TRENDS in Biochemical Sciences Vol.26 No.10 October 2001

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Molecular analysis of human tumors couldfacilitate the earlier detection of cancers, aswell as the subtyping of cancers on thebasis of prognosis or treatment modalities.DNA microarrays enable the relative levelsof mRNAs of thousands of genes to bemeasured simultaneously from any givensample. mRNA expression profiling of largesubsets of genes by microarray-basedstudies has already been successfullyemployed to subclassify diffuse large B-celllymphomas and acute leukemias. Totranslate microarray data into routineclinical use, it is necessary to identify asmall set of genes whose expression levelscan be used as markers for cancer diagnosisand outcome prediction. This can beachieved by evaluating the most promisingmarkers from microarray analysisindividually to assess their clinicalrelevance.

A recent study by Chinnaiyan andcolleagues1 used a microarray containingalmost 10 000 human cDNAs to examine thegene expression profiles of >50 normal orcancerous prostate tissue specimens, inaddition to those of three cell lines derivedfrom metastatic prostate cancer. Clusteringof tumors according their gene expressionprofiles was found to correspond to the four

different clinical states of the prostatespecimens. Normal prostate tissue andbenign conditions, such as benign prostatichyperplasia, formed a cluster that wasdistinct from all malignant conditions.Moreover, localized forms of prostatecancer could be easily distinguished frommetastatic prostate cancer based onpatterns of gene expression.

The serum level of prostate-specificantigen (PSA) is frequently used in thediagnosis and monitoring of prostate cancer.However, this assay is complicated by thefact that PSA serum levels can also beelevated in certain benign conditions of theprostate. The authors of the present studychose two genes that were upregulated inprostate cancer for further evaluation byimmunohistochemistry: hepsin, encoding atransmembrane serine protease, and pim-1,encoding a serine threonine kinase. Tissuemicroarrays on glass slides containingprostate samples were stained with eitheranti-hepsin antibody (738 samples) or anti-PIM1 antibody (810 samples). It was foundthat, in addition to localized and metastaticprostate cancer, an early lesion of prostatecancer termed HG-PIN showed an increasedexpression of hepsin protein. By contrast,PIM1 was expressed at moderate to high

levels in almost half of prostate cancerspecimens and was absent or weak inHG-PIN or normal prostate tissue. In a follow-up of the clinical data on most of the patients,an outcome analysis revealed a correlationbetween decreased expression of hepsin andPIM1 proteins, and poor patient outcome.

This study describes the identification oftumor markers by initial microarrayanalysis, followed by validation of a chosenset in patient samples. Alternativeproteomic methods based on two-dimensional gel electrophoresis or massspectrometry are more difficult as largeramounts of protein (which might not beavailable for tumors such as prostatecancer) are required for identification. Theresults of this study might, therefore,initiate adoption of an integrated approachto the discovery of not only cancer-related,but also other disease-specific, biomarkers.

1 Dhanasekaran, S.M. et al. (2001) Delineation ofprognostic biomarkers in prostate cancer.Nature 412, 822–826

Nieves Ibarrola

nibarrola@bmb.sdu.dkAkhilesh Pandey

pandey@cebi.sdu.dk

Integrating DNA and tissue microarrays for cancer profiling

News&Comment

In Brief

Battling AlzheimeristsAn open war isfought within theAlzheimer’s Disease(AD) researchcommunity. Twobattling groupsdispute primarilyover the nature ofthe exact initiation

event in AD, probably the most debatedtopic in neuroscience in recent years. Areβ-amyloid plaques and neurofibrillarytangles (both neuropathological hallmarksof AD) the cause or simply a byproduct of thewasting neurodegenerative disease? Thecurrent dogma is that there is unequivocalevidence that amyloid comes first andinduces the subsequent formation of fibrilsand tangles. However, because opponentssay plaques and tangles are generatedindependently, alternatives to the amyloid

hypothesis must be explored. In addition,these opponents firmly believe thattransgenic mouse models of the disease,largely used by the researchers whodominate the field, are artificial systems thatprovide misleading results. The recentpublication of two key studies in Science[(2001) 293, 1487–1491 and 1491–1495], isjust new gasoline that fuels the fire. The tworeports, both exploiting engineered micestrains, describe essentially the sameresults, which indicate a possible connectionbetween plaques and tangles. Meanwhile, atthe end of July, many high-profile advocatesof the dominant amyloid cascade hypothesisdeserted a conference organized by‘heretics’ colleagues in Cincinnati (OH,USA). At the meeting, expressively called‘Challenging Views of Alzheimer’s Disease’,participants lamented that non-mainstreamhypotheses go unfunded and unpublished(http://www.worldeventsforum.com/challengingviews.htm). Floating above all

this controversy and unrest, casting itsshade over the battlefield, is the huge pile ofmoney that will be linked to the patent forthe first effective drug. AR

Large biomolecules get anelectrostatic viewHoward Hughes Medical Instituteresearchers at the University of California(San Diego, CA, USA) have developed a newcomputer modelling method for studying theelectrostatic properties of large biomolecules[Proc. Natl. Acad. Sci. U. S. A. (2001) 98,10037–10041]. The method, parallel focusing,is a new approach to solving thePoisson–Boltzmann equation (a fundamentalelectrostatic equation), and is likely to have adeep impact within the field of moleculardynamics. Parallel focusing enables thedetermination of accurate electrostaticcalculations for supramolecular structures,thereby surpassing existing methods, which

TRENDS in Biochemical Sciences Vol.26 No.10 October 2001

http://tibs.trends.com 0968-0004/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved.

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have so far provided data for only relativelysmall biomolecules. By applying thistechnique, researchers have alreadysuccessfully calculated the electrostaticpotentials for microtubules and ribosomes,generating interesting clues as to the rolesplayed by electrostatics in the activities ofthese structures. It is ultimately planned tomake the software for parallel focusingavailable to interested scientists. AR(http://www.hhmi.org/news/mccammon.html)

Wellcome moves againstscientific misconductBy recently proposing its draft Guidelines onGood Practice in Biomedical Research, theWellcome Trust took a clear stand forintegrity in British scientific research. Asfrom October 2002, to qualify for Wellcomegrants, institutions are expected to have inplace their own published standards of goodresearch practice and formal writtenprocedures for the investigation of scientificmisconduct allegations. Although producedfor Trust-funded researchers, the guidelinescould well be of general application to otherbiomedical researchers. After years ofwatching US-borne scientific Watergateaffairs from the sideline, the Trust’s initiativehas finally spurred a wider debate overscientific frauds, and the measures neededto circumvent the problem, in the UK. RobertTerry, senior policy analyst at the Trust, toldThe Guardian, ‘The main intention of theseguidelines is to encourage best practice but,on rare occasion, where a serious scientificmisconduct has been proved, we would beprepared to take action’ (The Guardian,August 24, 2001). The guidelines havegenerally been received as a step in the rightdirection for British science, although somein the USA fear the draft might causecontroversy by broadening the definition ofmisconduct beyond the US government’sstandard [Science (2001) 293, 1411]. AR (http://www.wellcome.ac.uk)

Science journals and conflictof interests: a new dealFollowing the Public Library of Scienceinitiative [see Trends Biochem. Sci. (2001) 26,pp 14, 354 and 414], a new wave ofcontroversy and debate is swirling aroundmedical and scientific journals. The editors ofsome of the most authoritative medicaljournals, including the New England Journalof Medicine, the Lancet, the Annals ofInternal Medicine and the Journal of the

American Medical Association, have decidedto set a new policy designed to prevent thecensorship of research reports bypharmaceutical companies (The WahingtonPost, August 5, 2001). The move stems fromincreasing concern that drug companiesexercise too much control over the results ofthe research they fund, sometimes evenblocking publication of unfavourable studies.Under the new policy, journal editors willthus question papers if they suspect that theresearchers involved, usually from academicinstitutions, are not guaranteed scientificindependence. However, the issue ofpotential conflict of interests goes wellbeyond medical research. ‘This is a pervasiveproblem in medical research and it’s nowcreeping into basic science’, said RichardHorton, editor of the Lancet (Financial Times,August 23, 2001]. Nature’s editor PhilipCampbell agrees with this view and aims toimplement a ‘Declaration of financialinterests’ [Nature (2001) 412, 751], an explicitinvitation for Nature authors to disclosecompeting interests. A summary of thisinformation, or a note of abstinence shouldauthors decline the invitation, will bepublished alongside the author’s paper. So,with the mood obviously set within thescientific community, we can only speculateas to the origins of the next announcementpromoting scientific independence andtransparency. AR

Walking the copper trailNew work from agroup of researchersat the NorthwesternUniversity, Evanston(IL, USA) providesthe first image of thedocked complexbetween a copperchaperone and acopper-requiring

enzyme, namely superoxide dismutase(SOD). Found in a range of organisms, copperchaperones are soluble metal receptors thatfunction to deliver copper ions to specificcopper-dependent proteins within the cell, ina manner that prevents cytoplasmicexposure of these ions and thereforeoxidative damage. The study, published inNature Structural Biology [(2001) 8, 751–755],shows the 2.9 Å resolution structure of aSOD–metallochaperone complex comprisingone monomer of each protein. Theresearchers observed striking conformationalrearrangements in both the chaperone and

the target enzyme upon complex formation.Besides the purely biochemical importance,the finding has potential medical relevancebecause mutant forms of SOD with aberrantcopper chemistry are associated with severeneurodegenerative disorders, such as familialamyothrophic lateral sclerosis (also known asLou Gehrig’s disease). Scientists hope thatfurther understanding of the biochemistry ofcopper delivery, and of the function of copper,in SOD mutants, will lead to an effectiveapproach to intervention in the destructiveeffects of this disease. AR

Big metal surprise from a littlewormAccording to recent data from biologists atthe University of Pennsylvania, there ismore plant in an animal than previouslythought [J. Biol. Chem. (2001) 276,20817–20820]. The research team, led byplant biologist Philip A. Rea, demonstratedthat the ce-pcs-1 gene of the nematodeCaenorhabditis elegans encodes afunctional phytochelatin synthase, anenzyme that polymerizes the ubiquitoustripeptide glutathione into phytochelatins,heavy metal-binding peptides previouslyidentified only in plants and some fungalspecies. The finding is a breakthroughbecause it raises the possibility that, similarto plants, animals might use phytochelatinsfor detoxification of heavy metals such asarsenic, mercury and cadmium. Until now,heavy-metal detoxification in animals wasbelieved to be conducted exclusively byglutathione and the cysteine-rich, lowmolecular weight metallothionein proteins.Researchers ascertained that phytochelatinsynthase activity is crucial for heavy-metaltolerance by the nematode; worms in whichexpression of the gene encoding thisenzyme was ablated showed a increase insensitivity to heavy metals. Before beingidentified in the fully sequenced genome ofC. elegans, genes encoding phytochelatinsynthases were simultaneously identified in1999 by three different research groups, inArabidopsis, wheat and the yeastSchizosaccharomyces pombe [see TrendsPlant Sci. (1999) 4, 335–337]. AR(http://www.upenn.edu/pennnews/releases/2001/Q3/rea0901.html)

Andrea Rinaldi

rinaldi@unica.it