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Unravelling the complexities of signalling networks in hepatocellular carcinoma
▸ Kim W, Khan SK, Gvozdenovic-Jeremic J, et al. Hippo signaling interactions with Wnt/ beta-catenin and Notch signaling repress liver tumorigenesis. J Clin Invest 2017;127:137–52.
Dysregulation of signalling pathways has been associated with the development and progression of a range of human cancers including hepatocellular carcinoma (HCC). A detailed understanding of how such pathways interact in vivo is essential to allow therapeutic targeting of these pathways. In this study, the authors have dissected the role of a complex signalling network involving the Hippo, Notch and Wnt/β-catenin pathways on HCC formation and growth. Inactivation of liver Hippo signalling using transgenic mice deficient for mammalian sterile 20-like kinases (MST1 and MST2) resulted in augmentation of the activity of the transcription factors YAP and TAZ and the spontaneous development of HCC in 100% of mice. Hence, the authors confirmed a tumour-suppressive role of Hippo signalling in the liver. They proceeded to use a series of in vitro and in vivo models to determine that knockout of Hippo signalling in the liver resulted in activation of the Notch signalling pathway. Blockade of the Notch pathway using a chemical inhibitor called DAPT inhibited tumour growth. Furthermore, Wnt/β-catenin signalling seems to counteract the tumourpromoting effects of Hippo knockout, at least in part via the inhibition of Notch activation. These data nicely demonstrate the fact that complex signalling networks regulate tumorigenesis in vivo and highlight the difficulties in targeting such pathways therapeutically.
That gut feeling: grown in the lab
▸ Workman MJ, Mahe MM, Trisno S, et al. Engineered human pluripotent-stem-cell-derived intestinal tissues with a functional enteric nervous system. Nat Med 2017;23:49–59.
Organoids can be a useful three-dimensional (3D) in vitro simulation for intestinal cell growth but thus far have not incorporated the enteric nervous system. Intestinal organoids can be cultured from human-induced pluripotent stem cells (PSCs). In this study, they incorporate neural crest cells (NCCs), also developed from PSCs, by mechanically aggregating midgut/hindgut spheroids and NCCs. NCCs migrated into the intestinal mesenchyme and neurons and glia were observed, labelled by TUBB3 and S100β, respectively. Functionally there were neuronal calcium oscillations. Organoids were then engrafted into the kidney capsule of immunocompromised mice and developed crypt-villus structure with vascularity and smooth muscle layers. In addition, neurons and glia were again noted, and NOS1 was expressed at this stage, suggesting NCC maturation in vivo. Functionally, graft explants could trigger sustained waves of contraction and interstitial cells of Cajal were present. The resulting tissue differs from adult intestine in that submucosal plexus development is delayed and nerve bundles are smaller in the neuroglial plexus, and therefore is more analogous to fetal intestine. The authors offer this as a model for Hirschsprung’s disease, a congenital lack of enteric ganglia, for which the treatment is still surgical resection. A rare severe form of Hirschsprung’s disease is caused by PHOX2B mutation, and introducing this mutation into NCCs led to poor graft growth and reduced smooth muscle development. This is a novel method to create complex functional intestinal organoids. It brings us a step closer to using human pluripotent stem cells for regenerative medicine and producing patient-specific intestine for transplantation, as well as providing a more representative model for drug testing.
Could post-dieting microbial or metabolite supplementation overcome weight regain?
▸ Thaiss CA, Itav S, Rothschild D, et al. Persistent microbiome alterations modulate the rate of post-dieting weight regain. Nature 2016;540:544–51.
Maintaining weight loss after dieting is a huge challenge in battling the obesity epidemic. In humans, the challenge is greater for those who endure cycles of weight loss and regain. As with many health conditions and pathologies, the intestinal microbiome is now predicted to play a role in this process. The current study, conducted in mice, provides several new interesting insights to the story and offers some of the most direct evidence to date on how to combat this challenging phenomenon. The investigators first demonstrate the potentiating effect of cyclical weight gain and loss on biological and biometric parameters of obesity. They then illustrate that cycles of dieting are also reflected in alterations of the microbiota’s taxonomic makeup, where a dysbiosis persists even after the obesityinducing high-fat diet is removed and weight normalises. Antibiotics eliminated this effect. Taking the taxonomic 16S evaluation a step further, the investigators established a machine-learning model to show how post-dieting microbiota could predict weight regain. Taking this to the metabolite level, the investigators further identified that certain flavonoids were missing in the faecal microbiota that enhanced weight regain. The relevance of all these findings was further illustrated by experiments using faecal transplant and dietary supplementation with the missing flavonoids. Overall, these exciting findings suggest that post-dieting microbial or metabolite supplementation may have potential to overcome the challenge of potentiated weight regain. A critical next step will be to examine how these mouse-derived findings extend to humans, where dietary consumption and intestinal microbiota are exponentially more varied.
JAK-1 inhibition in Crohn’s disease: further enlarging the therapeutic armamentarium
▸ Vermeire S, Schreiber S, Petryka R, et al. Clinical remission in patients with moderate-tosevere Crohn’s disease treated with filgotinib (the FITZROY study): results from a phase 2, double-blind, randomised, placebo-controlled trial. Lancet 2017;389:266–75. doi: 10.1016/ S0140-6736(16)32537-5
The efficacy and safety of filgotinib, an orally selective Janus Kinase inhibitor, was tested in a randomised phase II study including 174 patients with Crohn’s disease with moderateto- severe disease. Active disease was confirmed by centrally read endoscopy in addition to clinical assessment. In the intention-to-treat analysis, 47% (60/128) of filgotinib 200 mg per day compared with 23% (10/44) of placebo-treated patients reached the primary endpoint of clinical remission (p=0.0077) at week 10. Among anti-tumour necrosis factor-naive patients, clinical remission was achieved in 60% (34/57) of filgotinib versus 13% (2/16) of placebo-treated patients, while these proportions changed to 37% (26/71) versus 29% (8/28) in anti-TNF-experienced patients. Endoscopic response (simple endoscopic score for Crohn’s disease improvement =50%) was achieved in 25% versus 14% (p=0.16), while rates of mucosal healing were 4% versus 2% in the filgotinib and placebo groups after 10 weeks. There were no differences in treatmentemergent adverse events between both groups in a pooled analysis, which also included an observational part of the study that examined maintenance of response till week 20, which was not powered for statistical analysis. There were however more serious infections in the filgotinib (3%) versus placebo (0%) group. The results clearly demonstrate clinical efficacy of filgotinib in patients with Crohn’s disease, likely representing another future treatment option in this debilitating disease. The smallmolecule filgotinib offers the advantage of an oral administration and the proposed benefit regarding lack of immunogenicity, and thereby prevention of loss of response, which is one of the unfavourable characteristics of antibody-based therapies. It will be interesting to see where filgotinib will find its place in our therapeutic algorithms and among its potential competitors. In this regard, it has to be noted that filgotinib showed only limited efficacy in anti-TNF refractory patients. It is therefore inevitable that future studies should identify possible predictors of therapeutic response, which would best be achieved by characterising the molecular mechanism of action. Only these findings will allow us to use the growing number of potent therapeutic substances in a rational way and avoid unguided and erratic applications, which would hinder an improved care of patients with Crohn’s disease.
Proton pump inhibitors and bone health
▸ Targownik LE, Goertzen AL, Luo Y, et al. Long-term proton pump inhibitor use is not associated with changes in bone strength and structure. Am J Gastroenterol 2017;112:95–101.
Proton pump inhibitors (PPIs) are widely prescribed, and long-term consequence of chronic use is a focus of interest. PPI use has been associated with increased risk of hip fractures possibly by interfering with osteoclast functioning. Most studies have shown no changes in bone mineral density (BMD) using DEXA scanning but alone may not be the most sensitive investigative tool. Targownik and colleagues performed a prospective study examining markers of metabolic bone health using DEXA, along with biochemical markers and 3D quantitative CT (QCT) of the femur. This technique assesses regional variations in BMD allowing for calculation of volumetric BMD and can separate the cortical and trabecular components to allow compartmental assessment. In total, 104 individuals were recruited, of which half were chronic PPI users and were well matched to those who were non-users. At baseline there were no differences in BMD measured using DEXA scanning or risk factors that might increase the risk of fracture. Other than serum gastrin, biochemical markers were also not significantly different including c-telopeptide (a marker of osteoclast function). QCT showed no differences in volumetric BMD in total bone, trabecular or cortical bone mineral mass. Multivariate analysis did not show any associations with PPI use. Follow-up of this cohort at a suitable time period would demonstrate whether there are any differences in rate of change of bone health in those using PPI or not. Similarly, this study focused on femoral markers and did not look at spinal or radial changes although these are likely to be the same. This is an important ‘negative’ study with reassuring results but longitudinal data would be more so.
Baveno VI criteria: a useful tool to avoid an unnecessary screening endoscopy?
▸ Maurice JB, Brodkin E, Arnold F, et al. Validation of the Baveno VI criteria to identify low risk cirrhotic patients not requiring endoscopic surveillance for varices. J Hepatol 2016;65:899– 905.
Variceal haemorrhage is an important complication of portal hypertension associated with significant morbidity and mortality. Transient elastography (TE) has become a widely used, noninvasive measure of liver stiffness and fibrosis, with numerous studies confirming that liver stiffness measurement (LSM) correlates well with portal pressure gradients of up to hepatic venous pressure gradient (HVPG) of 10–12 mm Hg. The Baveno VI conference guidelines suggest that cirrhotic patients with LSM <20 kPa and a platelet count >150 000/μL can avoid screening endoscopy, and is highly specific for detecting varices. In this retrospective cohort from two centres, TE patient data obtained from 2006–2015 were analysed to validate the Baveno VI guidelines. All patients with LSM =10 kPa were identified. All patients were also required to have an endoscopy within 12 months of TE and a confirmed diagnosis of chronic liver disease. After inclusion and exclusion criteria were met, TE data for 310 patients were analysed with 55% of patients having a diagnosis of HCV and varices were reported to be present in 23%. Overall 102/310 patients met Baveno VI criteria, with 11% of this group having varices and 2% having varices grade ≥2. Maurice and colleagues report that the Baveno VI criteria give a sensitivity of 0.87, specificity of 0.34, PPV 0.06 and NPV of 0.98 with positive likelihood ratio 1.31 and negative likelihood ratio of 0.39. AUROC for combined LSM and platelet count was 0.746. The authors conclude that the Baveno VI criteria correctly identified 98% of patients who could safely avoid endoscopy. Additional larger studies are required to validate the findings.
Dr Prakash Ramachandran, Dr Sujata Biswas, Dr Matthew Ciorba, Professor Raja Atreya, Dr John Leeds, Dr Norma McAvoy
Journal of Clinical Investigation, Nature Medicine, Nature, Lancet, American Journal of Gastroenterology, Journal of Hepatology.
Competing interests None declared.
Provenance and peer review Not commissioned; internally peer reviewed.