GI highlights from the literatureMairi H McLean, Education editor

BASIC SCIENCEAPEX-1 up-regulates Jagged/Notch activity to promotecolon cancer

▸ Kim MH, Kim HB, Yoon SP, et al. Colon cancer progression is driven by APEX1-mediatedupregulation of Jagged. J Clin Invest Published Online First: 21 July 2013. doi:10.1172/JCI65521

Apurinic-apyrimidinic endonuclease-1 (APEX1) is a proteinthat stimulates the DNA-binding activity of several transcrip-tional factors involved in cancer promotion and progression.Atypical expression and sub-cellular localisation of APEX1 havebeen related to clinical stage and poor prognosis in various solidtumors; however, its exact role in tumourigenicity remains to beelucidated. In this study, Kim and colleagues investigate the roleof APEX1 in colon cancer progression. Tumourigenic effects ofAPEX1 were evaluated in a noncancerous, immortalised humanfibroblast cell line, as well as colon cancer cell lines. APEX1knockdown resulted in reduced cell proliferation and tumouri-genic features in the cell lines, while over expression promotedcancer progression. The effects of APEX1 on tumour formationand progression were tested in vivo using mouse xenograftmodels. After injection of APEX1-knockdown colon cancer cellsinto nude mice, pulmonary tumour growth and metastasis weredecreased compared with controls. Conversely, there wasincreased tumour growth and metastasis when APEX1-overexpressed cells were injected into the mice. Using cDNAmicroarrays, JAG1, which encodes the major Notch ligandJagged1, was identified as a direct transcriptional target ofAPEX1. Jagged1 is up regulated in a number of cancers, includ-ing prostate, breast, ovarian, and colorectal. The APEX1mediated increase in Jagged1 transcription resulted fromincreased binding of the transcription factor EGR1 to theJagged1 promoter. EGR1 knockdown caused down regulationof Jagged1 in colon cancer cells that strongly expressed APEX1.Demonstrating clinical relevance, the authors identified strongexpression of APEX1 and Jagged1 in human colon carcinomatissues, while these proteins were expressed at low levels innormal colon tissues. Taken together, this study demonstratesthat APEX1 positively regulates Notch signalling by up regulat-ing Jagged1 expression and this promotes colon cancer tumouri-genesis. Therapeutic targeting of APEX1 may be a promisingfuture approach for treating or preventing colon cancer expres-sing high levels of Jagged1/Notch.

How aspirin prevents cancer in Barrett’s oesophagus

▸ Kostadinov RL, Kuhner MK, Li X, et al. NSAIDs modulate clonal evolution in Barrett’sesophagus. PLoS Genet 2013;9:e1003553.

Taking a regular aspirin, or another non-steroidal anti-inflammatory drug (NSAID), helps to prevent many cancers,including oesophageal adenocarcinoma that arises from its pre-cursor Barrett’s oesophagus. However, how these drugs exerttheir chemopreventative effect has remained a mystery. Canceris the consequence of somatic clonal evolution that occurs inthe body. In their elegant study, Kostadinov and colleagues rea-soned that the cancer-preventative effect of NSAIDs in Barrett’soesophagus was a consequence of the drugs impeding clonalevolution in the Barrett’s tissue. To test their hypothesis, theauthors studied Barrett’s patients who had switched their

NSAID use while under routine endoscopic surveillance. Foreach patient, the authors measured the evolution that occurredin the on-NSAID period and compared it to the evolution thatoccurred in the off-NSAID period. Evolution was measured bycomparing the somatic mutations found at the start of eachperiod with the mutations found at the end: Mutations weredetected genome-wide with single nucleotide polymorphismarrays. Remarkably, the authors found that mutations accumu-lated approximately 10 times slower while patients were takingNSAIDs. In other words, NSAIDs appeared to dramatically slowclonal evolution in Barrett’s oesophagus. Another surprise washow little clonal evolution actually occurred in the Barrett’stissue over the decades that the patients were under surveillance.In most patients, the Barrett’s tissue was made up of a patch-work of long-lived clones, with only minor changes in the muta-tion burden and clonal composition over time. The oneexception to this was a patient who showed a sudden massiveincrease in the number of detected mutations, and suggestively,three years later this individual progressed to cancer. These datasuggest that measures of the pattern of clonal evolution inBarrett’s tissue may be a powerful means to predict cancer riskin these patients.

Obesity promotes heptocellular carcinoma via changesin gut microbiota

▸ Yoshimoto S, Loo TM, Atarashi K, et al. Obesity-induced gut microbial metabolite promotesliver cancer through senescence secretome. Nature 2013;499:97–101.

Obesity is associated with an increased risk of a range ofcancers, including hepatocellular carcinoma (HCC). The exactmolecular mechanisms linking obesity and HCC risk areunknown. In this article, the authors have gone some way toexplaining this. Following administration of DMBA (dimethyl-benzanthracine), a chemical carcinogen, to mice during the neo-natal phase, they demonstrated that only obese mice, eitherfrom high fat diet (HFD) or genetically modified ob/ob mice,and not lean controls developed HCC by 30 weeks. Closer ana-lysis of these obesity-induced HCCs, showed that activatedhepatic stellate cells (HSCs) in the areas of the tumour expresseda series of senescence-associated genes, specifically a number ofcytokines and proteases previously termed the senescence-associated secretory phenotype (SASP). Using both interleukin(IL)-1β knockout mice and an HSC depletion strategy, they pro-ceeded to demonstrate that IL-1β dependent SASP expression byHSCs is critical for HCC formation in obese mice. But howdoes obesity induce a HSC senescence programme? Obesity hasbeen associated with changes in gut microbiota. The authorswent on to show that treatment of the mice with a 4 antibioticcocktail, significantly attentuated the development of HCCs inresponse to DMBA and obesity. Gene sequencing of gut micro-biota from HFD-treated mice showed a striking increase in thecontribution of Gram positive bacteria. Hence, treatment withvancomycin alone, to specifically target gram positive bacteria,was also able to inhibit obesity induced HCC formation. Finally,the authors identified deoxycholic acid (DCA) as the chemicalbiproduct produced by bacteria of the Gram positiveClostridium strain, which can induce DNA damage and contrib-ute to HSC senescence. Intriguingly, increased faecal levels ofDCA have also been seen in humans with HFDs. This study has

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provided novel insights into the pathogenesis of obesity-inducedHCC, with changes in gut microbiota leading to HSC senes-cence and consequent HCC formation. These findings couldlead to novel therapeutic avenues.

CLINICAL PRACTICEThe emergence of inflammatory bowel disease in the Asia—Pacific region

▸ Ng SC, Tang W, Ching JY, et al. Incidence and phenotype of inflammatory bowel diseasebased on results from the Asia-Pacific Crohn’s and colitis epidemiology study.Gastroenterology 2013;145:158–65.

Inflammatory bowel disease (IBD) has until recently predom-inately affected Western developed societies and the epidemi-ology in these areas is relatively well documented. Recentlyhowever the incidence and prevalence of IBD has been escalat-ing in societies with previously low incidences. The reasonsbehind these changes remain unclear but they do seem to beassociated with changes in lifestyle to adopt a ‘Western’ culture.This provides a fascinating opportunity to study the aetiologicalfactors in these developing nations, as IBD emerges to be a clin-ically significant phenomenon outside Western society. RecentlyNg and colleagues published an epidemiological study reportingthe incidence and phenotype of IBD presentation across ninenations in the Asia-Pacific region. Incidence in the Asian coun-tries was highest in China at 3.44 per 100 000 but still signifi-cantly lower than the industrialised western society of Australiawith 24.54 per 100 000. Considering disease phenotype, loca-tion of disease was similar but with a more severe disease coursein the Asian countries. Ulcerative colitis represented a signifi-cantly greater proportion of the IBD cases in Asia than Australiawith a ulcerative colitis: Crohn’s disease ratio of 2.0 in Asia and0.5 in Australia. In the discussion, the group indicates that thesedifferences may be a reflection of the healthcare systems but themore severe disease course in the Asian population is in keepingwith studies of immigrant populations in industrialised nations.Nonetheless, the emergence and study of IBD in these emergingregions will be vital to establishing the environmental factorsthat trigger onset.

Reduced rate of post ERCP pancreatitis using therendezvous procedure: Meeting in the middle?

▸ Swahn F, Nilsson M, Arnelo U, et al. Rendezvous cannulation technique reduces post-ERCPpancreatitis: a prospective nationwide study of 12,718 ERCP procedures. Am J Gastroenterol2013;108:552–59.

ERCP is a commonly performed procedure with a significantperi-procedural complication rate. Acute pancreatitis is perhapsthe most feared complication and several risk factors for thishave been documented. Failed cannulation and prolonged orrepeated attempts at cannulation are recognised as risk factorsand improving access should reduce the risk of post-ERCP pan-creatitis (PEP). Swahn and colleagues analysed the SwedishNational registry for gallstone surgery and ERCP over theperiod 2007–2009. Data are prospectively entered into theregistry including indication, cannulation technique, diagnosticfindings, therapeutic measures and complications. Particularemphasis was on the role of intra-operative rendezvous proce-dures comparing laparoscopic transcystic wire insertion to con-ventional ERCP with respect to PEP. During the study period,17 787 ERCPs were performed but 3337 (18.8%) wereexcluded due to previous sphincterotomy and 1732 (9.7%)were excluded due to incomplete data. At multivariate analysis,PEP was associated with younger age, female gender, inability to

clear the bile duct of stones, lack of biliary stent and longer pro-cedural time. Rendezvous procedure was associated with anadjusted OR of 0.5 (95% CI 0.2 to 0.9). Although this was nota randomised trial, the registry is added to prospectively anddata matched clinical records in 97.3% of cases. The procedurewas also performed by the majority of hospitals in Sweden bymultiple operators suggesting that the findings can be general-ised. However, given that the rate of PEP was low (3.6%), therisk reduction is only modest in real terms; down to 2.2%.Furthermore, the baseline characteristics of those who had arendezvous procedure did not match those who had a standardERCP. This procedure looks promising but despite this, theability to carry out ERCP in theatre essentially on demand maynot be a service that most UK hospitals would be able to accom-modate currently.

New oral anticoagulants are on the scene—how does thisimpact on the risk of gastrointestinal bleeding?

▸ Holster IL, Valkhoff VE, Kuipers EJ, et al. New oral anticoagulants increase risk forgastrointestinal bleeding: a systematic review and meta-analysis. Gastroenterology2013;145:105–12.

Anticoagulant therapy is in widespread use for a number ofmedical conditions, and with an aging population, this is likelyto rise. There is no doubt that traditional anticoagulants, suchas warfarin and low molecular weight heparin (LMWH) areeffective. There are now new oral anticoagulants (nOAC), suchas rivaroxaban and apixaban, inhibiting thrombin and FactorXa, respectively. This heralds a new era in anticoagulant use;eliminating blood monitoring, changes in coagulant status withantibiotics or concurrent illness and the need for subcutaneousinjection. However, how will this impact the gastroenterologist—what is the associated risk of gastrointestinal bleeding (GIB)?For the first time, Holster and colleagues report findings of asystematic review and meta-analysis examining this topic,incorporating 43 randomised control trials and over 150 000patients. Overall, nOAC use was associated with an increasedrisk of clinically relevant GIB compared to standard anticoagu-lant use (vitamin K antagonists, LMWH, anti-platelet therapy)with an OR 1.45 (CI 1.07 to 1.97). This risk varied along withindication, such that patients receiving nOAC for post ortho-paedic surgery prophylaxis were at lowest risk (OR 0.78 (CI0.31 to 1.96)) and those with acute coronary syndrome athighest risk (OR 5.21 (CI 2.58 to 10.53). This is thought toreflect concurrent additional anticoagulant/antiplatelet use incardiac patients. It would appear that as a gastroenterologist,patients prescribed these medications will be encountered withincreasing frequency. One main issue for the management ofGIB in this patient population is the absence of a reversal agentto use in acute bleeding emergencies.

ContributorsDr Miranda Hanson, Dr Trevor Graham, Dr PrakashRamachandran, Dr John Thomson, Dr John Leeds, Dr MairiMcLean.

Journals reviewedJournal of Clinical Investigation, PLoS Genetics, Nature,Gastroenterology, American Journal of Gastroenterology.

Competing interests None.

Provenance and peer review Not commissioned; internally peer reviewed.

To cite McLean MH. Gut 2013;62:1516–1517.

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GI highlights from the literature

Mairi H McLean

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