Gregory J. Gores

Hepatology: A Home for Hepatocellular Cancer Publications

In my last commentary, I highlighted the emerging discipline of hepatobiliary oncology and noted that Hepatology encouraged submission of excellent papers on hepatocellular cancer (HCC)(1). Our collective goal was to highlight Hepatology as a forum for communicating advances in HCC. In this commentary, I will explore this latter concept in greater detail. Have we achieved our goal? Has Hepatology become a home for outstanding clinical, translational and basic research on this enigmatic, devastating malignancy? On February 9, 2009 I examined the number of manuscripts published in biomedical journals. I performed a pubmed search for hepatocellular carcinoma with various limits. The number of publications generated by pubmed was then taken as the total for the defined parameters. I made no attempt to verify the results by reading titles and/or abstracts. Also, all publications were considered to be equal numerically whether peer-reviewed original papers, reviews, letters to the editor, discussions in Hepatology elsewhere, etc. Thus, in this respect, the data are unexpurgated. Because the defined parameters are the same for each time period and journal, the data are unbiased and useful for tracking trends or qualitative comparisons. Others may want a more refined analysis, but this more superficial approach does permit an initial exploration of the above questions. What did I learn from this exercise? First, my search suggested that approximately 2,934 publications on hepatocellular cancer were published in the last 12 months, a staggering number of publications, suggesting immense world-wide interest in hepatocellular carcinoma. Obviously, no single journal should or could publish all these manuscripts. For example, Hepatology published 349 papers in 2008, or approximately 30 per month. For Hepatology to publish all of these HCC publications there would need to be 100 issues published/year which would translate into 8-9 issues/month or two issues per week. This is neither practical nor would it be acceptable to the readership of Hepatology. This number of papers was also too large for my simplified approach and therefore, to further limit my analysis, I employed the ISI web of knowledge by Thomson Reuters to categorize journals by subject and impact factor. I searched the top-tiered journals in oncology, gastroenterology and hepatology, surgery, radiology and pathology. Only journals with leading impact factors in their subject matter which published at least 5 HCC citations in the last 12 months were further analyzed (Table I). The number of HCC papers in these journals accounted for 438 of the 2934; thus, 14% of all papers on HCC were published in these 21 journals. Given the multidisciplinary nature of HCC, this spread of papers over multiple discipline-related journals is not surprising. Of the top 7 journals publishing more than 20 HCC papers per year, 3 are in the subject category of gastroenterology and hepatology, 2 in surgery and 2 in oncology (Figure 1). Two of these 7 top tier journals are sponsored by the American Association for the Study of Liver Diseases; Hepatology and Liver Transplantation. Hepatology was the clear winner in this analysis with more than double the number of publications of the 2nd journal. Thus, our multidisciplinary society and its Journals feature prominently publications regarding HCC. Figure 1 The number of publications in 2008 on hepatocellular carcinoma by specialty Journal Table I Leading Sub-special Journals by Impact Factor Publishing >5 Papers on HCC in 2008 In my final cursory analysis, I asked if the number of HCC publications in Hepatology is static or increasing. The number of HCC publications in Hepatology increased significantly in 2008 (Figure 2). Perhaps my prior commentary and having HCC-oriented Associate Editors has promoted this trend. What is yet unclear is the potential impact factor of these publications. Such an analysis of the 2008 publications will need to wait until 2010 and thus, it is premature to address this question. However, I am optimistic that these papers will be cited as often as other topic-oriented papers in Hepatology given world-wide interest in this cancer. Figure 2 The number of publications in Hepatology per year on hepatocellular carcinoma Have we achieved our goal of providing a premier forum for excellent papers on HCC? The answer is, yes in part, but we can do better. These data indicate that Hepatology has become a forum for papers on HCC. Indeed, Hepatology is perhaps an ideal forum for HCC publications given its focus on ‘all things liver’ and the scope of its multidisciplinary publications covering basic, translational and clinical research. Hepatology was also third in Table 1 in regards to impact factor (Journal of Clinical Oncology and Gastroenterology had higher impact factors). Thus, Hepatology is increasing its visibility as a ‘cancer journal’. As I searched pubmed, I was impressed by the number of outstanding papers for which I was unaware. Many investigators choose to publish papers in journals which are sponsored by societies in which they are members or in journals specific to the geographic regime in which they live. They likely select these journals for their publications so that their colleagues see and read their papers. Local recognition can be important for referrals, academic promotions and stature. However, we emphasize the universal attraction of Hepatology as a journal for all disciplines to read and publish, given its high impact factor and its focus. We are a home for disciplinary integration for ‘all things liver’ and continue to welcome excellent HCC papers from our colleagues in surgical oncology, pathology, radiology and basic science.

Ballooned hepatocytes, undead cells, sonic hedgehog, and Vitamin E: Therapeutic implications for nonalcoholic steatohepatitis

Without question, nonalcoholic steatohepatitis (NASH) has emerged as a substantial public health problem. The complex and intertwined cellular and molecular mechanisms culminating in the pathophysiology of this disease process remain only partially understood and therapeutic options remain suboptimal. Lipotoxic hepatocyte injury is a cardinal feature of NASH pathogenesis (1, 2), and ballooned hepatocytes are a prominent histopathologic feature of lipotoxic hepatic injury. In fact, the magnitude of ballooned hepatocytes correlates with disease severity (3), and semiquantitation of hepatocyte ballooning is used to calculate the nonalcoholic fatty liver disease activity score, NAS (4). Dr. Diehl and co-workers made a seminal insight when they discovered that ballooned hepatocytes generate sonic hedgehog (Shh), a ligand of the hedgehog signaling pathway, which promotes hepatic fibrogenesis (5, 6). These data provided mechanistic insight into a mechanism contributing to hepatic fibrogenesis in NASH. However, several relevant questions remain. What is the ballooned hepatocyte, and why does it generate sonic hedgehog? Does NASH targeted therapy alter the number of ballooned hepatocytes in NASH? What is the spectrum of sonic hedgehog signaling in NASH? and Is hedgehog signaling inhibition a strategic pharmacologic strategy for NASH?

A novel, minimally invasive technique for management of peristomal varices

1) Anderson G, Beischlag TV, Vinciguerra M, Mazzoccoli G. The circadian clock circuitry and the AHR signaling pathway in physiology and pathology. Biochem Pharmacol 2013;85:14051416. 2) Lu P, Yan J, Liu K, Garbacz WG, Wang P, Xu M, et al. Activation of aryl hydrocarbon receptor dissociates fatty liver from insulin resistance by inducing fibroblast growth factor 21. HEPATOLOGY 2015;61:1908-1919. 3) Inagaki T, Dutchak P, Zhao G, Ding X, Gautron L, Parameswara V, et al. Endocrine regulation of the fasting response by PPARalpha-mediated induction of fibroblast growth factor 21. Cell Metab 2007;5:415-425. 4) Yu H, Xia F, Lam KS, Wang Y, Bao Y, Zhang J, et al. Circadian rhythm of circulating fibroblast growth factor 21 is related to diurnal changes in fatty acids in humans. Clin Chem 2011;57:691-700. 5) Kharitonenkov A, Shiyanova TL, Koester A, Ford AM, Micanovic R, Galbreath EJ, et al. FGF-21 as a novel metabolic regulator. J Clin Invest 2005;115:1627-1635.

Surveillance for cholangiocarcinoma in patients with primary sclerosing cholangitis: Effective and justified?

The cause of PSC is unknown, and there are currently no effective therapeutic strategies to prevent adverse outcomes of this progressive liver disease. Malignancies are the cause of death in up to 44% of patients with PSC. The risk for cholangiocarcinoma (CCA) development in patients with PSC is approximately 160to 1560-fold greater than for the general population. The absolute risk for CCA in PSC is approximately 9% over 10 years. The mean age of CCA diagnosis in patients with PSC is in the fourth decade of life versus the seventh decade in the general population. Hence given the increased risk for CCA in young adults with PSC, this question is frequently posed: Should surveillance strategies be used to detect early CCA in patients with PSC, and if so, how?

Proapoptotic signaling induced by deletion of receptor‐interacting kinase 1 and TNF receptor‐associated factor 2 results in liver carcinogenesis

Receptor-interacting kinase (RIPK) 1 critically controls signaling pathways triggered by the engagement of death receptors with their cognate ligands, such as tumor necrosis factor (TNF) receptor 1 and its ligand, TNF. Because of its unique position at the crossroad of multiple signaling cascades, RIPK1 has an essential role in the regulation of inflammation and cell death through the activation of nuclear factor-jB (NF-jB)mediated gene transcription, and control of both apoptosis and necroptosis. Interestingly, RIPK1 has very distinct kinase-dependent and -independent functions, which can have opposite effects on the same pathway. For example, RIPK1 kinase activity promotes caspase 8–mediated apoptosis and RIPK3-dependent necroptosis, but its kinase-independent scaffolding function inhibits both forms of cell death and contributes to NF-jB activation. The same level of complexity is found when studying the role of RIPK1 in the liver. RIPK1 kinase activity drives hepatocyte death and liver injury following concanavalin A injection (a model of T-cellmediated hepatitis), but its scaffolding function protects from massive apoptosis in the same model. Similarly, depletion of RIPK1 in the liver sensitizes hepatocytes to lipopolysaccharide-induced TNF-mediated cell death. It appears that TNF-induced apoptosis in RIPK1-depleted cells is associated with degradation of cellular FLICE-inhibitory protein (cFLIP), cellular inhibitors of apoptosis (cIAPs), and TNF receptorassociated factor 2 (TRAF2), and activation of the noncanonical NF-jB pathway. RIPK1 knockdown also exacerbates cell death in a-galactosylceramideinduced immune-mediated liver injury. It should be noted that RIPK1 has been investigated largely for its contribution to RIPK3-dependent necroptosis in various models of liver injury. However, RIPK3 is normally not expressed in hepatocytes, and even if its induction has been observed in chronic liver diseases, such as alcoholic and nonalcoholic steatohepatitis, the occurrence of RIPK3-dependent necroptosis in these diseases has not been unequivocally proven. Hence, the story of RIPK1 in liver biology and pathobiology is still evolving and poorly understood. A recent publication in Cancer Cell by Schneider et al. has shed new light on the role of RIPK1 in liver tumorigenesis. The investigators demonstrated that deletion of RIPK1 in liver parenchymal cells (LPCs) in vivo sensitized hepatocytes to TNFmediated apoptosis and acute hepatitis by promoting proteasomal degradation of TRAF2 and subsequent caspase 8 activation. The antiapoptotic effect of RIPK1 was attributed to its scaffolding functions given that degradation of TRAF2 in response to TNF stimulation was not prevented by the use of RIPK1 kinase inhibitors or in cells expressing catalytically inactive RIPK1. Genetic deletion of RIPK1 or TRAF2 in LPCs did not lead to a spontaneous phenotype; however, combined deletion of RIPK1 and TRAF2 in LPCs caused excessive hepatocyte apoptosis, hepatic inflammation, compensatory proliferation, and development of hepatocellular carcinoma (HCC; Fig. 1). Increased apoptosis was attributed to simultaneous activation of caspase 8 and impaired activation of the NF-jB canonical pathway, which resulted in decreased levels of the antiapoptotic proteins cFLIP and cIAP1. These observations suggested that RIPK1 and TRAF2 have partially redundant functions in controlling the apoptotic pathway and NF-jB activation. Unfortunately, the investigators do not report whether the noncanonical NF-jB pathway was affected in these mice given that this alternative pathway is activated in TRAF2 mice. Finally, analysis of RIPK1 and TRAF2 expression in 99 human HCC samples demonstrated that lower expression of these two proteins correlated with worse prognosis and survival. The study by Schneider et al. is an important confirmation that RIPK1 controls LPC cell fate in terms of life and death and highlights the diverse roles of RIPK1 mediated by either its kinase activity or scaffolding functions, a dichotomy clearly demonstrated in genetically modified mice. Mice expressing kinasedead RIPK1 (K45A or D138N point mutation) are viable and develop normally. In contrast, RIPK1

Acetaminophen knocks on death's door and receptor interacting protein 1 kinase answers

I n the current issue of HEPATOLOGY, the study by Dara et al. provides fundamental insights regarding the mechanisms of cell death during N-acetyl-p-aminophenol (acetaminophen; APAP)–induced liver injury. Hepatotoxicity with liver failure from intentional and unintentional overdoses of APAP continues to be a public health problem. Therapy is limited to early use of Nacetylcysteine, which is ineffective later in the course of liver injury. Thus, mechanistic insights concerning the mechanisms of APAP hepatotoxicity remain highly germane.

Paving the TRAIL to anti-fibrotic therapy

Hepatic fibrosis (HF) is a nefarious feature of chronic liver injury, regardless of the etiology, and when advanced, leads to portal hypertension and the well-recognized attendant deleterious sequela of this clinical syndrome. In its initial stages, HF can regress if the causative injury is removed, thereby preventing progression to advanced liver disease (e.g., hepatitis B, and so on). However, preventing or limiting HF by therapeutic strategies targeting the mechanisms of liver injury is currently not always feasible (e.g., primary sclerosing cholangitis, etc.). Therefore, development of effective antifibrotic drugs able to halt or even cause regression of HF would be therapeutically advantageous in many human chronic liver diseases. Fibrosis is the result of excessive deposition of extracellular matrix, including type I collagen, produced by wound-healing myofibroblasts. The origin of the myofibroblast population in the liver has been controversial, but it is now widely accepted that the largest portion of myofibroblasts are derived from activated hepatic stellate cells (aHSCs). Indeed, fate-tracing studies in different experimental models of murine HF have identified hepatic stellate cells (HSCs) as the predominant profibrogenic cell population in the liver, which renders this cell type the primary target for antifibrotic therapies. Consistent with this concept, deleting aHSCs either induces resolution or prevents progression of HF in mice. Moreover, the availability of new, more effective experimental tools, which permit the specific depletion of aHSCs in vivo by HSC-specific promoterdriven transgene expression, have provided a better understanding of the role of HSCs in promoting not only HF, but also liver injury. Therefore, depleting aHSCs is an attractive therapeutic strategy for treatment of human HF. One approach toward this goal is to develop a well-tolerated, selective “chemotherapy” for aHSCs, resulting in their selective depletion from the liver. Many chemotherapy-based cell-depleting strategies induce apoptosis in their target cell population. Based on these concepts, a potential therapeutic strategy for HF would be to induce aHSC apoptosis. TRAIL (tumor necrosis factor-related apoptosisinducing ligand/Apo-2-ligand; gene name TNFSF10) is a death ligand that can induce apoptosis in cells expressing its cognate receptors, TRAIL receptor 1 (TRAILR1, also known as death receptor 4 [DR4]; gene name TNFRSF10A) and/or TRAIL-R2 (also known as death receptor 5 [DR5]; gene name TNFRSF10B). TRAIL is abundantly expressed by cells of the innate immune system, especially natural killer (NK) cells. Because of its still enigmatic ability to selectively induce apoptosis in cancer cells in vitro, while showing no apparent toxicity to normal cells, TRAIL has been widely tested as a chemotherapeutic anticancer agent. However, despite promising results in vitro and in preclinical studies, efficacy of several recombinant TRAIL or TRAIL receptor agonists in clinical trials has been limited. Past observations by us reported that aHSCs in vitro up-regulate DR5 and, to a lesser extent, DR4 and acquire sensitivity to TRAILmediated apoptosis. Also, Gao et al. demonstrated that NK cells may delete aHSCs in murine models of liver fibrosis, in part, by a TRAIL-dependent mechanism. These observations provided the premise that TRAIL Abbreviations: aHSCs, activated HSCs; DR, death receptor; HF, hepatic fibrosis; HSC, hepatic stellate cells; NK, natural killer; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand; TRAILPEG, poly(ethylene glycol)(PEG)ylated human trimeric isoleucine-zipper fused TRAIL.