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See detailAcute depletion of endothelial beta3-integrin transiently inhibits tumor growth and angiogenesis in mice.
Steri, Veronica; Ellison, Tim S.; Gontarczyk, Aleksander Maksym et al

in Circulation Research (2014), 114(1), 79-91

RATIONALE: The dramatic upregulation of alphavbeta3-integrin that occurs in the vasculature during tumor growth has long suggested that the endothelial expression of this molecule is an ideal target for ... [more ▼]

RATIONALE: The dramatic upregulation of alphavbeta3-integrin that occurs in the vasculature during tumor growth has long suggested that the endothelial expression of this molecule is an ideal target for antiangiogenic therapy to treat cancer. This discovery led to the development of small-molecule inhibitors directed against alphavbeta3-integrin that are currently in clinical trials. In 2002, we reported that beta3-integrin-knockout mice exhibit enhanced tumor growth and angiogenesis. However, as beta3-integrin is expressed by a wide variety of cells, endothelial cell-specific contributions to tumor angiogenesis are muddied by the use of a global knockout of beta3-integrin function. OBJECTIVE: Our aim was to examine the endothelial-specific contribution beta3-integrin makes to tumor growth and angiogenesis. METHODS AND RESULTS: We have crossed beta3-integrin-floxed (beta3-floxed) mice to 2 endothelial-specific Cre models and examined angiogenic responses in vivo, ex vivo, and in vitro. We show that acute depletion of endothelial beta3-integrin inhibits tumor growth and angiogenesis preventatively, but not in already established tumors. However, the effects are transient, and long-term depletion of the molecule is ineffective. Furthermore, long-term depletion of the molecule correlates with many molecular changes, such as reduced levels of focal adhesion kinase expression and a misbalance in focal adhesion kinase phosphorylation, which may lead to a release from the inhibitory effects of decreased endothelial beta3-integrin expression. CONCLUSIONS: Our findings imply that timing and length of inhibition are critical factors that need to be considered when targeting the endothelial expression of beta3-integrin to inhibit tumor growth and angiogenesis. [less ▲]

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