of NE-398, a selective COX-2 inhibitor, is derived from. PPAR-mediated ..... Cheng J, Imanishi H, Amuro Y, Hada T. NS-398, a selective cyclooxygenase-2 ...
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Hepatocellular Carcinoma: Is there a Potential for Chemoprevention Using Cyclooxygenase-2 Inhibitors? Hironori Koga,
M.D.
Second Department of Medicine, and Kurume University Research Center for Innovative Cancer Therapy, Kurume University, Kurume, Japan.
Inhibitors of cyclooxygenase-2 (COX-2) have proapoptotic and antiangiogenic effects on malignant tumors and inhibit their invasion to surrounding tissues. These properties are derived from COX-dependent and/or COX-independent signaling via peroxisome proliferator-activated receptor ␥. Although the role of COX-2 involvement in human hepatocarcinogenesis has not been determined yet, selective COX-2 inhibitors with COX-independent properties may potentially suppress hepatocarcinogenesis. This hypothesis should be confirmed in in vivo studies using animal models. These studies may provide insights into any application of the COX-2 inhibitor for primary and/or secondary chemoprevention. Cancer 2003; 98:661–7. © 2003 American Cancer Society.
KEYWORDS: hepatitis C virus (HCV), cyclooxygenase-2 (COX-2), hepatocellular carcinoma (HCC), chemoprevention, angiogenesis, retinoid, peroxisome proliferatoractivated receptor.
H
epatocellular carcinoma (HCC) is one of the most common causes of malignancy-related death in Africa and Asia,1 where the incidence of the disease is approximately 30 per 100,000 individuals per year. The prevalence of patients with HCC has increased in many countries since World War II, particularly in areas where hepatitis C virus (HCV) infection is more common than hepatitis B virus (HBV) infection.2–5 In Japan, HCV-based cirrhosis is a serious problem because it develops to HCC at a ratio of 7.9% per year.6 A peak in the HCV epidemic in the U.S. has been forecasted to occur approximately 20 –30 years after the peak of the epidemic in Japan, requiring urgent U.S. projects to prevent HCC trends similar to those current in Japan.7
Treatment Strategies for Hepatocellular Carcinoma
Address for reprints: Hironori Koga, M.D., Second Department of Medicine, and Kurume University Research Center for Innovative Cancer Therapy, Kurume University, Kurume 830-0011, Japan; Fax: (011) 81-942-34-2623; E-mail: hirokoga@med. kurume-u.ac.jp Received October 21, 2002; revision received May 5, 2003; accepted May 12, 2003. © 2003 American Cancer Society DOI 10.1002/cncr.11576
Recent advances in serologic tests for HBV and HCV have made it easy to identify patients with virus-associated chronic liver disease. These patients, especially those with active chronic viral hepatitis or cirrhosis, can be categorized into a high-risk group for HCC at outpatient clinics. Identification of the high-risk group for HCC and continuous follow-up of this group with precise imaging diagnostics enable both an early detection and an early treatment of HCC. Several efficient treatment options are available for patients with HCC, whether at an early or advanced stage of disease. These options include surgical resection,8 percutaneous ethanol injection,9,10 percutaneous radiofrequency ablation,11 and transcatheter arterial embolization.12,13 However, the early diagnosis and treatment of HCC have not necessarily contributed to improvement in prognosis.5,14 Two main reasons account for the difficulty in achieving a curative treatment of HCC. One is the multicentric occurrence of HCC in the liver with HBV- or
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HCV-associated chronic hepatitis or cirrhosis;15,16 the other is the often severely deteriorated liver function at the time of HCC treatment.17,18 Preexisting treatment modalities might not improve prognosis in patients with HCC, which asynchronously and multicentrically develops in a cirrhotic liver. Liver transplantation, due to recent progress in surgical techniques and the establishment of medical ethics, is a good treatment option for HCC. However, an organ shortage and the rapid and frequent recurrence of HCC in the transplanted liver limit the potential of this option.19 –22 Therefore, promising new chemopreventive strategies for HCC are required that do not contribute any deterioration to the functional liver reserve.
Recent Achievements in the Inhibition of Hepatocellular Carcinoma It is not yet fully understood how HBV and HCV are each involved in human hepatocarcinogenesis. Accumulating evidence has suggested that HBV encodes an oncogenic HBx gene that functions as a transactivator, up-regulating the expression of multiple cellular genes such as c-myc and c-jun.23,24 In addition, data obtained from serial analysis of gene expression demonstrated that HBx strongly regulated protein systhesis, gene transcription, and protein degradation.25 In rodents, the HCV core protein overexpressed in the liver caused HCC with steatosis and demonstrated a histologic similarity to HCC occurring in HCV-associated chronic liver diseases in humans. This observation strongly suggests an oncogenic role of the HCV core protein in hepatocarcinogenesis.26 In addition, the HCV core protein activates nuclear factor kappaB via both the inflammatory and the proliferation process.27–30 These findings confer therapeutic priority to eradication of hepatotropic viruses such as HBV and HCV from the liver to prevent virus-related HCC development. Several preliminary studies have demonstrated the chemopreventive potential of interferon (IFN) on HCC,6,31,32 although the precise mechanism for its tumor-suppressive effect remains unclear. Initially, IFN treatments were aimed at primary chemoprevention targeting initial hepatocarcinogenesis. Currently, prospective IFN trials are investigating the role of IFN in secondary chemoprevention of recurrent HCC.33,34 Acyclic retinoids are also being studied in secondary chemoprevention.35,36 Acyclic retinoids induce apoptosis and differentiation in human hepatoma cells37,38 and may eradicate malignant clones, which are transformed in the liver with HCV-associated chronic hepatitis or cirrhosis.39 To our knowledge, Muto et al.35,36 were the first to document the inhibitory effect of an acyclic retinoid, polyprenoic acid, on the occurrence of a second primary HCC after
initial surgical resection for a primary HCC. The potential of a chemopreventive strategy using this retinoid is being investigated in multicentered clinical trials in Japan.
Tumorigenic Potential of Cyclooxygenase-2 Cyclooxygenase-2 (COX-2), a key enzyme in arachidonic acid metabolism, is overexpressed in many types of malignant tumors. COX-2 induces the following advantageous properties for tumorigenesis: the angiogenenic property through accelerated production of both vascular endothelial growth factor (VEGF) and prostaglandins;40 – 44 the antiapoptotic property mediated by Bcl-2 and protein kinase B (Akt/PKB) signaling;45– 48 and the highly invasive property via activation of matrix metalloproteinases.49 –51 Therefore, COX-2 is believed to be a promising target for antitumor treatment because a wide range of tumorpromoting signal pathways can, theoretically, be covered by the selective COX-2 inhibitors, which so far are categorized as nonsteroidal antiinflammatory drugs (NSAIDs). The capability for daily and long-term administration of NSAIDs may also support the feasibility for the chemopreventive use of selective COX-2 inhibitors. Extensive data from both in vitro and in vivo studies have confirmed the chemopreventive effect of COX-2 inhibitors in colon carcinogenesis.52–56 Celecoxib, a selective COX-2 inhibitor, inhibits the growth of adenomatous polyps in patients with familial adenomatous polyposis.57 Targeting COX-2 by its selective inhibitors to prevent HCC development seems to be a fascinating therapeutic strategy. The expression of COX-2 in human HCC and the antitumor potential of COX-2 inhibitors for hepatoma cells have been investigated.51,58 – 65 However, the actual involvement of COX-2 remains unclear in human hepatocarcinogenesis.58
Possible Roles of COX-2 in “Inflammation-Mediated” Hepatocarcinogenesis The persistent inflammation in HCV-associated chronic liver disease facilitates hepatocarcinogenesis,5 although the development of HBV-associated HCC does not always require persistent hepatic inflammation. Previous studies have shown that suppressing the levels of serum alanine aminotransferase achieved a significant decline in the frequency of the development of HCC in patients with HCV-associated chronic hepatitis or cirrhosis.66,67 Although these studies were preliminary and lacked prospective design, they suggested a theoretic basis for the concept of “inflammation-mediated” hepatocarcinogenesis.68 The carcinogenic state influences the incidence of somatic genetic events in hepatocytes, through increasing the number
COX-2 Inhibitors for Chemoprevention of HCC?/Koga
of target cells or through the proliferation of once-hit hepatocytes, eventually leading to HCC.68 Several transcription factors (e.g., nuclear factor kappaB (NF-B), NF-interleukin 6, activator protein 2, polyoma virus enhancer protein 3, activating transcription factor 3, cyclic adenosine monophosphate response element, and Ebox) have the potential to regulate COX-2 expression,69 –72 suggesting involvement of inflammation-mediated induction of COX-2 in inflammation-mediated carcinogenesis. Etiologically-distinct chronic inflammations, such as ulcerative colitis and Helicobacter pyloriassociated gastritis, have been demonstrated to be potentially carcinogenic states, involving increased COX-2 expression.73–75 A significant increase in COX-2 expression occurs in noncancerous liver tissue in parallel with disease progression from chronic hepatitis to cirrhosis.58 – 60,64 In addition, a positive correlation between an increase in the COX-2 expression in nontumor liver tissue and a shorter disease-free survival has been demonstrated in patients with HCC.60 Therefore, the suppression of both proinflammatory cytokine cascades and the down-stream transcription factors to reduce the COX-2 expression may serve as a target in chemoprevention of HCC. To our knowledge, little is known regarding COX-2 expression in the dysplastic nodule (designated as adenomatous hyperplasia and atypical adenomatous hyperplasia in Japan), a precancerous lesion leading to overt HCC. However, it is noteworthy that the preserved expression of COX-2 has been demonstrated in the dysplastic nodule and in early HCC.58,60 These findings suggest the involvement of COX-2 in early-stage hapatocarcinogenesis.
COX-2 Is Not a Key Player in Late-Stage Hepatocarcinogenesis? It is also necessary to consider whether COX-2 is involved in the entire process of human hepatocarcinogenesis. In advanced HCC, which usually consists of moderately and/or poorly differentiated HCC components, COX-2 does not play a major role in promoting dedifferentiation of the tumor.58 – 60,64 Histologically, well differentiated HCC expresses profound COX-2, whereas less differentiated HCC expresses little or no COX-2.58 – 60 Advanced HCC produces VEGF76,77 and, therefore, can be described as hypervascular. VEGF production is regulated by COX-2, suggesting a promoting role of COX-2 in tumor angiogenesis through the COX-2/VEGF system.40 – 44 In HCC progression, the COX-2/VEGF system is not well understood because little or no COX-2 expression in advanced HCC should lack the potential to induce VEGF production. A similar discrepancy has been found between decreased COX-2 expression and the enhanced properties of both antiapoptosis and the high invasiveness in ad-
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FIGURE 1. Dual staining for cyclooxygenase-2 (COX-2; brown) and cytokeratin-19 (dark blue) in ductular reactions. Bile duct-like structures are comprised of both COX-2–positive and COX-2–negative cells. The COX-2–negative cells express cytokeratin-19, a phenotypic marker for biliary, but not hepatocyte, leanage.
vanced HCC. Although the mechanism for the reduced COX-2 expression in less-differentiated HCC remains unclear, it may be postulated that the decrease in the COX-2 expression is a phenotype different from hepatocytes. Immunohistochemical observations of ductular reactions, in which hepatocyte regeneration frequently occurred, have shown that no expression of COX-2 was found in bile ductule-like compartments58 (Fig. 1). It is believed that profound COX-2– expressing tumor cells have high proliferative activity.78 However, in our current in vivo observations, human HCC cells with profound COX-2 expression were negative for Ki-67 antigen staining (Fig. 2). This finding was consistent with the results from a COX-2 gene-transfection experiment, in which the COX-2– overexpressing cells were arrested at the G1 phase of the cell cycle.79 It has been demonstrated recently that overexpression of COX-2 inhibited the proliferation of mesangial cells via induction of p53, p21WAF1/Cip1, and p27Kip1.80 These findings do not always support a tumorigenic role for COX-2 in advanced HCC.
COX-Independent Antitumor Potential of COX-2 Inhibitors The antitumor effects of selective COX-2 inhibitors have been attributed to antiangiogenesis and proapoptosis. Recent studies have revealed a new antiangiogenic mechanism by which COX inhibitors increased the von Hippel Lindau protein level, which participated in the ubiquitination of hypoxia-inducible factor-1␣ (HIF-1␣), eventually leading to the down-regulation of VEGF via HIF-1␣ degradation.81 In addition, COX inhibitors inhibited integrin-mediated and Rac-dependent endothelial cell migration.82 The
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FIGURE 2.
Dual staining for cyclooxygenase-2 (COX-2; brown) and Ki-67 (dark blue) in human hepatocellular carcinoma (HCC) tissue specimens. COX-2 is localized to the cytoplasm of the HCC cells, in contrast to the localization of Ki-67 to the nucleus. Note that the HCC cells that are strongly positive for COX-2 express faint or no Ki-67 (closed arrows), whereas the HCC cells that clearly are positive for Ki-67 express weak COX-2 (open arrows). This observation suggests that COX-2 does not contribute to the cellular proliferation in human HCC.
antiapoptotic mechanism has been based predominantly on the down-regulation of the antiapoptotic Bcl-2 family proteins.45– 48 Recently, the COX-independent biologic effects of COX inhibitors have been discovered:83 the COX inhibitors (NSAIDs) act as agonists for peroxisome proliferator-activated receptor (PPAR) ␣ and ␥,83,84 which are members of the nuclear hormone receptor superfamily. PPARs regulate cellular proliferation and differentiation.85– 87 Indeed, the PPAR␥-mediated growth-inhibitory effect induced by COX inhibitors has been found in human oral squamous carcinoma cells, rheumatoid synovial cells, and lung carcinoma cells.88 –90 It is therefore suggested in human hepatoma cells that the previously-demonstrated COX-2-independent growth-inhibitory effect of NE-398, a selective COX-2 inhibitor, is derived from PPAR␥-mediated action.62,63 Indeed, previous studies have demonstrated a clear growth-inhibitory function through PPAR␥ stimulated by its ligands in human hepatoma cells.91,92 Future in vitro experiments should assess the PPAR-activating potential of “selective” COX-2 inhibitors because human hepatoma cells generally express little COX-2.58 – 60,64
ing angiogenesis, and inhibit HCC growth predominantly through the COX-independent mechanism. Further in vivo studies of animal models are required to confirm the antitumor effects of the COX-2 inhibitors on HCC.93 In future clinical settings, COX-2 inhibitors, like other NSAIDs, should be used cautiously to prevent unwanted adverse effects, including renal toxicity and hepatotoxicity.94 –98 Because NSAIDs (COX inhibitors) accumulate in the hepatobiliary compartment, forming reactive metabolites and leading to mitochondrial damage through oxidative stress,98 careful assessment of their toxicologic effects may be required, especially in patients with cirrhosis and hepatic decompensation.97 In addition, the COX-2 inhibitor has PPAR␥ ligand-like action, which may lead to severe hepatotoxicity.99,100 Gastrointestinal toxicity induced by the COX-2 inhibitor, although lower in risk than that induced by nonselective NSAIDs, may be neglected.101,102 The antitumor effects of COX-2 inhibitors are enhanced in combination therapy with conventional anticancer agents,103,104 radiotherapy,105,106 and photodynamic therapy.107 These findings might expand the therapeutic potential of COX-2 inhibitors. The PPAR␥ ligand-like action of the COX-2 inhibitor suggests another combination with ligands for the retinod X receptor (RXR), a heterodimerized partner of PPAR␥. Recent evidence, although fragmentary, has suggested synergistic antitumor effects using both the PPAR␥ and the RXR ligands.108 –110 It is important to determine the actual role(s) of COX-2 in human hepatocarcinogenesis to identify the potential role of COX-2 inhibitors in primary and/or secondary chemoprevention of HCC.
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