[Frontiers in Bioscience 16, 1574-1588, January 1, 2011]

Targeting the anthrax receptors, TEM-8 and CMG-2, for anti-angiogenic therapy

Lorna M. Cryan, Michael S. Rogers

Vascular Biology Program, Department of Surgery, Children's Hospital Boston, Boston, MA 02115

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Anthrax toxin receptors - TEM-8 and CMG-2
3.1. TEM-8 and CMG-2 in anthrax toxicity
3.2. Diseases linked to TEM-8 and CMG-2 mutations
3.3. TEM-8 and CMG-2 protein structures
3.4. Expression of TEM-8 and CMG-2
4. TEM-8 and CMG-2 expression and function within the vasculature
4.1. Interactions of TEM-8 and CMG-2 with ECM
4.2. Signaling downstream of the anthrax receptors
4.3. TEM-8 and endothelial cell function
4.4. CMG-2 and endothelial cell function
5. TEM-8 as a targeting molecule in cancer
6. Anti-angiogenic and tumoricidal strategies using biological anthrax toxin molecules
6.1. Tumoricidal effects of LeTx
6.2. Anti-angiogenic effects of LeTx
6.3. Anti-angiogenic effects of EdTx
7. Perspective
8. Acknowledgements
9. References

1. ABSTRACT

The anthrax toxin receptors tumor endothelial marker-8 (TEM-8) and capillary morphogenesis gene-2 (CMG-2) are responsible for allowing entry of anthrax toxin into host cells. These receptors were first discovered due to their enhanced expression on endothelial cells undergoing blood vessel growth or angiogenesis in model systems. Inhibition of angiogenesis is an important strategy for current anti-cancer therapies and treatment of retinal diseases. Functional roles for TEM-8 and CMG-2 in angiogenesis have recently emerged. TEM-8 appears to regulate endothelial cell migration and tubule formation whereas a role for CMG-2 in endothelial proliferation has been documented. TEM-8 and CMG-2 bind differentially to extracellular matrix proteins including collagen I, collagen IV and laminin and these properties may be responsible for their apparent roles in regulating endothelial cell behavior during angiogenesis. TEM-8-binding moieties have also been suggested to be useful in selectively targeting anti-angiogenic and anti-tumorigenic therapies to tumor endothelium. Additionally, studies of modified forms of lethal toxin (LeTx) have demonstrated that targeted inhibition of MAPKs within tumor vessels may represent an efficacious anti-angiogenic strategy.