Abstract
In b3-floxed/Pdgfb.Creert2 positive mice treated with tamoxifen, allograft tumours grow significantly smaller when compared to their growth in Cre negative littermate controls. This correlates with decreased microvascular density observed in Cre-postive compared to Cre-negative tumour sections. In contrast, constitutive deletion of endothelial b3-integrin via Tie1.Cre leads to enhanced tumour angiogenesis. These findings are re-capitulated in the aortic ring model. VEGF-induced microvessel sprouting is inhibited in b3-floxed/Pdgfb.Creert2 positive mice compared to Cre-negative littermates. In marked contrast, sprouting is enhanced in b3-floxed/Tie1.Cre positive mice compared to b3-floxed/Tie1.Cre negative mice. Conclusions These findings strengthen the argument that endothelially-expressed b3-integrin remains a valid target of antiangiogenic tumour therapy. However, taken together, these data suggest that the timing and length of exposure to b3-integrin endothelial genetic inhibition impacts on the angiogenic response. These data highlight the need to enhance our understanding of the molecular basis of angiogenesis in order to develop improved therapeutic treatments.
Highlights
Angiogenesis, the formation of new vessels from pre-existing ones, is essential for tumour growth and metastasis
Endothelial cells play a central role in this process: they drive blood vessel formation in response to signals from the local environment, by a mechanism that is integrindependent
We are interested in understanding what role avb3-integrin plays in governing tumour angiogenesis
Summary
Angiogenesis, the formation of new vessels from pre-existing ones, is essential for tumour growth and metastasis. Endothelial cells play a central role in this process: they drive blood vessel formation in response to signals from the local environment, by a mechanism that is integrindependent. We are interested in understanding what role avb3-integrin plays in governing tumour angiogenesis. Anti-angiogenic therapy targeting avb3-integrin has proven somewhat disappointing. In part this likely relates to the fact that avb3-integrin is not expressed solely by endothelial cells, but across a wide range of cell types that each contribute to angiogenesis. The aim of the research we present here is to elucidate the role of avb3-integrin in tumour growth and angiogenesis as it is expressed by endothelial cells
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