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Hepatocellular carcinoma (HCC), the most common primary liver cancer, of which ∼800 000 new cases will be diagnosed worldwide this year, portends a five-year survival rate of merely 17% in patients with unresectable disease. This dismal prognosis is due, at least in part, from the late stage of diagnosis and the limited efficacy of systemic therapies. As a result, there is an urgent need to identify risk factors that contribute to HCC initiation and provide targetable vulnerabilities to improve patient survival. While myriad risk factors are known, elevated copper (Cu) levels in HCC patients and the incidence of hepatobiliary malignancies in Wilson disease patients, which exhibit hereditary liver Cu overload, suggests the possibility that metal accumulation promotes malignant transformation. Here we found that expression of the Cu transporter genes ATP7A, ATP7B, SLC31A1, and SLC31A2 was significantly altered in liver cancer samples and were associated with elevated Cu levels in liver cancer tissue and cells. Further analysis of genomic copy number data revealed that alterations in Cu transporter gene loci correlate with poorer survival in HCC patients. Genetic loss of the Cu importer SLC31A1 (CTR1) or pharmacologic suppression of Cu decreased the viability, clonogenic survival, and anchorage-independent growth of human HCC cell lines. Mechanistically, CTR1 knockdown or Cu chelation decreased glycolytic gene expression and downstream metabolite utilization and as a result forestalled tumor cell survival after exposure to hypoxia, which mimics oxygen deprivation elicited by transarterial embolization, a standard-of-care therapy used for patients with unresectable HCC. Taken together, these findings established an association between altered Cu homeostasis and HCC and suggest that limiting Cu bioavailability may provide a new treatment strategy for HCC by restricting the metabolic reprogramming necessary for cancer cell survival.

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 13 carbon-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- 13 C-pyruvate and its downstream metabolites, 1- 13 C-lactate and 1- 13 C-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., (© 2019 by the American Association for the Study of Liver Diseases.)

Purpose: To test the hypotheses that (i) heavier rats demonstrate improved survival with diminished fibrosis in a diethylnitrosamine (DEN)-induced model of hepatocellular carcinoma (HCC) and (ii) transarterial embolization via femoral artery access decreases procedure times versus carotid access., Materials and Methods: One hundred thirty-eight male Wistar rats ingested 0.01% DEN in water ad libitum for 12 weeks. T2-weighted magnetic resonance imaging was used for tumor surveillance. Rats underwent selective embolization of ≥ 5 mm tumors via carotid or femoral artery catheterization under fluoroscopic guidance. Rats were retrospectively categorized into 3 groups by initial weight (< 300, 300-400, > 400 g) for analyses of survival, tumor latency, and fibrosis. Access site was compared relative to procedural success, mortality, and time., Results: No significant differences in tumor latency were related to weight group (P = .310). Rats weighing < 300 g had shorter survival than both heavier groups (mean, 88 vs 108 d; P < .0001), and more severe fibrosis (< 300 g median, 4.0; 300-400 g median, 1.5; > 400 g median, 1.0; P = .015). No significant difference was found in periprocedural mortality based on access site; however, procedure times were shorter via femoral approach (mean, 71 ± 23 vs 127 ± 24 min; P < .0001)., Conclusions: Greater initial body weight resulted in improved survival without prolonged tumor latency for rats with DEN-induced HCCs and was associated with less severe fibrosis. A femoral approach for embolization resulted in decreased procedure time. These modifications provide a translational animal model of HCC and transarterial embolization that may be suited for short-term survival studies., (Copyright © 2017 SIR. Published by Elsevier Inc. All rights reserved.)