Date of Award
Fall 2001
Document Type
Dissertation - Restricted
Degree Name
Doctor of Philosophy (PhD)
Department
Biomedical Engineering
Abstract
Tumor angiogenesis is the growth of blood vessels from surrounding tissue into a solid tumor caused by the release of chemicals by the tumor cells, a process necessary to sustain the growth and proliferation of the tumor. Thus, the prevention of this growth i.e. antiangiogenesis could be a potentially powerful new anticancer therapy. The principal goal of this research was to determine whether susceptibility contrast (SC) MR methods could provide accurate and sensitive measurements of angiogenic growth in vivo. Recent evidence suggests that in contrast to the prevailing view that most tumors began as avascular masses, some initially grow by co-opting existing host vessels. This co-opted vasculature does not immediately undergo angiogenesis but instead initially regresses and is then followed by angiogenesis, which suggests that correlation with microvessel density (MVD) - a traditional marker for angiogenesis, is tumor stage dependent. Since only a limited fraction of the tumor is sampled for diagnosis and it is not clinically feasible to regularly obtain MVD samples invasively from the patient, to obtain more specific information about the tumor vasculature it may be better to measure blood volume (BV) using MRI. The rationale for this is: (i) with MRI we measure the fractional BV within each voxel and not the MVD. This BV takes into account both vessel diameter and density, which is especially important since the diameter of tumor capillaries can be 3-4 times that of normal capillaries; (ii) MRI is non-invasive, and (iii) the potential sensitivity of SC MRI to various aspects of vasculature could make it a unique tool for assessing the vascular remodeling that accompanies angiogenesis. Use of SC MRI requires an understanding of the biophysical relationship between the MR parameters being measured and the underlying microvascular parameters being characterized, for both normal and tumor tissue. This was accomplished as follows: (i) MR studies were conducted to determine whether the gradient-echo (GE) and spin-echo (SE) susceptibility calibration factors remained independent of imaging parameters, contrast concentration and vascular morphology. Simulations were conducted to elucidate the biophysical factors affecting these calibration factors. (ii) The utility of measuring the ratio of the GE and SE relaxation rate change (D-R2*/LiR2), as a marker of averaged vessel diameter was determined. (iii) The relationships between the susceptibility markers and different vascular morphometric parameters (i.e. rCBV and MVD) were characterized to determine the most appropriate morphological correlate for MR assays of angiogenesis. (iv) Clinical applications of SC MR in detecting angiogenesis were examined. (v) The research culminated with the development of a novel microvascular geometry-independent approach for modeling the SC mechanism. The above issues were addressed by conducting SC (using the contrast agent MION) MR measurements in a rat tumor (9L gliosarcoma) model with correlative histologic measurements. The wealth of information gleaned from SC MR regarding angiogenesis demonstrates the potential to be of significant clinical importance in the noninvasive detection and treatment of cancer.