For personal use. Only reproduce with permission The Lancet Publishing Group.

THE LANCET Neurology Vol 3 February 2004 http://neurology.thelancet.com 75

Newsdesk

Researchers from the University ofCalifornia have identified a subset ofcells in paediatric brain tumours thatare likely candidates for the elusive“brain-cancer stem cells”.

Unlike normal stem cells, tumour-specific types “have a very high rate ofproliferation and give rise to daughtercells that are abnormal”, explains lead author Harley Kornblum. Theresearchers’ discovery adds to growingevidence that only a small proportion oftumour cells can drive malignancy.

By use of surgical samples frompatients with brain tumours, andcontrol samples from patients withintractable epilepsy, Kornblum andcolleagues searched for similaritiesbetween cancerous cells and normalneural stem cells. To establish stem-cell-like properties, the researchersencouraged the tumour samples toform neurospheres—tiny aggregates ofbrain cells that include stem cells andtheir progeny at different stages of

development (Proc Natl Acad Sci USA2003; 100: 15178–83). “The tumourstem cells express many of the samegenes and proteins as neural stem cells”,explains Kornblum. “They also sharecommon characteristics, including self-renewal and multipotency”.

Peter Dirks (Hospital for SickChildren, Toronto, ON, Canada)comments that because the brain-tumour stem cells were shown to besimilar to neural stem cells, Kornblumand colleagues’ work provides cluesabout the cell of origin of braintumours. “[The findings] suggest thatnormal neural stem cells may be moresensitive targets for cancer formationthan with other cell types”. However,he cautions that because Kornblumand colleagues did not show that thetumour-derived cells could formtumours in an animal model, it isimpossible to be sure that they areresponsible for driving tumourgrowth.

Previous studies have implicated aself-renewing subset of tumour cells in the development and maintenance of tumours. For example, althoughtumours shed millions of cells into theblood stream every day, only a verysmall proportion of these cells have theability to give rise to secondary cancers(metastases).

“The majority of cancer cells have a limited capacity for proliferation and self renewal”, explains Dirks. “Stem cells, however, divide to renewthemselves. . . generating daughter cellsthat differentiate to make up the rest ofthe tumour.”

Kornblum believes this work hasthe potential to improve treatment forchildhood brain cancers. “We hope toidentify genes that regulate the pro-liferation of stem cells and tumour stemcells and to target these genes (and thepathways they regulate) with a variety oftreatment approaches”, he says.Hannah Brown

Cancer stem cells may drive growth of paediatric brain tumours

The use of methylphenidate hydro-chloride (MPH; Ritalin) to treatattention-deficit/hyperactivity disorder(ADHD) is back in the news. Despitelarge trials that confirm the safety andefficacy of MPH for ADHD, concernsremain over its long-term use,including a potential predisposition oftreated juveniles to drug abuse.Prescription of MPH has increasedsubstantially over the past decade, andis now being prescribed to people whodo not fit strict diagnostic criteria.

To investigate such fears, research-ers have returned to preclinical studiesand have reported that MPH treatmentin young rats causes long-term brainchanges and altered behaviour. Teamsfrom University of Texas SouthwesternMedical Center (Dallas, TX), HarvardMedical School (Belmont, MA), andFinch University of Health Sciences(Chicago, IL) separately investigatedthe effects of chronic MPH treatmentof young rats on their neuro-behavioural responses as adults (BiolPsychiatry 2003; 54: 1317–29; 1330–37;1338–44).

Nora Volkow (director of theNational Institute on Drug Abuse) andThomas Insel (National Institute ofMental Health, Bethesda, MD)comment that, together, the studiesshow changes in the function of braindopamine cells and altered behaviours,such as increased sensitivity to stressfulstimuli and decreased threshold forhelplessness.

Cindy Brandon and colleagues inChicago confirmed previous findingsthat MPH increases the reinforcingproperties of cocaine in adolescent rats,although William Carlezon’s team inBelmont reported that MPH decreasedthe reward potential of cocaine inyounger animals. However, because thelatter report, and one by the Dallasteam led by Eric Nestler, suggest thatchronic MPH decreased sensitivity tonatural reinforcers in real life decreasedsensitivity to cocaine could still result inhigh rates of cocaine use or use of highdoses.

Given the wealth of clinical data, allexperts are keen to point out that MPHused for ADHD remains safe and

effective. “It would be a big mistake towithhold Ritalin from such childrenbased on this series of papers”, saysNestler. Indeed, because the studiesused healthy rats, the findings areunlikely to be applicable to people withADHD.

What the studies do emphasise isthe importance of an accurate diag-nosis of ADHD, and should cautionagainst prescribing MPH to individualswho do not fit strict criteria. “We haveknown for some time that Ritalin is notan ideal treatment for ADHD, and thatwe need to develop better treatments.We also need to develop more objectivediagnostic tests for ADHD so that wecan better target the children who trulyneed treatment”, concludes Nestler.Carlezon adds: “Ritalin and otherstimulants are not drugs that work for awhile and then are gone without atrace. They leave their signature on thebrain, maybe forever. It is critical thatwe understand that, and make sure it iswhat we really want, and be ready todeal with all of the consequences.”Kelly Morris

Rat studies of Ritalin emphasise need for proper ADHD diagnosis