The role of vessel maturation and vessel functionality in spontaneous fluctuations of T2*-weighted GRE signal within tumors

Acute hypoxia (transient cycles of hypoxia-reoxygenation) is known to occur in solid tumors and is generally believed to be caused by tumor blood flow instabilities. It was recently demonstrated that T-2*-weighted (T-2*w) gradient echo (GRE) MRI is a powerful non-invasive method for investigating periodic changes in tumor pO(2) and blood flow associated with acute hypoxia. Here, the possible correlation between tumor vessel immaturity, vessel functionality and T-2*w GRE signal fluctuations was investigated. Intramuscularly implanted FSa II fibrosarcoma-bearing mice were imaged at 4.7T. Maps of spontaneous fluctuations of MR signal intensity in tumor tissue during air breathing were obtained using a T-2*w GRE sequence. This same sequence was also employed during air-5% CO, breathing (hypercapnia) and carbogen breathing (hypercapnic hyperoxia) to obtain parametric maps representing vessel maturation and vessel function, respectively. Vascular density, vessel maturation and vessel perfusion were also assessed histologically by using CD31 labeling alpha-smooth muscle actin immunoreactivity and Hoechst 33242 labeling, respectively. About 50% of the tumor fluctuations occurred in functional tumor regions (responsive to carbogen) and 80% occurred in tumor regions with immature vessels (lack of response to hypercapnia). The proportion of hypercapnia-responsive voxels were found to be twice as great in fluctuating than in non-fluctuating tumor areas (P: 0.22 vs 0.13). Similarly, the proportion of functional voxels was somewhat greater in fluctuating tumor areas (P: 0.54 vs 0.43). The mean values of MR signal changes during hypercapnia (VD) and during carbogen breathing (VF) (significant voxels only) were also larger in fluctuating than in non-fluctuating tumor areas (P < 0.05). This study demonstrated that adequate vessel functionality and advanced vessel maturation Could explain at least in part the occurrence of spontaneous T-2*w GRE signal fluctuations. Functionality and maturation are not required for signal fluctuations, however, because a large fraction Of fluctuations could still occur in non-perfused and/or immature vessels. Copyright (c) 2006 John Wiley & Sons, Ltd.