Transarterial chemoembolization (TACE) is the main treatment for intermediate stage hepatocellular carcinoma (HCC) with Barcelona Clinic Liver Cancer classification because of its exclusive arterial blood supply. Although TACE achieves substantial necrosis of the tumor, complete tumor necrosis is uncommon, and the residual tumor generally rapidly recurs. We combined tirapazamine (TPZ), a hypoxia-activated cytotoxic agent, with hepatic artery ligation (HAL), which recapitulates transarterial embolization in mouse models, to enhance the efficacy of TACE. The effectiveness of this combination treatment was examined in HCC that spontaneously developed in hepatitis B virus X protein (HBx) transgenic mice. We proved that the tumor blood flow in this model was exclusively supplied by the hepatic artery, in contrast to conventional orthotopic HCC xenografts that receive both arterial and venous blood supplies. At levels below the threshold oxygen levels created by HAL, TPZ was activated and killed the hypoxic cells, but spared the normoxic cells. This combination treatment clearly limited the toxicity of TPZ to HCC, which caused the rapid and near-complete necrosis of HCC. In conclusion, the combination of TPZ and HAL showed a synergistic tumor killing activity that was specific for HCC in HBx transgenic mice. This preclinical study forms the basis for the ongoing clinical program for the TPZ-TACE regimen in HCC treatment.hypoxia | hepatocellular carcinoma | orthotopic | transarterial embolization H epatocellular carcinoma (HCC), the sixth most common solid malignancy, accounts for approximately three-quarters of a million deaths worldwide every year (1). Over the past two decades, the incidence of HCC has remained high in Asia and has steadily increased in the United States and Europe (1). Treatment for HCC largely depends on the stage of the disease. Diagnosis is usually delayed, as ∼30-40% of the patients are already in the intermediate stage at their initial visit, and transarterial chemoembolization (TACE) is the most commonly used treatment for these patients (2). However, TACE achieves only a 20-30% tumor remission rate, and recurrence is common, resulting in a 3-y survival rate of only ∼30% (3). This poor survival rate needs to be improved.The mechanism by which arterial embolization preferentially kills HCC but spares adjacent liver tissues arises from the unique dual blood supply to the liver. Normal liver receives 75% of its blood supply from the portal vein (PV) and the remaining 25% from the hepatic artery (HA) (4). In contrast, HCC almost exclusively receives its blood supply from the HA (5). Based on this unique pattern, embolization has been used to selectively block the arterial blood supply to HCC, causing transient but profound ischemia and depriving HCC cells from essential oxygen and nutrients, thus killing the tumors.However, because of the heterogeneity of the tumor vessels within HCC, the embolization of the tumor-feeding arteries usually results in different degrees of ischemia and hypoxia, rang...

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Background Obesity-induced hepatocellular carcinoma (HCC) is more prevalent in males than in females, but the underlying mechanism remains unclear. The influence of hepatic androgen receptor (AR) pathway on the gender difference of HCC has been well documented. Here we investigated the role of hepatic lipogenesis, which is elevated in the livers of obese and nonalcoholic fatty liver disease (NAFLD) patients, in stimulating the AR pathway for the male preference of obesity induced HCC. Methods Male C57BL/6J mice were fed a fructose-rich high carbohydrate diet (HCD) to induce hepatic lipogenesis. The effect of hepatic lipogenesis on AR was examined by the expression of hydrodynamically injected AR reporter and the endogenous AR target gene; the mechanism was delineated in hepatoma cell lines and validated in male mice. Results The hepatic lipogenesis induced by a fructose-rich HCD enhanced the transcriptional activity of hepatic AR in male mice, which did not happen when fed a high fat diet. This AR activation was blocked by sh-RNAs or inhibitors targeting key enzymes in lipogenesis, either acetyl-CoA carboxylase subunit alpha (ACCα), or fatty acid synthase (FASN), in vivo and in vitro. Further mechanistic study identified that specific unsaturated fatty acid, the oleic acid (C18:1 n-9), incorporated DAGs produced by hepatic lipogenesis are the key molecules to enhance the AR activity, through activation of Akt kinase, and this novel mechanism is targeted by metformin. Conclusions Our study elucidates a novel mechanism underlying the higher risk of HCC in obese/NAFLD males, through specific DAGs enriched by hepatic lipogenesis to increase the transcriptional activity of hepatic AR, a confirmed risk factor for male HCC.

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