Abstract
Deguelin is a nature-derived chemopreventive drug. Endothelial progenitor cells (EPCs) are bone-marrow (BM)-derived key components to induce new blood vessels in early tumorigenesis and metastasis. Here we determined whether deguelin inhibits EPC function in vitro and in vivo at doses not affecting cancer cell apoptosis. Deguelin significantly reduced the number of EPC colony forming units of BM-derived c-kit+/sca-1+ mononuclear cells (MNCs), proliferation, migration, and adhesion to endothelial cell monolayers, and suppressed incorporation of EPC into tube-like vessel networks when co-cultured with endothelial cells. Deguelin caused cell cycle arrest at G1 without induction of apoptosis in EPC. In a mouse tumor xenograft model, tumor growth, lung metastasis and tumor-induced circulating EPCs were supressed by deguelin treatment (2 mg/kg). In mice tranplanted with GFP-expressing BM-MNCs, deguelin reduced the co-localization of CD31 and GFP, suggesting suppression of BM-derived EPC incoporation into tumor vessels. Interestingly, focal adhesion kinase (FAK)-integrin-linked kinase (ILK) activation and actin polymerization were repressed by deguelin. Decreased number of focal adhesions and a depolarized morphology was found in deguelin-treated EPCs. Taken together, our results suggest that the deguelin inhibits tumorigenesis and metastasis via EPC suppression and that suppression of focal adhesion by FAK-integrin-ILK-dependent actin remodeling is a key underlying molecular mechanism.
Highlights
It is clear that tumor blood vessel formation is not due exclusively to sprouting from pre-existing vessels
Evidence indicates that the term endothelial progenitor cells (EPCs), endothelial colony forming cells (ECFCs) and colony forming unit-EC (CFU-EC) are used depending on their current methods of identifying or quantifying the EC lineage potential, and has similar phenotypes or properties that contribute to postnatal vasculogenesis, to the vasculogenesis associated with tumor progression [2, 3]
It suggests that EPCs or ECFCs or colony-forming units (CFUs)-ECs play an essential role in tumor development and metastasis [4, 5] and that these cells be viewed as a potential target in cancer
Summary
It is clear that tumor blood vessel formation is not due exclusively to sprouting from pre-existing vessels. Evidence indicates that the term EPCs, endothelial colony forming cells (ECFCs) and colony forming unit-EC (CFU-EC) are used depending on their current methods of identifying or quantifying the EC lineage potential, and has similar phenotypes or properties that contribute to postnatal vasculogenesis, to the vasculogenesis associated with tumor progression [2, 3]. It suggests that EPCs or ECFCs or CFU-ECs play an essential role in tumor development and metastasis [4, 5] and that these cells be viewed as a potential target in cancer. It is already www.impactjournals.com/oncotarget refined EPC-colony-forming units (CFUs) for their heirachical relationship between primitive small-CFUs and definite large-CFUs in vitro [6] and we adpoted this method and consider these-CFUs as functional EPCs [2, 6, 7]
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