The biologic basis of in vivo angiogenesis imaging

Knowledge of the different physiology and endothelial markers present in tumor vessels is essential to enable both the development of new anti-angiogenic chemotherapeutic agents and of more specific imaging techniques. Tumor blood vessels are disorganized, irregular in caliber, tortuous, and do not have specialized features of normal arterioles, capillaries or venules. Neo-angiogenic tumor vessels have large gaps between or through cells, loose pericytes, and discontinuities or redundant layers within the basement membrane, rendering these vessels hyper-permeable. Furthermore, the endothelia of tumor vessels may express unique markers on their surface. Imaging is becoming increasingly important in the evaluation of angiogenesis. Clinical imaging is minimally invasive and enables sampling of the whole tumor in a nondestructive manner. The patterns of increased permeability seen on Dynamic contrast-enhanced Magnetic Resonance Imaging (DCE-MRI) mirror the known ultrastructural defects associated with angiogenic vessels. Conventional low-molecular weight contrast agents are currently in clinical use for DCE-MRI studies and have proven successful in detecting changes related to novel angiogenic inhibitors. However, they are relatively non-specific. Macromolecular contrast media may be more suitable for imaging tumor vessels. It is hoped that imaging modalities can be adapted to specifically target markers expressed on the endothelium of tumor vessels. The number of cell surface markers of angiogenesis is relatively low, and only small amounts of contrast agents can bind to these receptors; currently only Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT) tracers have sufficient sensitivity to allow detection at this low level. Despite limitations in their spatial resolution, PET and SPECT imaging are more likely to enter the clinic as targeted angiogenesis imaging methods. The quest for selective targets on the tumor vasculature continues, currently the integrin family of receptors offer the most promise but other targets are being pursued by investigators. Serial analysis of gene expression or in vivo phage display may help identify new, more selective, markers that can be utilized for the targeted imaging and treatment of angiogenesis.