Acute Depletion of Endothelial β3-Integrin Transiently Inhibits Tumor Growth and Angiogenesis in Mice
Rationale: The dramatic up-regulation of αvβ3-integrin that occurs in the vasculature during tumor growth has long suggested that the endothelial expression of this molecule is an ideal target for anti-angiogenic therapy to treat cancer. This discovery led to the development of small molecule inhibitors directed against αvβ3-integrin that are currently in clinical trials. In 2002, we reported that β3-integrin knockout mice, surprisingly, exhibit enhanced tumor growth and angiogenesis. However, as β3-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 β3 function.
Objective: To examine the endothelial-specific contribution β3-integrin makes to tumor growth and angiogenesis.
Methods and Results: We have crossed β3-integrin-floxed mice to two endothelial-specific Cre models and examined angiogenic responses in vivo, ex vivo and in vitro. We show that acute depletion of endothelial β3-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 a number of molecular changes, such as reduced levels of FAK expression and a misbalance in FAK phosphorylation, which may lead to a release from the inhibitory effects of decreased endothelial β3-integrin expression.
Conclusions: Our findings imply timing and length of inhibition are critical factors that need to be considered when targeting the endothelial expression of β3-integrin to inhibit tumor growth and angiogenesis.
- Received April 14, 2013.
- Revision received October 4, 2013.
- Accepted October 8, 2013.