Data from Interstitial Fluid Pressure and Associated Lymph Node Metastasis Revealed in Tumors by Dynamic Contrast-Enhanced MRI

Abstract

<div>Abstract<p>Elevated interstitial fluid pressure (IFP) in tumors can cause metastatic dissemination and treatment resistance, but its study poses a challenge because of a paucity of noninvasive imaging strategies. In this study, we address this issue by reporting the development of a noninvasive tool to assess tumor IFP and interstitial hypertension-induced lymph node metastasis. Using mouse xenograft models of several types of human cancer, we used gadolinium diethylene-triamine penta-acetic acid (Gd-DTPA) as a contrast agent for dynamic contrast-enhanced MRI (DCE-MRI). Immediately after Gd-DTPA administration, a high-signal-intensity rim was observed in the tumor periphery, which moved outward with time. Assuming the velocity of Gd-DTPA to be equal to the fluid flow velocity, we used a simple model of peritumoral interstitial fluid flow to calculate the fluid flow velocity at the tumor surface (<i>v</i><sub>0</sub>) based on the rim movement. Significant positive correlations were found between <i>v</i><sub>0</sub> and IFP in all tumor xenografts. Moreover, the primary tumors of metastasis-positive mice displayed higher IFP and <i>v</i><sub>0</sub> than the primary tumors of metastasis-negative mice. Findings were confirmed in cervical cancer patients with pelvic lymph node metastases, where we found <i>v</i><sub>0</sub> to be higher compared with patients without lymph node involvement (<i>P</i> < 0.00001). Together, these findings establish that Gd-DTPA-based DCE-MRI can noninvasively visualize tumor IFP, and they reveal the potential for <i>v</i><sub>0</sub> determined by this method to serve as a novel general biomarker of tumor aggressiveness. <i>Cancer Res; 72(19); 4899–908. ©2012 AACR</i>.</p></div>