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into the centre of the galaxy. That could fuel a burst of star formation there, or perhapseven trigger an energetic eruption from a cen-tral black hole. Drawing clear conclusionsfrom a single object is difficult, but furtherobservations will reveal how widespread such processes are in young spiral galax-ies. Both these and other results2 from the same programme are challenging theorists to account for the existence of such massiveand well-formed galaxies at such early cosmicepochs.

What impresses most about these results isthat in-depth studies of the structure and theinternal dynamics of young galaxies are nowdemonstrably within our reach. The next tech-nological step will be the mating of adaptive-optics systems with laser guide stars4 — a laserbeam shot up into the sky where no appropri-ate star is available for calibration of atmos-pheric effects. That should allow these kinds ofobservations to be extended to virtually anygalaxy in the sky. Such facilities are under con-struction or being commissioned on several of the world’s largest telescopes, and observa-tions of young galaxies are central to the casefor the planned next generation of observa-tories with 20–40-metre-aperture telescopes.Just one adolescent spiral galaxy has shown what the scientific potential of those facilitiesmight be. ■

Robert C. Kennicutt Jr is at the Institute ofAstronomy, University of Cambridge, MadingleyRoad, Cambridge CB3 0HA, UK.e-mail: robk@ast.cam.ac.uk

1. Genzel, R. et al. Nature 442, 786–789 (2006).2. Förster-Schreiber, N. M. et al. Astrophys. J. 645, 1062–1075

(2006).3. Erb, D. K. et al. Astrophys. J. 646, 107–132 (2006).4. Wizinowich, P. L. et al. Publ. Astron. Soc. Pacif. 118, 297–309

(2006).5. Springel, V. et al. Nature 435, 629–636 (2005).6. Springel, V., Frenk, C. S. & White, S. D. M. Nature 440,

1137–1144 (2006).

Edwin Hubble’s ‘tuning fork’ classification dividesgalaxies into two principal categories. First, thereare the relatively featureless elliptical galaxies.These are subdivided into categories from E0 to E7 with increasing ‘eccentricity’ (deviation from a spherical form). Elliptical galaxies tend to consist of older stars, show very little activestar formation, and are dominated by randommotion.

Second, spiral galaxies — our own Milky Way is an example — consist of a central ‘bulge’,resembling an elliptical galaxy, surrounded by a flat, rotating disk of younger stars in acharacteristic arm formation. Spiral galaxies arebroken down into barred and normal spirals, andclassified according to how tightly the arms of the disk are wound around the bulge.

Observations of galaxies at early times in theUniverse’s evolution present an opportunity to

see how the Hubble sequence looked back then.The widely accepted hierarchical theory ofstructure formation presents a ‘bottom-up’picture, in which large galaxies grow by theaccretion of smaller fragments and by mergers.This gravitational clumping is guided by theunseen hand of so-called cold dark matter5,6.

Simulations based on the hierarchical modelreproduce impressively the large-scale structureof the Universe and compact protogalaxies seenat early cosmic times. These protogalaxies thenevolve into elliptical galaxies and the centralbulges of spiral galaxies. But the models havedifficulty producing more than a few large, spiralgalaxy disks — especially at early times. Genzeland colleagues’ observation1 of a spiral galaxythat seems well on its way to being fully formed atan early epoch is thus a considerable challenge tothese established models. R.C.K.

Box 1 | The Hubble sequence and the evolution of structure

E0 E5

Ellipticals

E3 E7 S0

Sa

SBa

SBb

Spirals

SBc

Sb

Sc

CANCER BIOLOGY

A game of subversionEmmanuelle Passegué

Just as stem cells are crucial for tissue development and regeneration, cancerstem cells underlie tumour formation and maintenance. But do cancer stem cells invariably arise from normal stem cells?

It is now clear that certain tumours can be sustained by a rare population of cancer stemcells, which share one of the defining proper-ties of normal stem cells — the ability torenew themselves. Self-renewal is what allowsstem cells to persist during the lifetime of the organism and to provide new cells for tis-sue genesis, maintenance and regeneration following stress or injury. These properties are exactly what cancer stem cells exhibit ininitiating and maintaining malignant growth

— and, unfortunately, in regenerating atumour when the cancer stem cells escapetreatment.

A key question therefore is whether cancerstem cells are always derived from normalstem cells that run amok, producing cancercells instead of normal cells (Fig. 1a, b). Thisidea is certainly plausible because many can-cer-stem-cell populations express cell-surfaceproteins that are also found on normal stemcells. But stem cells might not be the only

source of cancer stem cells. On page 818 of thisissue, Krivtsov and colleagues1 report the gen-eration of cancer stem cells by a leukaemia-associated protein that has found a way to trick non-stem cells into acquiring stem-cell-like behaviour and supporting tumour forma-tion (Fig. 1c)*.

Human leukaemias often harbour recurrentchromosome translocations, where segmentsof the chromosomes have been moved around.For instance, the ‘mixed lineage leukaemia’gene (MLL) is repeatedly found fused to vari-ous partners, including the AF9 gene used byKrivtsov et al.1. MLL is the vertebrate homo-logue of the fruitfly trithorax gene that regu-lates many developmental programmes bymaintaining expression of the Hox family of genes2, which are master regulators of devel-opment. MLL fusion genes are associated with

*This article and the paper concerned1 were published onlineon 16 July 2006.

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the development of acute-typemyeloid leukaemias3. In mice,they can initiate leukaemia whenexpressed either in the blood-forming stem cells or, more rele-vant to this study, in myeloidprogenitors only4,5. Myeloid prog-enitors are cells that are producedby the blood-forming stem cellsand that have begun to specialize,so they do not self-renew and arenormally destined solely to giverise to mature white blood cells ormyeloid cells6.

Cellular differentiation is usu-ally considered to be a one-wayprocess of specialization as thecells develop the functions of theirultimate fate and lose their imma-ture characteristics such as self-renewal. So how does the fusiongene ‘transform’ myeloid progeni-tors into cancer-forming cells,given that these progenitor cellshave seemingly gone past the stageof self-renewal? Krivtsov et al.1

answer this question by showingthat MLL–AF9 induces the aber-rant expression of a specific set of‘stem cell genes’ in myeloid prog-enitor cells. This makes the cellsself-renew and turns them intocancer stem cells capable of initiat-ing, maintaining and propagatingthe leukaemia.

Self-renewal is not yet fully understood atthe molecular level, but it can be tracked usingmicroarrays to profile the expression levels of hundreds of genes7. Hence, stem-cell iden-tity can be summed up as a gene-expressionsignature that differs from the signature ofnon-stem-cell populations. Some of these dif-ferences are likely to underpin self-renewaland other stem-cell-specific properties. WhatKrivtsov et al.1 show is that transformedmyeloid progenitors aberrantly express a smallnumber of stem-cell genes (363 genes), whilestill displaying the overall gene-expressionprofile of myeloid progenitor cells. So thetransformed progenitors do not become stem cells but rather acquire stem-cell-likebehaviour. The authors show that the acquiredstem-cell signature is lost when the cancerstem cells are forced to give up their self-renewal properties. This result strongly sug-gests that the stem-cell genes identified doindeed mediate the aberrant self-renewal ofthe myeloid progenitor cells.

But what are these genes and how can theymake non-stem cells self-renew? This is the real million-dollar question, and Krivtsov et al.1have begun to address it. First, they provide evidence that the stem-cell self-renewal programme is hierarchical in nature, with a specific set of genes activated as an earlyresponse to MLL–AF9 expression. This earlyprogramme includes known regulators of

stem-cell self-renewal activity, such as mem-bers of the Hox gene family8. Second, theauthors examine one of these early-responsegenes, Mef2c, and show that it modulates stem-cell behaviour in vitro and in vivo. The overallarchitecture of the self-renewal programme stillneeds to be defined, as do the specific genesand/or pathways that are crucial for its estab-lishment both in normal- and cancer-stem-cellpopulations. However, Krivtsov and colleagues’results bring hope that interfering with suchderegulated self-renewal genes may prevent orreverse the formation of cancer stem cells.

One concern in the cancer field is whetheracquisition of stem-cell features in non-stemcells occurs in human diseases or whether it isan artefact of using the mouse as a diseasemodel. Krivtsov et al.1 weigh in to this long-standing debate by showing that part of themouse stem-cell self-renewal signature isexpressed in cells isolated from humanpatients suffering from leukaemia associatedwith MLL fusion genes. Although the presenceof contaminating normal stem cells withinthese leukaemia specimens cannot beexcluded, these findings support the idea thatsubversion of stem-cell properties in non-stem-cell populations can happen in thecourse of a human disease.

Is this really so unexpected? A fundamentalproperty of cancer cells is the ability to subvertthe normal mechanisms that restrain un-fettered growth. The loss of self-renewal

potential during normal differ-entiation might be viewed assuch a safeguard, so it followsthat uncoupling the propertyof self-renewal from otherstem-cell characteristics couldhave potent cancerous effects.MLL is a particularly strongcandidate for this sort of sabo-tage as it normally regulatesstem-cell-fate decisions bymaintaining the expression ofHox genes, which in turn sup-port self-renewal2,8. It is nownecessary to find out whetherMLL fusion genes can trans-form human progenitor cells,either directly or as a conse-quence of transforming stemcells, and whether this occursby a true activation of self-renewal genes rather than by alack of gene repression. It isalso necessary to determinewhether this type of subversionoccurs with other fusion genesin leukaemia and with othertypes of cancer.

Krivtsov and colleagues’findings are a step towardsdefining what could be a uni-versal self-renewal signaturefor human leukaemia. Such asignature would clearly have

a bearing on cancer treatment, not onlyenabling targeting of the cancer stem cells thatemerge from non-stem-cell populations, butalso identifying the self-renewal mechanismsthat can go awry in normal stem cells to makethem cancerous9. Cancer genes play a subtlegame of subversion that we could ultimatelyuse against them. By appropriating mecha-nisms that are essential to the functions theywant to gain (here self-renewal), cancer genesteach us how these processes work, and give usthe opportunity to identify molecular targetsthat could be used for cancer treatment. ■

Emmanuelle Passegué is in the Developmental and Stem Cell Biology Program and the Department of Medicine,University of California, San Francisco, 513 Parnassus Avenue, San Francisco, California 94314, USA.e-mail: passeguee@stemcell.ucsf.edu

1. Krivtsov, A. V. et al. Nature 442, 818–822 (2006).2. Ernst, P., Mabon, M., Davidson, A. J., Zon, L. I. & Korsmeyer,

S. J. Curr. Biol. 14, 2063–2069 (2004).3. Daser, A. & Rabbitts, T. Genes Dev. 18, 965–974

(2004).4. Cozzio, A. et al. Genes Dev. 17, 3029–3035 (2003).5. So, E. et al. Cancer Cell 3, 161–171 (2003).6. Akashi, K., Traver, D., Miyamoto, T. & Weissman, I. L.

Nature 404, 193–197 (2000).7. Forsberg, E. C. et al. PLoS Genet. 1, e28 (2005).8. Abramovich, C. & Humphries, R. K. Curr. Opin. Hematol. 12,

210–216 (2005).9. Passegué, E., Jamieson, C. H. M., Ailles, L. E. & Weissman,

I. L. Proc. Natl Acad. Sci. USA 100, 11842–11849 (2003).

Stemcells

a b c

Progenitors

Mature cells Cancer Acutecancer

Self-renewal

Cancer stem cells

Subvertedprogenitors

self-renewal

Subverted

Subvertedstem cells

Cancerstem cells

Subvertedstem cells

Cancerstem cells

Figure 1 | Sources of cancer stem cells. a, Normal stem cells are the only cellsthat self-renew for the lifetime of the organism, and they produce the progenitorand mature cell populations required for tissue function and maintenance(here, the blood system). b, Cancer genes can subvert the stem-cell populationto turn it into cancer stem cells, which then produce cancer cells instead ofnormal cells. c, Krivtsov et al.1 find that some cancer genes involved in acutemyeloid leukaemia can also turn progenitor cells into cancer stem cells byinducing expression of a specific set of stem-cell genes. This expression subvertsthe progenitor cells to self-renew and to support tumour formation.

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