Hyperpolarized Metabolic Imaging Detects Latent Hepatocellular Carcinoma Domains Surviving Locoregional Therapy

Abstract

Background and Aims Advances in cancer treatment have improved survival; however, local recurrence and metastatic disease—the principal causes of cancer mortality—have limited the ability to achieve durable remissions. Local recurrences arise from latent tumor cells that survive therapy and are often not detectable by conventional clinical imaging techniques. Local recurrence after transarterial embolization (TAE) of hepatocellular carcinoma (HCC) provides a compelling clinical correlate of this phenomenon. In response to TAE‐induced ischemia, HCC cells adapt their growth program to effect a latent phenotype that precedes local recurrence. Approach and Results In this study, we characterized and leveraged the metabolic reprogramming demonstrated by latent HCC cells in response to TAE‐induced ischemia to enable their detection in vivo using dynamic nuclear polarization (DNP) magnetic resonance spectroscopic imaging (MRSI) of 13carbon‐labeled substrates. Under TAE‐induced ischemia, latent HCC cells demonstrated reduced metabolism and developed a dependence on glycolytic flux to lactate. Despite the hypometabolic state of these cells, DNP‐MRSI of 1‐13C‐pyruvate and its downstream metabolites, 1‐13C‐lactate and 1‐13C‐alanine, predicted histological viability. Conclusions These studies provide a paradigm for imaging latent, treatment‐refractory cancer cells, suggesting that DNP‐MRSI provides a technology for this application.

Suppressing DRP1-mediated mitochondrial fission and mitophagy increases mitochondrial apoptosis of hepatocellular carcinoma cells in the setting of hypoxia

“…In excised HCC specimens, peripheral residuals of viable tumor cells are common after TAE/TACE, which may contribute to local recurrence 7 . Furthermore, emerging evidences show that HCC cells capable of surviving TAE/TACE obtain a more invasive phenotype 8 . However, how HCC cells develop an adaptation to survive the ischemic hypoxia induced by TAE/TACE is unclear.…”

Elastin-specific MRI of extracellular matrix-remodelling following hepatic radiofrequency-ablation in a VX2 liver tumor model

“…If translated into clinical scenarios, this imaging biomarker would be especially valuable when used in combination with other molecular imaging techniques e.g. capable of visualizing physiological conditions such as tumor pH or metabolic output 34 , 35 .…”

Pharmacodynamics and pharmacokinetics of hyperpolarized [1‐13C]‐pyruvate in a translational oncologic model

“…Autochthonous HCCs were induced in male Wistar rats with DEN according to established protocols. 19,21 Rats were regularly screened for tumor development, as previously described, with T 2 -weighted MRI (FOV: 70 mm x 70 mm, grid size: 256 x 256, slice thickness: 2 mm, TR minimum: 1.4 s [respiratory gated], TE: 59.1 ms, minimum of averages: 4) using a Polarean proton-tuned (200.1 MHz) birdcage resonator and an Agilent 4.7-T 40-cm horizontal bore MR spectrometer with a 25 Gauss/cm gradient tube interfaced to an Agilent DirectDrive console. 19 Rats bearing HCCs measuring approximately 100 mm 3 were selected for subsequent imaging studies.…”

“…The measurements of tumoral substrate delivery and metabolism presented in the current study occurred against a background of liver disease and in the presence of respiratory motion, permitting the deconvolution of these potential confounders that will be required for clinical translation. [17][18][19][20]…”