In vivo mapping of fractional plasma volume (fpv) and endothelial transfer coefficient (Kps) in solid tumors using a macromolecular contrast agent: Correlation with histology and ultrastructure

Abstract

Contrast-enhanced MRI, immunostaining and electron microscopy were used to detect areas of intense angiogenesis in experimental tumors. This work was also aimed at evaluating the possible effect of the surrounding tissues on tumor microvasculature and at studying the penetration of macromolecules in avascular areas. Human colon carcinoma cells were implanted in subcutaneous tissue of nude mice. Dynamic T 1 -weigthed 3D pulse sequences were acquired before and after administration of Gd-DTPA-albumin to obtain parametric maps of fractional plasma volume (fpv) and transendothelial permeability (Kps). The maps suggested that tumor can be subdivided into 4 zones located in the peripheral rim (zones I-II) or in the core (zones III-IV) of the tumor itself. Significant differences (p<0.001) were found in the values of Kps and fpv of zones I-II with respect to zones III-IV. In the peripheral rim, permeability was significantly higher (p<0.01) in the muscle-peripheral region (zone I) with respect to the skin-peripheral region (zone II). In areas with high Kps, histological and ultrastructural examination revealed clusters of newly formed vessels and signs of intense permeability. Numerous vascular vesicular organs were visible in these areas. In the tumoral core, analysis of the microcirculatory parameters revealed regions with mild permeability (zone III) and regions with negligible permeability (zone IV). These 2 zones were discriminated by the average value of Kps (p<0.05), while their fpv was not significantly different. Upon histological examination, the tumoral core exhibited necrotic areas; CD31 immunocytochemistry exhibited that it was diffusely hypovascularized with large avascular areas. Upon ultrastructural examination, capillaries were rarely visible and exhibited signs of endothelial cell damage. The results suggest that segmentation based on microvascular parameters detects in vivo zones characterized by immunocytochemical and ultrastructural aspects of intense angiogenesis. The finding that a certain amount of contrast agent penetrates in the tumoral core suggests that high oncotic and hydrostatic pressure only partially hinders the penetration of macromolecules. Tumor-induced angiogenesis plays an important role in tumor growth and there is a significant interest in attacking the tumor vasculature using anti-angiogenesis or vascular targeting therapies. 1,2 The study of the vascular function in tumors is hampered by the lack of an in vivo model of the complex microenvironment present in the tumor stroma. New magnetic resonance imaging (MRI)-based methods allow morphological and functional evaluation of the microvascular bed in living animals at high spatial/ temporal resolution. An interesting approach is dynamic contrastenhanced MRI (DCE-MRI), which detects peculiar properties of vascular beds by virtue of the differential distribution of contrast media in normal and pathological regions. 3,4 MRI enhanced with small molecular contrast media (Ͻ1 kDa) is currently being used to define tumor microvasculature...

Visual MRI: Merging information visualization and non-parametric clustering techniques for MRI dataset analysis

“…• kPS and f PV space: the considered parameters kPS and f PV, previously described, are derived from MRI slices applying the pharmacokinetics model introduced in [19]. For each pixel of a selected MRI image there is a value for kPS and f PV, respectively.…”

“…For this reason, human computer interaction and information visualization (IV) [3] methodologies have been proven to be very useful in supporting physicians in decision-based activities, such as those related to diagnoses and therapies. Furthermore, when dealing with a huge amount of data, automatic techniques for the reduction and simplification of the given data set as well as for the recognition of relevant patterns are needed: several kinds of data mining (DM) techniques have been proposed to deal with trast Enhanced MRI (DCE-MRI) techniques play a relevant role in this field [19,20]. DCE-MRI with macromolecular contrast agents has been used to measure characteristics of tumor microvessels such as transendothelial permeability (kPS) and fractional plasma volume (f PV) that are accepted surrogate markers of tumor angiogenesis [19].…”

In Vivo Assessment of Antiangiogenic Activity of SU6668 in an Experimental Colon Carcinoma Model

“…The aim of this study was to evaluate whether a time course of noninvasive DCE-MRI was able to assess antiangiogenic effects of SU6668 in vivo. An automated method for generation of quantitative anatomical maps of kPS and fPV has been developed (11), and this provides the unique opportunity to explore tumor vasculature heterogeneity in vivo. The effect of SU6668 on tumor vascularity was assessed for the first time quantitatively and noninvasively by MRI at different time points after treatment to better understand the sequence of vascular events that precede tumor growth inhibition.…”

Use of dynamic contrast-enhanced MRI to evaluate acute treatment with ZD6474, a VEGF signalling inhibitor, in PC-3 prostate tumours

“…The tumour rim is known to be highly enhancing, and the centres of tumours are known to contain variable degrees of necrosis (Marzola et al, 2003). However, methods for analysing groups of K trans maps are not well developed and generally manually selected ROI are used.…”