Regulation of Breast Tumor Angiogenesis by Interactive FGFR-Notch Signaling

摘要

Jagged-Notch interactions regulate a transmembrane ligand-receptor signaling pathway involved in the regulation of cell fate determination as well as myoblast and endothelial cell differentiation. To further examine the role of the transmembrane ligand, Jagged-1, in the regulation of cell differentiation, we stably transfected NIH 3T3 cells with a truncated form of Jagged(J)-1, which results in the secretion of a soluble(s) form of the protein. Comparison of gene expression by serial analysis demonstrated that among the 227 transcdpts differentially regulated in the sJ-1 transfectants, the expression of the pro- rj-2(l) collagen transcript and pm-%U collagen translation product was predominantly repressed in sJ-1 transfectants. When plated on extracellular matdces, sJ-1 transfectants formed prominent chord-like structures on type I collagen but not on fibrin, fibronectin, or vitronectin. Whlle the sJ-1 transfectants exhibited growth kinetics similar to control cells and were unable to grow in soft agar, the cells were less sensitive to contact inhibition of growth in vitro and sJ- I allografts formed tissue masses in nude mice after a prolonged latency pedod and exhibited an abundance of host-dedved micro vascular endothelial cells. These data suggest that J-1 may be able to modulate, in ability to promote the development of chord4ike structures.