Death rates from hepatocellular carcinoma (HCC) are steadily increasing, yet therapeutic options for advanced HCC are limited. We identify a subset of mouse and human HCCs harboring VEGFA genomic ...amplification, displaying distinct biologic characteristics. Unlike common tumor amplifications, this one seems to work via heterotypic paracrine interactions; stromal VEGF receptors (VEGFR), responding to tumor VEGF-A, produce hepatocyte growth factor (HGF) that reciprocally affects tumor cells. VEGF-A inhibition results in HGF downregulation and reduced proliferation, specifically in amplicon-positive mouse HCCs. Sorafenib-the first-line drug in advanced HCC-targets multiple kinases, including VEGFRs, but has only an overall mild beneficial effect. We found that VEGFA amplification specifies mouse and human HCCs that are distinctly sensitive to sorafenib. FISH analysis of a retrospective patient cohort showed markedly improved survival of sorafenib-treated patients with VEGFA-amplified HCCs, suggesting that VEGFA amplification is a potential biomarker for HCC response to VEGF-A-blocking drugs.
Using a mouse model of inflammation-driven cancer, we identified a subclass of HCC carrying VEGFA amplification, which is particularly sensitive to VEGF-A inhibition. We found that a similar amplification in human HCC identifies patients who favorably responded to sorafenib-the first-line treatment of advanced HCC-which has an overall moderate therapeutic efficacy.
Fibroblast growth factor receptor 2 (FGFR2) fusion proteins (FFs) are oncogenic drivers in 10-15% of intrahepatic cholangiocarcinoma (iCCA). FGFR-specific inhibitors provide temporary benefit in FF
...unresectable patients. Recent work with mouse iCCA models has documented the necessary role of RAS-ERK downstream to FFs and provided examples of preclinical experimentation aimed at improving FF targeting in iCCA.
Transarterial chemo-embolisation (TACE) is recommended for patients with BCLC intermediate stage hepatocellular carcinoma (stage B), particularly in patients with good underlying liver function and ...minimal symptoms. The hepatoma arterial embolisation prognostic (HAP) score combines measures of liver function and tumour-related factors to offer a simple prognostic scoring system. The Albumin-Bilirubin (ALBI) grade permits assessment of the impact of liver function on survival. We aimed to investigate these two models and vascular invasion (VI).
In an international cohort of 3030 patients undergoing TACE, we examined the impact of liver function as assessed by the ALBI score, the HAP score and VI on survival.
Classification according to ALBI grade resulted in non-overlapping survival curves in the overall data set and all regional cohorts. The HAP score was also validated. Tumour number, aetiology and VI were identified as additional independent prognostic risk factors not currently included in the HAP score. Survival was particularly poor for patients with VI.
The ALBI grade categorised patients receiving TACE into three clear prognostic groups, thereby emphasising the importance of underlying liver function in the outcome of TACE. The HAP score has been validated internationally and the serious adverse impact of VI is clearly shown.
In 1950, Waldenström was the first to describe a chronic form of hepatitis in young women. Subsequently, the disease was found to be associated with other autoimmune syndromes and was later termed ...“lupoid hepatitis” because of the presence of antinuclear antibodies. In 1965, it became designated by Mackay et al. as “autoimmune hepatitis” at an international meeting, at which the general concept of autoimmunity was endorsed by the scientific community. In the early 1960s and 1970s, the value of immunosuppressive therapy with glucocorticoids and/or azathioprine was well documented in several studies. The original association of autoimmune hepatitis (AIH) and HLA alleles, which has remarkably stood the test of time, was published in 1972. In the 1970s and 1980s, several autoantibodies were identified in patients with autoimmune hepatitis directed against proteins of the endoplasmatic reticulum expressed in liver and kidney and against soluble liver antigens. Subsequently, the molecular targets of these antibodies were identified and more precisely characterized. In the last two decades many additional pieces of the AIH puzzle have been collected leading to the identification of additional antibodies and genes associated with AIH and to the emergence of new therapeutic agents. Meanwhile, the immunoserological and genetic heterogeneity of AIH is well established and it has become obvious that clinical manifestations, disease behavior, and treatment outcome may vary by racial groups, geographical regions and genetic predisposition. Currently, the International Autoimmune hepatitis group is endorsing multi‐center collaborative studies to more precisely define the features at disease presentation and to define prognostic indices and appropriate treatment algorithms. Given the importance of serological testing, the IAHG is also working on guidelines and procedures for more reliable and standardized testing of autoantibodies. (Hepatology 2006;43;S132–S144.)
The receptor for advanced glycation endproducts (RAGE) is a multiligand receptor and member of the immunoglobulin superfamily. RAGE is mainly involved in tissue damage and chronic inflammatory ...disorders, sustaining the inflammatory response upon engagement with damage‐associated molecular pattern molecules (DAMPs) such as S100 proteins and high‐mobility group box 1 (HMGB1). Enhanced expression of RAGE and its ligands has been demonstrated in distinct tumors and several studies support its crucial role in tumor progression and metastasis by still unknown mechanisms. Here we show that RAGE supports hepatocellular carcinoma (HCC) formation in the Mdr2−/− mouse model, a prototype model of inflammation‐driven HCC formation, which mimics the human pathology. Mdr2−/− Rage−/− (dKO) mice developed smaller and fewer HCCs than Mdr2−/− mice. Interestingly, although in preneoplastic Mdr2−/− livers RAGE ablation did not affect the onset of inflammation, premalignant dKO livers showed reduced liver damage and fibrosis, in association with decreased oval cell activation. Oval cells expressed high RAGE levels and displayed reduced proliferation upon RAGE silencing. Moreover, stimulation of oval cells with HMGB1 promoted an ERK1/2‐Cyclin D1‐dependent oval cell proliferation in vitro. Finally, genetic and pharmacologic blockade of RAGE signaling impaired oval cell activation in an independent mouse model of oval cell activation, the choline deficient ethionine‐supplemented dietary regime. Conclusion: Our data identified a novel function of RAGE in regulating oval cell activation and tumor development in inflammation‐associated liver carcinogenesis. (Hepatology 2013)
Epigenetic inactivation by aberrant DNA methylation has been reported for many microRNA genes in various human malignancies. However, relatively little is known about microRNA gene methylation in ...hepatocellular carcinoma (HCC). Therefore, a systematic screen for identification of aberrantly hypermethylated microRNA genes in HCC was initiated. The methylation status of 39 intergenic CpG island associated microRNA genes was analyzed in HCC cell lines (n = 7), immortalized hepatocytes (n = 2) and normal liver samples (n = 5). Subsequently, 13 differentially methylated microRNA genes were analyzed in primary human HCC samples (n = 40), benign liver tumors (n = 15) and the adjacent liver tissues employing pyrosequencing. Expression of microRNA genes was measured using quantitative real‐time polymerase chain reaction (RT‐PCR). In addition, DNA methylation and expression of microRNA genes were measured after DNMT1 knockdown or DNMT inhibition. Aberrant hypermethylation and concomitant reduction in expression of intergenic microRNA genes is a frequent event in human HCC: hsa‐mir‐9‐2 (23%), hsa‐mir‐9‐3 (50 %), hsa‐mir‐124‐1 (20%), hsa‐mir‐124‐2 (13%), hsa‐mir‐124‐3 (43%), hsa‐mir‐129‐2 (58%), hsa‐mir‐596 (28%) and hsa‐mir‐1247 (38%). Altogether, it affects 90% of the HCC specimens under study. MicroRNA gene methylation is not found in hepatocellular adenoma (n = 10) and focal nodular hyperplasia (n = 5). DNMT1 knockdown or DNMT inhibition reduced microRNA gene methylation and stimulated expression. In primary human HCC specimens hypermethylation and expression of microRNA genes showed an inverse correlation. Concordant hypermethylation of three or more microRNA genes is a highly specific marker for the detection of HCC and for poor prognosis.
What's new?
Inactivation of miRNAs by methylation occurs in various cancers, but little is known so far about methylation of miRNAs in liver cancer. In this study, the authors compared the methylation status of 13 differentially methylated miRNAs in primary hepatocellular carcinoma, benign liver tumors, and normal liver specimens. They found epigenetic inactivation by methylation in most of the cancer cell lines. This hypermethylation could be used to distinguish between cancerous and benign liver tumors.
Hepatocellular carcinoma (HCC) is one of the most common and deadly malignancies worldwide. The multikinase inhibitor sorafenib still remains the only approved agent for advanced HCC. In most cases, ...HCC develops based on advanced liver cirrhosis, whereas the underlying risk factors can be identified in the vast majority of patients.
Here, we summarise and review the pathomechanisms in dependence of the underlying disease, gene signatures and frequent mutations in HCC.
Worldwide, HCC is most commonly caused by viral hepatitis B and C. It is less frequently associated with chronic exposure to toxins or hereditary liver diseases. Non-alcoholic fatty liver disease is an emerging risk factor with increasing prevalence nowadays. Emerging innovative technologies including whole-genome or -exome analyses have been applied for molecular and prognostic classifications as well as therapeutic implications. Mutations leading to activation of the Wnt pathway and inactivation of p53 were most frequently identified in HCC.
Recent advances have significantly improved our understanding of the molecular pathogenesis of HCC and its complex genetic landscape. The emerging data will open the door towards novel and more effective targeted and personalized therapies in this devastating disease.
Adjuvant therapy of biliary tract cancers Kefas, Joanna; Bridgewater, John; Vogel, Arndt ...
Therapeutic Advances in Medical Oncology,
01/2023, Letnik:
15
Book Review, Journal Article
Recenzirano
Odprti dostop
Biliary tract cancers (BTCs) are rare and heterogeneous malignant tumours including cholangiocarcinoma and gallbladder cancer. They are very aggressive, often refractory to chemotherapy and ...associated with an overall poor prognosis. Surgical resection remains the only potentially curative treatment option but less than 35% present with resectable disease. Adjuvant treatments have been widely used but until recently, supportive data were limited to non-randomised, non-controlled retrospective studies. Recent evidence from the BILCAP trial has established adjuvant capecitabine as the standard of care. But there are still unanswered questions as to the role of adjuvant therapy. Further prospective data and translational research with reproducible evidence of clinical benefit are needed. In this review of adjuvant therapy in resectable BTCs, we will summarise the latest evidence setting current treatment standards and highlight future prospects.
Hepatocellular carcinoma (HCC) frequently arises in the context of chronic injury that promotes DNA damage and chromosomal aberrations. The cyclin‐dependent kinase inhibitor p21 is an important ...transcriptional target of several tumor suppressors, which promotes cell cycle arrest in response to many stimuli. The aim of this study was to further delineate the role of p21 in the liver during moderate and severe injury and to specify its role in the initiation and progression of HCC. Deletion of p21 led to continuous hepatocyte proliferation in mice with severe injury allowing animal survival but also facilitated rapid tumor development, suggesting that control of compensatory proliferation by high levels of p21 is critical to the prevention of tumor development. Unexpectedly, however, liver regeneration and hepatocarcinogenesis was impaired in p21‐deficient mice with moderate injury. Mechanistically, loss of p21 was compensated by activation of Sestrin2, which impaired mitogenic mammalian target of rapamycin (mTOR) signaling and activated cytoprotective Nrf2 signaling. Conclusion: The degree of liver injury and the strength of p21 activation determine its effects on liver regeneration and tumor development in the liver. Moreover, our data uncover a molecular link in the complex mTOR, Nrf2, and p53/p21‐signaling network through activation of Sestrin2, which regulates hepatocyte proliferation and tumor development in mice with liver injury. (Hepatology 2013;53:1143–1152)
Background & Aims
The prognosis of biliary tract cancer (BTC) is poor. Standard treatment for advanced BTC is a chemotherapy (CT) with gemcitabine and cisplatin. Phase III evidence for a second‐line ...(2L) CT is lacking. We aimed to investigate the feasibility of a 2L CT, to estimate the outcome and to identify prognostic markers.
Methods
Patients of our institution with advanced BTC between 2000 and 2015 receiving CT were included. Data were analysed in univariate and multivariate analysis.
Results
Three‐hundred and fifteen and 144 patients (45.7%) received first‐line (1L) and 2L CT respectively. The OS of patients receiving 2L CT was 16.67 and 9.9 months from the beginning of 1L and 2L CT respectively. The overall response rate and the disease control rate after 3 months were 9.7% and 33.6% respectively. Adverse events of grade 3 or more were observed in 26.1%. One patient died of gemcitabine‐related haemolytic uraemic syndrome. Age of more than 70 years was not associated with a poor outcome. In multivariate analysis, CEA levels of >3 µg/L (P = 0.004, hazard ratio HR 1.89, 95% CI 1.22, 2.91), cholinesterase (CHE) levels of <5 kU/L (P = 0.001, HR 2.11, 95% CI 1.34, 3.31) and leukocytosis (P = 0.001, HR 2.90, 95% CI 1.51, 5.56) were associated with poor survival.
Conclusions
Despite a relevant toxicity, our data suggest that 2L CT may be feasible in fit BTC patients. CEA elevation, leukocytosis and low CHE levels are unfavourable prognostic markers. Results from prospective randomized trials are urgently awaited.
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