Cancer and Metastasis Reviews 19: 39–43, 2000. © 2000 Kluwer Academic Publishers. Printed in the Netherlands. Preclinical MRI experience in imaging angiogenesis Michal Neeman Department of Biological Regulation, The Weizmann Institute of Science, Rehovot, Israel Key words: angiogenesis, MRI, permeability, in vivo imaging, hypoxia Abstract Magnetic resonance imaging (MRI) provides a range of non-invasive measures for visualization of tumor angiogen- esis in the clinic as well as in experimental tumor models. MRI methods were developed for assessment of spatial and temporal changes in perfusion, blood volume fraction, vascular permeability, vascular function, vascular mat- uration, vessel diameter and tortuosity. Molecular targeted contrast agents were used for mapping specific markers of neovasculature. These approaches were applied for analysis of a number of regulatory mechanisms controlling tumor angiogenesis and for preclinical evaluation of tumor response to antiangiogenic agents. Introduction Angiogenesis provides a critical checkpoint for ini- tiation and progression of malignant tumors [1,2]. The regulation of angiogenesis depends on a balance between proangiogenic and antiangiogenic signals. In tumors, induction of proangiogenic signals can be a result of selection of clones showing constitutive over-expression of an angiogenic growth factor or suppression of endogenous inhibitors of angiogene- sis. Alternatively, tumor angiogenesis can develop in response to the same physiological cues that trigger angiogenesis during development, the female estrous cycle and wound repair (see recent review [3]). In vivo models are essential for the study of angiogenesis, and should be coupled with methods for quantitative mon- itoring of vascular remodeling. The approaches for detection of angiogenesis vary in their invasiveness, information content and adaptability to the various bio- logical models. Histology is by far the lowest cost and most popular and allows mapping of many molecular markers, but is also the most invasive. The loss of tem- poral information is less critical for tightly programmed angiogenesis, as in embryonic development, but is a serious limitation in pathological angiogenesis, which shows large intrinsic spatial and temporal variance. Semi-invasive methods such as intravital microscopy [4] provide high spatial and temporal resolution but very limited flexibility in the biological models, and are complicated by the inevitable background angio- genesis. As will be summarized here, non-invasive monitoring of angiogenesis can be done by magnetic resonance imaging (MRI). The low intrinsic sensitivity of MRI is countered by the non-invasive nature of this methodology, providing full 3D data with similar spa- tial resolution for any location in the body, and the wide range of physiological parameters that can be mapped. These advantages provide for larger freedom in the design of biological models and reduce the problem associated with background angiogenesis. Moreover, MRI methods developed for imaging angiogenesis in experimental models are potentially transferable to the clinic. This commentary will outline examples of pre- clinical and experimental MRI studies of angiogene- sis. The methods described include the use of intrinsic contrast originating from deoxyhemoglobin [5]; sig- nal changes associated with change in oxygenation or response to vasomodulators; steady state approaches to measurement of perfusion by arterial spin label- ing tagging of the NMR signal of water [6,7]; and contrast enhanced approaches for detection of blood volume, vessel diameter, permeability and expression of specific endothelial cell markers. Obviously, angio- genesis cannot be described by a single parameter. MRI provides an arsenal of approaches that can high- light different aspects of the process and can thus