Abstract:
:The formation of a microvascular endothelium plays a critical role in the growth and metastasis of established tumors. The ability of a fragment from the first type III repeat of fibronectin (III(1C)), anastellin, to suppress tumor growth and metastasis in vivo has been reported to be related to its antiangiogenic properties, however, the mechanism of action of anastellin remains unknown. Utilizing cultures of human dermal microvascular endothelial cells, we provide evidence that anastellin inhibits signaling pathways which regulate the extracellular signal-regulated (ERK) mitogen-activated protein kinase pathway and subsequent expression of cell cycle regulatory proteins. Addition of anastellin to primary microvascular endothelial cells resulted in a complete inhibition of serum-dependent proliferation. Growth inhibition correlated with a decrease in serum-dependent expression of cyclin D1, cyclin A and the cyclin-dependent kinase, cdk4, key regulators of cell cycle progression through G(1) phase. Consistent with a block in G(1)-S transition, anastellin inhibited serum-dependent incorporation of [(3)H]-thymidine into S-phase nuclei. Addition of anastellin to serum-starved microvessel cells resulted in a time-dependent and dose-dependent decrease in basal levels of phosphorylated MEK/ERK and blocked serum-dependent activation of ERK. Adenoviral infection with Ad.DeltaB-Raf:ER, an inducible estrogen receptor-B-Raf fusion protein, restored levels of active ERK in anastellin-treated cells, rescued levels of cyclin D1, cyclin A, and cdk4, and rescued [(3)H]-thymidine incorporation. These data suggest that the antiangiogenic properties of anastellin observed in mouse models of human cancer may be due to its ability to block endothelial cell proliferation by modulating ERK signaling pathways and down-regulating cell cycle regulatory gene expression required for G(1)-S phase progression.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Ambesi A,Klein RM,Pumiglia KM,McKeown-Longo PJsubject
Has Abstractpub_date
2005-01-01 00:00:00pages
148-56issue
1eissn
0008-5472issn
1538-7445pii
65/1/148journal_volume
65pub_type
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