NMR IMAGING OF TUMOR ANGIOGENESIS by Jo 1 lle

Cancer remains a major medical problem accounting for over 500,000 deaths in the US annually. A common feature of most human tumors is their ability to induce the proliferation of new blood vessels, i.e. angiogenesis. Considerable evidence now exists which demonstrates that these tumor vessels are associated with a distinct range of morphological and physiological properties which are not present in normal tissue vasculature. Several studies now document that in a wide variety of tumor models, average tumor vessels have diameters two times those of normal tissue vessels. NMR techniques based on magnetic susceptibility mechanisms are sensitive to varying sizes of blood vessels. By using gradient echo (GE) and spin echo (SE) pulse sequences and different concentrations of an exogenous contrast agent, it is possible to determine the signal contribution from small versus large vessels by examining the change in T2 and T2* rates (AR2 and AR2*), i.e. the ratio of AR2* to AR2 increases with vessel size. This ratio provides an index for the average size of vessels within a voxel. The central goal of this research was to utilize such a tool in order to obtain a regional picture of the tumor vascular bed. Rats, inoculated with C6 glial cells, underwent an MR imaging series nineteeti days after implantation, which comprised conventional SE and GE images prior to and foll6wing serial injections of an equilibrium iron oxide contrast agent (MION). Regions within the tumor and in the contralateral normal gray matter were identified. The change in the T2 rate and T2* rate (AR2 and AR2*) were calculated for each region. Since susceptibility contrast mechanisms designed to study the distribution of vessel sizes rely entirely on the compartmentalization of the contrast agent within the vasculature, the first set of experiments was designed to demonstrate the stability of MION to remain within the vasculature, despite the disruption in the blood brain barrier. The second experiments measured AR2 and AR2* as a function of contrast agent concentration and TE. The MR measurements were compared with predicted values of AR2 and AR2* made from histological assessment of vessel sizes and theoretical Monte Carlo simulation results. The steady state measurements of AR2 and AR2* in the first experiments demonstrated that once the maximum contrast agent concentration had been reached, the values of AR2 and AR2* remained stable over 90 minutes, suggesting that MION remains within the vasculature. In the second experiments, significant differences were observed between the tumor and contralateral deep gray matter. Specifically, the ratio of R2*/ R2 was greater in the tumor than the normal brain, by a factor of 1.9 ± 0.2. From histologic sections and numerical simulations, the corresponding ratio was predicted to be 1.9 ± 0.1. These ratios are suggestive of a greater relative density of large vs small vessels. Maps of the ratio AR2*/AR2 were also produced on a pixel by pixel basis. Regions of high intensity on these maps (indicating a higher ratio of AR2*/AR2) corresponded well with the location of the tumor as determined using conventional images. Thesis Supervisor: Dr. Bruce R. Rosen Title: Co-Director, MGH NMR Center Associate Professor, Harvard Medical School Visting Associate Professor, Massachusetts Institute of Technology