Vascular differences detected by MRI for metastatic versus nonmetastatic breast and prostate cancer xenografts

Abstract

Several studies have linked vascular density, identified in histologic sections, to "metastatic risk." Functional information of the vasculature, not readily available from histologic sections, can be obtained with contrast-enhanced MRI to exploit for therapy or metastasis prevention. Our aims were to determine if human breast and prostate cancer xenografts preselected for differences in invasive and metastatic characteristics established correspondingly different vascular volume and permeability, quantified here with noninvasive MRI of the intravascular contrast agent albumin-GdDTPA. Tumor vascular volume and permeability of human breast and prostate cancer xenografts were characterized using MRI. Parallel studies confirmed the invasive behavior of these cell lines. Vascular endothelial growth factor (VEGF) expression in the cell lines was measured using ELISA and Western blots. Metastasis to the lungs was evaluated with spontaneous as well as experimental assay. Metastatic tumors formed vasculature with significantly higher permeability or vascular volume (P<.05, two-sided unpaired t test). The permeability profile matched VEGF expression. Within tumors, regions of high vascular volume usually exhibited low permeability whereas regions of low vascular volume exhibited high permeability. We observed that although invasion was necessary, without adequate vascularization it was not sufficient for metastasis to occur.

Figure 1

Kinetics of albumin-GdDTPA in mouse blood for normal mouse (+), mouse with MDA-MB-231 tumor (o) and mouse with DU-145 tumor (x). Blood levels of albumin-GdDTPA remain constant up to 30 minutes and longer.

Figure 2

High-power micrographs (x400) of 5-µm-thick histologic sections stained with hematoxylin and eosin. Sections D, E, F, G, H, and I are primary tumor sections obtained from MDA-MB-435, MDA-MB-231, MCF-7, MatLyLu, PC-3, and DU-145 tumors. Arrows indicate tumor vessels. Sections A, B, C, J, K, and L are lung sections demonstrating metastasis of MDA-MB-435 (spontaneous metastasis), MDA-MB-231 (spontaneous metastasis), MCF-7 (experimental metastasis), MatLyLu (spontaneous metastasis), PC-3 (experimental metastasis), and DU-145 (experimental metastasis) cancer cells.

Figure 3

(A) Raw images from a central slice of a MatLyLu tumor (180 mm³) presented to show the actual distribution of the contrast agent; the corresponding maps of vascular volume and permeability-surface area product (PSP) are shown in (B). The frequency distribution of vascular volume and PSP for this tumor are shown in (C). 3D reconstructed fusion maps of vascular volume (red channel) and permeability (green channel) obtained from multislice data for this tumor are displayed in (D). The 3D fusion images show triplanar and volume rendered views of the fused maps. A histologic section stained with hematoxylin and eosin of the central slice of this tumor is shown in (E). Hematoxylin and eosin staining revealed necrosis and edema in the central region of this tumor.

Figure 4

Vascular volume and permeability “mismatch” characteristics of breast and prostate cancer tumor models. Representative red and green fusion maps for each of the tumor models are shown in (A); red corresponds to vascular volume, green to permeability. The mean value of the highest 25% values of vascular volume (■), and the mean vascular volumes spatially corresponding to the highest 25% values of permeability () are shown in (B). The mean value of the highest 25% of permeability values (■), and the permeability spatially corresponding to the highest 25% values of vascular volume () are shown in (C). A significant difference (P<.05) was observed for all the tumor models. The only exception to this was for the MDA-MB-231 tumor group.

Figure 5

(A–F): “Metabolic Boyden chamber assay” demonstrating differences in invasive characteristics of the breast (A–C) and prostate cancer (D–F) cell lines at approximately 47 hours. The T₁-weighted ¹H MR images show the bright Matrigel layer, which is significantly degraded by (A) MDA-MB-435, (B) MDA-MB-231, (D) MatLyLu, and (E) PC-3 cells, but not by the (C) MCF-7 or (F) DU-145 cells.