HIGHLIGHTS

NATURE REVIEWS | CANCER VOLUME 4 | MARCH 2004 | 169

The activity of the peroxisome-pro-liferator-activated receptor (PPAR)family members has been impli-cated in various tumour types,although the evidence for one ofthese proteins — PPARβ/δ — hasbeen contradictory. RaymondDuBois and colleagues have there-fore used a mouse model of colo-rectal cancer, along with a Pparβ/δselective agonist, to more clearlydemonstrate the role of Pparβ/δ intumour growth.

PPARs are a family of nuclear hormone receptors that function asligand-activated transcription factors.PPARβ/δ is involved in development,wound healing, fatty-acid metabo-lism and repression of the inflamma-tory response. More importantly, theexpression and activity of PPARβ/δare increased after loss of the adeno-matous polyposis coli (APC) tumoursuppressor, which implicates it in thepathogenesis of colorectal cancer. Tosupport this, a study showed that lossof both PPARβ/δ alleles from a col-orectal cancer cell line slowed tumourgrowth. A separate study, however,reported that disruption of Pparβ/δdid not affect polyp formation inApcmin mice — a model of intestinalpolyposis that progresses to colorectalcancer, in which Apc is mutated.DuBois and colleagues therefore testedanother approach to this problem —they treated Apc min mice with theselective Pparβ/δ agonist GW501516.

Pparβ/δ is expressed primarily inthe intestinal epithelial cells of boththe normal intestinal epithelia and

adenomas of Apc min mice. Treatingthese mice with GW501516 led to atwofold increase in polyp number in the small intestine, but no changein the number of colon polyps. Themice that were treated with thePparβ/δ agonist also showed a five-fold increase in polyps larger than 2 mm, so Pparβ/δ activation seems toaffect the rate of polyp growth morethan polyp formation. The polyps inthese mice also had a slightly higherdegree of dysplasia, indicating a moreadvanced stage of progression.

How does Pparβ/δ activationpromote tumour growth? AlthoughGW501516 had no effect on prolif-eration of colorectal cancer cells in vitro, it suppressed apoptosis in adose-dependent manner. DuBoisconcluded that Pparβ/δ stimulatesthe growth and development ofintestinal adenomas by activatinganti-apoptotic pathways in intestinalepithelial cells.

This finding has important impli-cations for the clinic, as activating ligands of PPARβ/δ (includingGW501516) are in the later stages ofdevelopment as drugs to treat dys-lipidaemia syndromes, obesity and atherosclerosis. PPARβ/δ agonistsshould be administered with caution,as they might increase the risk ofcancer in individuals with familialadenomatous polyposis — a diseasein which APC mutations lead to ahigh incidence of colorectal cancer.

Kristine Novak

References and linksORIGINAL RESEARCH PAPER Gupta, R. A. et al. Activation of nuclear hormone receptorperoxisome proliferator-activated receptor-δaccelerates intestinal adenoma growth. NatureMed. 1 Feb 2004 (doi:10.1038/nm993)FURTHER READING Michalik, L., Desvergne, B.& Wahli, W. Peroxisome-proliferator-activatedreceptors and cancers: complex stories. NatureRev. Cancer 4, 61–70 (2004)WEB SITERaymond DuBois’ lab:https://medschool.mc.vanderbilt.edu/facultydata/php_files/show_faculty.php?id3=760

Conflict resolution

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

HIGHLIGHT ADVISORS

AVI ASHKENAZI

GENENTECH, INC., SOUTH SAN FRANCISCO, CA, USA

JOSE BASELGA

VALL D’HEBRON UNIVERSITYHOSPITAL, BARCELONA, SPAIN

ANTON BERNS

NETHERLANDS CANCERINSTITUTE, AMSTERDAM, THE NETHERLANDS

MARIA BLASCO

CENTRO NACIONALDE INVESTIGACIONESONCÓLOGICAS, MADRID, SPAIN

RON DEPINHO

HARVARD MEDICAL SCHOOL,BOSTON, MA, USA

GLENN DRANOFF

DANA–FARBER CANCERINSTITUTE, BOSTON, MA, USA

RAKESH JAIN

MASSACHUSETTS GENERALHOSPITAL, BOSTON, MA, USA

CHRISTOPH LENGAUER

THE SIDNEY KIMMELCOMPREHENSIVE CANCERCENTER, BALTIMORE, MD, USA

LANCE LIOTTA

NATIONAL CANCER INSTITUTE,BETHESDA, MD, USA

JOHN D. POTTER

FRED HUTCHINSON CANCERRESEARCH CENTER, SEATTLE, WA, USA

DAVID SIDRANSKY

JOHNS HOPKINS UNIVERSITYSCHOOL OF MEDICINE,BALTIMORE, MD, USA

BERT VOGELSTEIN

THE SIDNEY KIMMELCOMPREHENSIVE CANCERCENTER, BALTIMORE, MD, USA

ROBERT WEINBERG

WHITEHEAD INSTITUTE FORBIOMEDICAL RESEARCH,CAMBRIDGE, MA, USA

ZENA WERBUNIVERSITY OF CALIFORNIA ATSAN FRANCISCO, CA, USA