Abstract
PURPOSE: Hepatic thermal ablation therapy can result in c-Met-mediated off-target stimulation of distal tumor growth. The purpose of this study was to determine if a similar effect on tumor metabolism could be detected in vivo with hyperpolarized (13)C MRI. MATERIALS AND METHODS: In this prospective study, female Fisher rats (n = 28, 120-150 g) were implanted with R3230 rat breast adenocarcinoma cells and assigned to either: sham surgery, hepatic radiofrequency ablation (RFA), or hepatic RFA + adjuvant c-Met inhibition with PHA-665752 (RFA + PHA). PHA-665752 was administered at 0.83 mg/kg at 24 h post-RFA. Tumor growth was measured daily. MRI was performed 24 h before and 72 h after treatment on 14 rats, and the conversion of (13)C-pyruvate into (13)C-lactate within each tumor was quantified as lactate:pyruvate ratio (LPR). Comparisons of tumor growth and LPR were performed using paired and unpaired t-tests. RESULTS: Hepatic RFA alone resulted in increased growth of the distant tumor compared to sham treatment (0.50 ± 0.13 mm/day versus 0.11 ± 0.07 mm/day; p < 0.001), whereas RFA + PHA (0.06 ± 0.13 mm/day) resulted in no significant change from sham treatment (p = 0.28). A significant increase in LPR was seen following hepatic RFA (+0.016 ± 0.010, p = 0.02), while LPR was unchanged for sham treatment (-0.048 ± 0.051, p = 0.10) or RFA + PHA (0.003 ± 0.041, p = 0.90). CONCLUSION: In vivo hyperpolarized (13)C MRI can detect hepatic RFA-induced increase in lactate flux within a distant R3230 tumor, which correlates with increased tumor growth. Adjuvant inhibition of c-Met suppresses these off-target effects, supporting a role for the HGF/c-Met signaling axis in these tumorigenic responses.