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Hyperpolarized Metabolic Imaging Detects Latent Hepatocellular Carcinoma Domains Surviving Locoregional Therapy.
Hepatology 2019Hep

Abstract

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 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. In this study, we characterize and leverage the metabolic reprogramming demonstrated by latent HCC cells in response to TAE-induced ischemia to enable their detection in vivo using dynamic nuclear polarization magnetic resonance spectroscopic imaging (DNP-MRSI) of 13 Carbon-labeled substrates. Under TAE-induced ischemia, latent HCC cells demonstrate reduced metabolism and develop a dependence on glycolytic flux to lactate. Despite the hypometabolic state of these cells, DNP-MRSI of 1-13 C-pyruvate and its downstream metabolites, 1-13 C-lactate and 1-13 C-alanine, predicted histologic viability. These studies provide a novel paradigm for imaging latent, treatment-refractory cancer cells that are undetectable using existing clinical imaging paradigms suggesting that DNP-MRSI provides a unique technology for this application.

Authors+Show Affiliations

Penn Image-Guided Interventions Laboratory, Hospital of the University of Pennsylvania, Philadelphia, PA, 19104. Department of Radiology, Hospital, University of Pennsylvania, Philadelphia, PA, 19104.Penn Image-Guided Interventions Laboratory, Hospital of the University of Pennsylvania, Philadelphia, PA, 19104. Howard Hughes Medical Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104.Penn Image-Guided Interventions Laboratory, Hospital of the University of Pennsylvania, Philadelphia, PA, 19104. Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104.Department of Radiology, Hospital, University of Pennsylvania, Philadelphia, PA, 19104.Penn Image-Guided Interventions Laboratory, Hospital of the University of Pennsylvania, Philadelphia, PA, 19104. Department of Radiology, Hospital, University of Pennsylvania, Philadelphia, PA, 19104.Department of Radiology, Hospital, University of Pennsylvania, Philadelphia, PA, 19104.Penn Image-Guided Interventions Laboratory, Hospital of the University of Pennsylvania, Philadelphia, PA, 19104. Department of Radiology, Hospital, University of Pennsylvania, Philadelphia, PA, 19104.Penn Image-Guided Interventions Laboratory, Hospital of the University of Pennsylvania, Philadelphia, PA, 19104. Department of Radiology, Hospital, University of Pennsylvania, Philadelphia, PA, 19104.Penn Image-Guided Interventions Laboratory, Hospital of the University of Pennsylvania, Philadelphia, PA, 19104. Department of Radiology, Hospital, University of Pennsylvania, Philadelphia, PA, 19104.Department of Radiology, Hospital, University of Pennsylvania, Philadelphia, PA, 19104.Department of Radiology, Hospital, University of Pennsylvania, Philadelphia, PA, 19104.Department of Radiology, Hospital, University of Pennsylvania, Philadelphia, PA, 19104.Department of Nephrology, Children's Hospital of Philadelphia, Philadelphia, PA, 19104.Penn Image-Guided Interventions Laboratory, Hospital of the University of Pennsylvania, Philadelphia, PA, 19104. Department of Radiology, Hospital, University of Pennsylvania, Philadelphia, PA, 19104.Penn Image-Guided Interventions Laboratory, Hospital of the University of Pennsylvania, Philadelphia, PA, 19104. Department of Radiology, Hospital, University of Pennsylvania, Philadelphia, PA, 19104.Department of Pathology, Hospital of the University of Pennsylvania, Philadelphia, PA, 19104.Department of Radiology, Hospital, University of Pennsylvania, Philadelphia, PA, 19104.Penn Image-Guided Interventions Laboratory, Hospital of the University of Pennsylvania, Philadelphia, PA, 19104. Department of Radiology, Hospital, University of Pennsylvania, Philadelphia, PA, 19104. Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31553806

Citation

Perkons, Nicholas R., et al. "Hyperpolarized Metabolic Imaging Detects Latent Hepatocellular Carcinoma Domains Surviving Locoregional Therapy." Hepatology (Baltimore, Md.), 2019.
Perkons NR, Kiefer RM, Noji MC, et al. Hyperpolarized Metabolic Imaging Detects Latent Hepatocellular Carcinoma Domains Surviving Locoregional Therapy. Hepatology. 2019.
Perkons, N. R., Kiefer, R. M., Noji, M. C., Pourfathi, M., Ackerman, D., Siddiqui, S., ... Gade, T. P. F. (2019). Hyperpolarized Metabolic Imaging Detects Latent Hepatocellular Carcinoma Domains Surviving Locoregional Therapy. Hepatology (Baltimore, Md.), doi:10.1002/hep.30970.
Perkons NR, et al. Hyperpolarized Metabolic Imaging Detects Latent Hepatocellular Carcinoma Domains Surviving Locoregional Therapy. Hepatology. 2019 Sep 25; PubMed PMID: 31553806.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Hyperpolarized Metabolic Imaging Detects Latent Hepatocellular Carcinoma Domains Surviving Locoregional Therapy. AU - Perkons,Nicholas R, AU - Kiefer,Ryan M, AU - Noji,Michael C, AU - Pourfathi,Mehrdad, AU - Ackerman,Daniel, AU - Siddiqui,Sarmad, AU - Tischfield,David, AU - Profka,Enri, AU - Johnson,Omar, AU - Pickup,Stephen, AU - Mancuso,Anthony, AU - Pantel,Austin, AU - Denburg,Michelle R, AU - Nadolski,Gregory J, AU - Hunt,Stephen J, AU - Furth,Emma E, AU - Kadlecek,Stephen, AU - Gade,Terence P F, Y1 - 2019/09/25/ PY - 2019/9/26/entrez PY - 2019/9/26/pubmed PY - 2019/9/26/medline KW - dynamic nuclear polarization KW - hepatocellular carcinoma KW - locoregional therapy JF - Hepatology (Baltimore, Md.) JO - Hepatology N2 - 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 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. In this study, we characterize and leverage the metabolic reprogramming demonstrated by latent HCC cells in response to TAE-induced ischemia to enable their detection in vivo using dynamic nuclear polarization magnetic resonance spectroscopic imaging (DNP-MRSI) of 13 Carbon-labeled substrates. Under TAE-induced ischemia, latent HCC cells demonstrate reduced metabolism and develop a dependence on glycolytic flux to lactate. Despite the hypometabolic state of these cells, DNP-MRSI of 1-13 C-pyruvate and its downstream metabolites, 1-13 C-lactate and 1-13 C-alanine, predicted histologic viability. These studies provide a novel paradigm for imaging latent, treatment-refractory cancer cells that are undetectable using existing clinical imaging paradigms suggesting that DNP-MRSI provides a unique technology for this application. SN - 1527-3350 UR - https://www.unboundmedicine.com/medline/citation/31553806/Hyperpolarized_Metabolic_Imaging_Detects_Latent_Hepatocellular_Carcinoma_Domains_Surviving_Locoregional_Therapy L2 - https://doi.org/10.1002/hep.30970 DB - PRIME DP - Unbound Medicine ER -