xenografted human small cell lung cancer alone or combined with chemotherapy

“…Particularly, numerous papers have shown that both c-kit and PDGFR were expressed in endothelial cells, as we have observed in our samples of SCLC tumors. [51][52] Langley et al recently showed that STI571 blocked PDGFR signaling of cultured endothelial cells, suggesting that the in vivo antitumor effect of STI571 could be due to an inhibition of tumor angiogenesis. 53 Our results of in vivo combination therapy were in concordance with those reported in Ewing's sarcoma treated by doxorubicin and STI571.…”

Autophagy promotes radiation-induced senescence but inhibits bystander effects in human breast cancer cells

“…Endothelial cells play a major role in angiogenesis, and it has been demonstrated that HUVECs are able to form capillarylike structures and maintain the phenotype of endothelial cells in vivo, including angiogenesis. [29][30][31] To investigate whether CM increased the invasive or migratory ability of endothelial cells, HUVECs were incubated with CM. We found that CM induced the invasion and migration of HUVECs (Fig.…”