Recently, we have demonstrated the feasibility of using hemodynamic response imaging (HRI), a functional magnetic resonance imaging (MRI) method combined with hypercapnia and hyperoxia, for monitoring vascular changes during liver pathologies without the need of contrast material. In this study, we evaluated HRI ability to assess changes in liver tumor vasculature during tumor establishment, progression, and antiangiogenic therapy. Colorectal adenocarcinoma cells were injected intrasplenically to model colorectal liver metastasis (CRLM) and the Mdr2 knockout mice were used to model primary hepatic tumors. Hepatic perfusion parameters were evaluated using the HRI protocol and were compared with contrast-enhanced (CE) MRI. The hypovascularity and the increased arterial blood supply in well-defined CRLM were demonstrated by HRI. In CRLM-bearing mice, the entire liver perfusion was attenuated as the HRI maps were significantly reduced by 35%. This study demonstrates that the HRI method showed enhanced sensitivity for small CRLM (1-2 mm) detection compared with CE-MRI (82% versus 38%, respectively). In addition, HRI could demonstrate the vasculature alteration during CRLM progression (arborized vessels), which was further confirmed by histology. Moreover, HRI revealed the vascular changes induced by rapamycin treatment. Finally, HRI facilitates primary hepatic tumor characterization with good correlation to the pathologic differentiation. The HRI method is highly sensitive to subtle hemodynamic changes induced byCRLM and, hence, can function as an imaging tool for understanding the hemodynamic changes occurring during CRLM establishment, progression, and antiangiogenic treatment. In addition, this method facilitated the differentiation between different types of hepatic lesions based on their vascular profile noninvasively.
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Abbreviations: CE-MRI, contrast-enhanced MRI; CRLM, colorectal liver metastasis; fMRI, functional MRI; Gd-DTPA, gadolinium–diethylene-triaminepenta-acetate; HCC, hepatocellular carcinoma; HPF, high-power microscopic fields; HRI, hemodynamic response imaging; MRI, magnetic resonance imaging; RAPA, rapamycin; ROI, region of interest; SMA, smooth muscle actin; T1W, T1-weighted; T2W, T2-weighted; ΔSCO2, signal intensity change due to hypercapnia; ΔSO2, signal intensity change due to hyperoxia; VEGF, vascular endothelial growth factor Address all correspondence to: Rinat Abramovitch, PhD, The Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Medical Center, PO Box 12000, Jerusalem 91120, Israel. E-mail: email@example.com 1This research was supported in part by grant number 1243/10 from the Israel Science Foundation (for R.A.) and by the Horwitz Foundation through The Center for Complexity Science (for R.A. and Y.E.). 2This article refers to supplementary materials, which are designated by Figures W1 and W2 and are available online at www.neoplasia.com. 3These authors contributed equally to this work. Received 16 September 2010; Revised 2 December 2010; Accepted 8 December 2010 Copyright © 2011 Neoplasia Press, Inc. All rights reserved 1522-8002/11/$25.00 DOI 10.1593/neo.101354