H I G H L I G H T S

Defective division

G E N O M I C I N S TA B I L I T Y

Centrosomes are frequently amplifiedin cancer cells, and this amplificationhas been proposed to contribute totumorigenesis because cells with sev-eral spindles are genomically unsta-ble. But what is the mechanism ofamplification? Patrick Meraldi et al.report in The EMBO Journal thatcentrosome amplification is a conse-quence, rather than a cause, of defec-tive division.

Overexpression of the mitotickinase Aurora-A — which occurs inmany cancers — causes centrosomeamplification. Both wild-typeAurora-A and a kinase-dead (KD)mutant caused an increase in cen-trosome number when overex-pressed in CHO cells, indicatingthat the kinase activity is notrequired for centrosome duplica-tion. Addition of hydroxyurea (HU)— a drug that blocks cells in Sphase, thereby allowing multiplerounds of centrosome duplicationwithout DNA replication — alsoincreased the percentage of cells

with more than two centrosomes,but Aurora-A expression did notenhance this number above that ofwild-type CHO cells.

So does Aurora-A induce centro-some amplification by mimickingHU and blocking cells in S phase?Overexpression of Aurora-A in HeLacells — which are unable to duplicatetheir centrosomes during S-phasearrest — still increases centrosomenumber, but only in the absence ofHU, indicating that Aurora-A overex-pression does not induce S-phasearrest and that cells must passthrough mitosis to increase theirnumber of centrosomes.

Closer examination of theAurora-A-overexpressing HeLa cellsrevealed that most cells (75%) withmultiple centrosomes were alsomultinucleate, so could the increasein centrosome number be an indi-rect consequence of aberrant celldivision? The number of multinu-cleate and tetraploid cells increasesas Aurora-A is overexpressed, indica-

tive of a cytokinesis defect. So canother defects that lead to an aberrantcytokinesis also cause centrosomeamplification? Overexpression of theAurora-B and PLK-1 mitotickinases, which also result in multi-nucleate cells, leads to centrosomeamplification, as does addition ofthe cytokinesis-inhibitory drugcytochalasin D.

Although most people don’t thinkmuch of mucus, its importantfunctions, such as lubricating theepithelia and protecting againstinfection, are undisputed. Recentfindings, reported in the 1 Marchissue of Science, reveal a newfunction for thisunderappreciated substance —preventing the development ofcolorectal cancer.

A family of high-molecular-weight secreted glycoproteinsknown as mucins are a primarycomponent of the mucus layer. Sofar, 13 different mucins have beendiscovered (MUC1–13), and foundto be expressed in different tissues.Alterations in mucin expressionand glycosylation pattern havebeen observed in human colon

cancer samples, and MUC2 — themost abundant gastrointestinalmucin — is reportedlydownregulated in humancolorectal carcinomas. Little isknown, however, about MUC2function at the molecular level.

To evaluate the role of MUC2 intumorigenesis, Anna Velcich et al.created Muc2-null mice. Muc2 ishighly expressed by the mucus-producing goblet cells of theintestine. The authors found thatMuc2-null mice did not developrecognizable goblet cells in anyregion of the intestine, and weretherefore defective in mucusproduction. Muc2-null mice areable to digest food and absorbnutrients, as they gained weight atthe same rate as their

heterozygous and wild-typelittermates. But 65% of Muc2-nullmice developed gastrointestinaltumours by the time they are 1year old. These tumours werefound in the small and largeintestine and rectum, but not inthe stomach, where Muc2 is notnormally expressed.

So what is the function of Muc2in the intestinal epithelium?Velcich et al. believe that Muc2 isinvolved in regulating cellproliferation and migration, asintestinal epithelial cells of Muc2-null mice had a higherproliferation:apoptosis ratio thanthose of wild-type epithelium,resulting in elongated crypts.Muc2-null epithelial cells alsomigrated faster in the intestinalmucosa than did wild-type cells —in mice injected withbromodeoxyuridine, labelledepithelial cells of Muc2-null micemigrated more rapidly to proximalregions of intestinal villi. Tumours

More than meets the eye

T U M O U R S U P P R E S S O R S

244 | APRIL 2002 | VOLUME 2 www.nature.com/reviews/cancer

Meeting of minds

• http://www.cancer-researchuk.org/

Those of us in the UnitedKingdom cannot have failedto notice that its two leadingcancer research charities —the Imperial CancerResearch Fund and theCancer Research Campaign— have merged to formCancer Research UK. Themerging of their web sites isproof that two heads arebetter than one.

The front page is aimedsquarely at the generalpublic, with news,information on fundraisingevents and prominent links topatient resources. But a large‘science and research’button at the top of the pagetakes cancer researchersstraight to the informationthat’s most relevant to them.

Navigation within this‘science wing’ is through fivetabs. The ‘researchers’section is a simple directory,searchable by name, keywordor free text. Information onindividual researchers andtheir projects varies in detail; itwould be useful to have keypublications for all of them.There’s also a clickable mapthat takes you to Cancer-Research-UK-fundedinstitutes and labs around theUnited Kingdom. The‘research institutes’ section ispresented as a hypertext-linked list, each institute takingyou to a list of group leaders;clinical centres are presentedsimilarly but, unfortunately, arenot yet clickable.

Cancer Research UK nowawards an almost bewilderingarray of grants; these areorganized into broadcategories in the Grantsapplication section, andsufficient information is givenfor you to work out whetheryou’re eligible and when youshould apply; forms are notavailable on the web, butthere is information on how tosend for application packs.

Finally, in the enigmatic‘other sites’ section, don’tmiss the links list; this trackscancer research across theglobe, making it a usefulresource for all cancerresearchers.

Cath Brooksbank

WEB WATCH