Schistosoma mansoni and Hepatocellular Carcinoma: Is It All About c‐Jun and Signal Transducer and Activator of Transcription 3?
Authors: Diego F. Calvisi
Journal: Hepatology (2020)

SEE ARTICLE ON PAGE 627 Potential conflict of interest: Nothing to report. Schistosomiasis is a chronic helminthic disease caused by parasitic flatworms called schistosomes, infecting >207 million persons in 78 countries worldwide, and provoking >200,000 deaths annually.(1,2) Schistosomiasis is the cause of a spectrum of serious diseases affecting several organs, belonging to the genitourinary, digestive, and nervous systems.(1,2) In the liver, schistosomiasis induces hepatic fibrosis, hepatosplenomegaly, and portal hypertension. Pathogenetically, emerging evidence implies that schistosome eggs, rather than adult worms, are responsible for the morbidity induced by this infection.(1,2) Although the association between Schistosoma haematobium and bladder squamous‐cell carcinoma is well established,(3) cumulating findings point to the involvement of the Schistosoma genus in the development and/or progression of several other tumor types as well, including colorectal carcinoma, prostate adenocarcinoma, giant follicular lymphoma, and hepatocellular carcinoma (HCC).(4,5) In human HCC, experimental and clinical investigations suggest Schistosoma mansoni and japonicum as the species associated with liver carcinogenesis.(6) Specifically, it has been found that S. mansoni infection in a liver cancer mouse model resulted in shortened tumor latency and accelerated cancer formation.(6) Furthermore, it has been hypothesized that Schistosomiasis potentiates liver injury in association with hepatitis B virus and hepatitis C virus (HCV) chronic infections.(6) In agreement with this hypothesis, concomitant infection by S. mansoni and HCV, which occurs mainly in developing countries, more often leads to chronic hepatitis and aggravates liver damage.(6) Also, patients with HCV and Schistosoma mansoni coinfection exhibit a markedly accelerated and more severe hepatic fibrosis when compared to HCV infection alone. Noticeably, patients coinfected with HCV and Schistosomiasis seem to have a higher risk to develop HCC, with the related tumors showing peculiar features, such as being histopathologically and clinically aggressive, multifocal, and of large size.(6) Despite these concordant data, whether S. mansoni truly possesses liver carcinogenic potential remains a matter of discussion. Similar to other hepatic flukes, it is plausible that infection by S. mansoni triggers several genotoxic‐inducing events in the liver, including chronic inflammation with granuloma formation, oxidative stress induced by parasite‐derived products, and tissue damage. These harmful events would eventually trigger a plethora of tissue repair mechanisms consisting of elevated compensatory cell turnover as well as dysregulation of the tumor microenvironment compartment and the immune milieu, ultimately leading to hepatocarcinogenesis (HCG).(4‐6) However, more solid data, especially at the molecular level, are necessary to further substantiate this hypothesis as well as to develop innovative therapeutic strategies aimed at preventing and/or limiting the oncogenic effects of S. mansoni infection on the liver. In the present issue of Hepatology, Roderfeld et al.(7) take a further step in understanding the molecular mechanisms linking S. mansoni infection to HCC. Through a series of elegant and complementary experiments, the researchers investigated whether infection by this trematode is associated with activation of c‐Jun and signal transducer and activator of transcription 3 (STAT3) proto‐oncogenes, whose role in liver inflammation and carcinogenesis is well established.(8,9) For this purpose, S. mansoni–infected hamsters, Huh7 HCC cells, primary hepatocytes, and human liver biopsies were used. To maintain the S. mansoni life cycle, Biomphalaria glabrata snails were used as intermediate hosts, whereas Syrian hamsters were used as final hosts. The parasite's eggs were prepared from livers of bisex‐infected hamsters at day 46 postinfection, and soluble egg antigens (SEAs) were extracted from the schistosomes. The researchers found that the trematode's eggs enter the liver of the hamster by the portal vein, getting trapped in the sinusoids around the portal tracts and attracting inflammatory and immune cells, leading to the creation of periovular granulomas. Based on these findings, the researchers concluded that this hamster model for S. mansoni infection is a valuable system for further experiments, given that it faithfully recapitulates the major features of the human disease. Subsequently, the researchers demonstrated, using a phospho‐kinase approach, that administration of SEAs stimulated primary hepatocytes to activate c‐Jun and STAT3 proteins. In addition, livers of S. mansoni–infected hamsters exhibited nuclear translocation of c‐Jun (a sign of its transcriptional activation) in the hepatocytes located around granulomas and directionally from granulomas to the central veins, as assessed by immunohistochemistry. Altogether, these intriguing data suggest that the substances released from schistosome eggs are responsible for the observed effects. Noticeably, the hepatocytes displaying c‐Jun activation showed signs of proliferation stress and DNA damage (activation of Ki67, proliferating cell nuclear antigen, p27, and gamma‐H2A histone family member X). To further corroborate the observations from the hamster model, a validation study was conducted in human liver biopsies from patients with schistosomiasis. Intriguingly, the analysis of these biopsies revealed the presence of hepatic histopathological and molecular alterations resembling those detected in the hamster system, further underlying the possible clinical relevance of the experimental findings. Furthermore, induction of c‐Jun and STAT3 as well as activation of the DNA repair machinery were recapitulated by administering SEAs and culture supernatants of live schistosome egg to primary hepatocytes and Huh7 cells. These molecular events were also recapitulated by the administration of a major component secreted by schistosome eggs, namely IPSE/alpha‐1 (interleukin [IL]‐4‐inducing principle from S. mansoni eggs),(10) alone. The researchers conclude that substances released from tissue‐trapped schistosome eggs trigger the permanent activation of c‐Jun and STAT3 proto‐oncogenes, whose induction could significantly contribute to HCC development in S. mansoni–infected patients (Fig. 1).FIG. 1: Schematic representation of the pathogenetic events linking the infection by S. mansoni to HCC development, based on the study by Roderfled et al. (A) Simplified view of the hepatic lobule in physiological conditions. (B) Following S. mansoni infection, some of the schistosome eggs enter the liver through the portal venous system, remain lodged in the sinusoids around the portal tracts, and attract inflammatory and immune cells, eliciting an intense granulomatous inflammatory response and the consequent damage or death of adjacent hepatocytes (C). In addition, S. mansoni's eggs produce bioactive molecules (indicated here as SEAs), such as IPSE/alpha‐1, which transcriptionally activate c‐Jun and STAT3 proto‐oncogenes. (D) The combined activity of the schistosomes' eggs, immune cells, and the microenvironment compartment, together with the compensatory hepatocyte proliferation, leads to derangement of the hepatic lobule structure. (D) As a consequence, liver fibrosis and portal hypertension develop; in addition, hepatocyte production of c‐Jun and STAT3 stimulated by SEAs (presumably in association with the secretion of cytotoxic and mutagenic substances by immune and nonparenchymal cells) triggers further rounds of hepatocyte replication, induces genomic instability, and ultimately might lead to HCC development.The excellent study by Roderfeld et al provides novel and important insights into the pathogenesis (and related molecular mechanisms) of S. mansoni–mediated liver carcinogenesis. In particular, the study identifies a number of possible targets whose inhibition might be able to either abolish or significantly downgrade the oncogenic properties of the schistosome eggs. In addition, the results of the investigation might have therapeutic implications for HCC cases associated with S. mansoni infection. However, although the present study has significantly improved our knowledge on the molecular mechanisms associated with S. mansoni–associated HCG, several questions remain unanswered and further investigation is required on this topic. Indeed, although the present study shows that S. mansoni infection induces multiple histopathological and molecular alterations in the liver, it does not fully prove that schistosome egg–driven modifications ultimately suffice to malignantly transform hepatocytes in vitro and to drive HCG in vivo. Ad‐hoc experiments in cell lines and long‐term animal studies would be presumably helpful to address this important issue. Furthermore, the use of c‐Jun and STAT3 knockout cells and animal models as well as treatment with specific chemical inhibitors should be used to decisively establish whether the activity of these two proto‐oncogenes is necessary or dispensable for schistosome‐associated HCG. To further strengthen the relevance of c‐Jun and STAT3 activity in schistosome‐driven HCG in humans, large cohorts of HCC patients infected by S. mansoni should be analyzed for c‐Jun and STAT3 activation. Moreover, given that both c‐Jun and STAT3 induce activation of a plethora of targets, investigations should be conducted to identify the downstream effectors of the two proto‐oncogenes whose inhibition is detrimental for their liver oncogenic properties. In this study, the researchers uncovered c‐Jun N‐terminal kinases (JNKs) as a relevant target of c‐Jun induced by S. mansoni in the infected liver. Given that selective and potent JNK inhibitors are available, they might represent an effective therapeutic option in this context. Furthermore, the molecular mechanisms responsible for c‐Jun and STAT3 activation by IPSE/alpha‐1 should be fully delineated to better understand the molecular pathogenesis of liver cancer associated with schistosome infection as well as to design new therapeutic approaches. For instance, it would be important to narrow down the upstream inducers of STAT3 specifically activated by IPSE/alpha‐1 (Janus kinase [JAK]1, JAK2, IL‐6, etc.), given that several drugs already approved by the U.S. Food and Drug Administration for other diseases (ruxolitinib, tocilizumab, etc.) are able to selectively inhibit the activity of these proteins. The hamster model and the in vitro systems used in the present study might represent precious preclinical tools for initial drug screening and testing. Finally, it should be determined the specific contribution of immune cells and the tumor microenvironment as well as the role of the substances produced by these cells (reactive oxygen and nitrogen species, cytokines, growth factors, etc.) in the hepatocarcinogenic process driven by the schistosome.