Abstract
The importance of tumor vascular behavior in clinical application is that the delivery of drugs and oxygen relied on the vascular function and morphology can determine the therapy response. To assess the vasculatures within tumors with the high spatial resolution and sensitivity, high-frequency ultrasound power Doppler imaging with a center frequency of 25 MHz was adopted. In power Doppler imaging, the vascular function was quantified based on the color-weighted flow area (CWFA) and color pixel density (CPD), which reflect the perfusion and the fraction of perfused vascular density within the tumor, respectively. Besides, the branching index (BI), defined as the perimeter of blood vessels divided by their area, was also proposed to reveal the morphology of the tumor vasculatures by describing the degree of branching per unit length of blood vessels. The first part of this dissertation is to longitudinally investigate the difference characteristics between angiogenesis and vsculogenesis pathways in primary and recurrent tumors, as described in Chapter 2. Murine tumors were transplanted in non-irradiated and pre-irradiated tissues to imitate the primary and recurrent tumor models, respectively. During tumor progression of 11 days, the CWFA and CPD increased in primary tumors but did not change significantly in recurrent tumors. The recurrent tumors showed less vascular function than in the primary tumors. These results were verified by immunohistochemistry analysis. Besides, the recurrent tumors exhibited more dilated and continuous vasculatures than the primary tumors, which reflect the BI value should theoretically be lower for recurrent tumors than for primary tumors. Nevertheless, due to the vasculature distributions being chaotic and malformed throughout the tumors, the actual morphological patterns of vasculatures in the whole tumors was obtained by three-dimensional power Doppler imaging. Second, tumor heterogeneity is another major obstacle to therapy, and thus, not only longitudinally but also spatially assessing of tumor vascular behavior is necessary. In Chapter 3, tumor perfusion and vascular density within the primary tumors assessed by power Doppler imaging and immunohistochemical analysis were spatially and longitudinally investigated, respectively. The parameter of value was defined as the rate at which vascular signals increase with the fractional sizes of the peripheral area within the tumor that can objectively quantify the spatial features of the tumor vasculature. To demonstrate the potential of the value, the primary tumors were adopted in this dissertation. During primary tumor progression, the estimated tumor perfusion by power Doppler imaging and vascular density by immunohistochemical analysis exhibited good temporal correlations, but they did not present good spatial correlations. The value calculated from power Doppler images decreased, which indicated tumor perfusion changed from homogeneous to heterogeneous. However, there were no significant differences in the immunohistochemical images, which reflected the vascular density still maintained uniformly homogeneous distribution. In clinical, since tumors exhibit heterogeneity, how to achieve the maximal therapeutic gain in tumor suppression is an important issue. Exploring the differences in features of tumor vascular patterns between two tumor models is helpful for developing anti-angiogenic and anti-vasculogenic drugs. Furthermore, both longitudinal monitoring the change in tumor vascular behavior and spatially evaluating the different weighting of tumor vasculatures within the tumor central and peripheral regions are helpful for providing the complete tumor physiology information and adjusting appropriate dose in therapy.