Interstitial fluid pressure and associated lymph node metastasis revealed in tumors by dynamic contrast-enhanced MRI

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 (v(0)) based on the rim movement. Significant positive correlations were found between v(0) and IFP in all tumor xenografts. Moreover, the primary tumors of metastasis-positive mice displayed higher IFP and v(0) than the primary tumors of metastasis-negative mice. Findings were confirmed in cervical cancer patients with pelvic lymph node metastases, where we found v(0) to be higher compared with patients without lymph node involvement (P < 0.00001). Together, these findings establish that Gd-DTPA-based DCE-MRI can noninvasively visualize tumor IFP, and they reveal the potential for v(0) determined by this method to serve as a novel general biomarker of tumor aggressiveness.