TUMOUR REGRESSIONRAS, the magician
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NATURE REVIEWS | CANCER VOLUME 2 | APRIL 2002 | 249 HIGHLIGHTS RAS, the magician TUMOUR REGRESSION Spontaneous disappearance is, unfortunately, a rare event in oncology, but neuroblastomas are more likely to play this trick than other tumours. What makes them regress? Paradoxically, the overexpression of two oncogenes — HRAS and TRKA — has been associated with a good prognosis, but the mechanism of regression has remained a mystery. Possibilities include apoptosis and differentiation, but Chifumi Kitanaka and colleagues now bring a third possibility onto the scene: non-apoptotic cell death. Japan has a population-screening programme for neuroblastoma in infants, which permits the detection of neuroblastomas that might otherwise spontaneously regress. The authors first compared tumour samples from mass-screened patients with clinically detected tumours from older children who had advanced-stage neuroblastomas. Patches of HRAS staining occurred more frequently in mass-screened tumours than in clinically detected tumours, and these patches frequently colocalized with areas of degenerating cells. However, these regions did not stain for two classical apoptotic markers — active caspase-3 or fragmented 3′ DNA ends (TUNEL assay). Instead, staining with the periodic- acid–Schiff reagent and electron- microscopic analysis hinted that the cells might be eating themselves (autophagy). The authors then turned to neuroblastoma cell lines to determine whether HRAS expression could kill these cells by a non-apoptotic mechansism. Expression of either wild-type HRAS or RASV12, a constitutively active HRAS mutant, caused the cells to round up and fragment, whereas expression of an inactive HRAS mutant had no effect. Furthermore, the degenerating cells looked quite different from those that were induced to apoptose by stauropsorine or serum withdrawal. Again, no DNA fragmentation was apparent in TUNEL assays, and electron microscopy revealed increased numbers of lysosomes, characteristic of autophagic degeneration. Is caspase activation required for this peculiar form of HRAS- mediated cell death? Caspase inhibitors did not prevent HRAS- induced cell death, but did block staurosporine-mediated apoptosis. Furthermore, poly(ADP-ribosyl) transferase (PARP), which is invariably attacked by active caspases, was not fragmented in RAS-expressing neuroblastoma cells. Finally, overexpression of the anti-apoptotic protein BCL-X L did not block HRAS-mediated cell death, but did prevent staurosporine-mediated death. Active HRAS, then, can kill cells by a mechanism that is distinct from apoptosis. Expression of both HRAS and the gene for the nerve growth factor (NGF) receptor TRKA is a better indicator of good prognosis than either gene alone, so the authors wanted to know whether TRKA could augment HRAS-mediated cell death. NGF increased the proportion of HRAS-mediated cell degeneration, but only when TRKA was overexpressed. Can we learn some magic tricks from this study? If there are other ways to activate this apparently autophagic pathway, perhaps one day we’ll be able to make neuroblastomas — and maybe other tumours, too — disappear even if they don’t express favourable markers. Cath Brooksbank References and links ORIGINAL RESEARCH PAPER Kitanaka, C. et al. Increased Ras expression and caspase- independent neuroblastoma cell death: possible mechanism of spontaneous neuroblastoma regression. J. Natl Cancer Inst. 94, 358–368 (2002) FURTHER READING Reynolds, C. P. Ras and seppuku in neuroblastoma. J. Natl Cancer Inst. 94, 319–321 (2002) WEB SITE The Neuroblastoma Hope Foundation: http://www.acor.org/diseases/cns/nblastoma/ Mammography moves on A new analysis of data from four Swedish randomized controlled trials might finally bring an end to the debate surrounding the benefits of mammography screening. In the 16 March issue of The Lancet, Lennarth Nystrom and colleagues report that mammography screening for breast tumours does lead to a statistically significant reduction in cancer mortality in women aged 55 years or over. The study is an updated analysis of the large Swedish clinical trials that have been at the centre of that controversy. In a study published in 2001, Ole Olsen and Peter Gotzsche raised concern that mammography randomized trials — including the Swedish trials — were flawed, and did not provide reliable evidence to support the benefit of this screening procedure. Nystrom et al. therefore extended their analysis, performing a long-term follow-up study of the outcomes of 247,000 women over almost 16 years. They also determined the age-specific and trial-specific effects of mammography on breast cancer mortality, and re-examined their earlier data in light of Olsen and Gotzsche’s critiques of their randomization procedures. In comparing the relative risks for breast cancer death (and death from all causes) between women who received mammography screening and controls, the authors reported 584 breast cancer deaths among the 1,688,440 women in control groups, but only 511 breast cancer deaths in 1,864,770 women who were invited for mammography screening. This represents a statistically significant overall reduction in breast cancer mortality of 21%. The reduction was greatest (33%) in the age group 60–69 years at entry to the trials. Nystrom et al. also report statistically significant effects in the age groups 55–59, 60–64 and 65–69 years, but only a small relative risk reduction (5%) in women aged 50–54 years. So, the benefits of mammography increase with age. In an editorial accompanying the research, Karen Gelmon claims that the study shows “real but modest” benefits for screening, and states that the new analysis “reassures us that the Swedish data are believable”. Hopefully, the research will settle the debate among scientists and statisticians over the value of mammograms, and lend credence to the US government’s recent recommendation that women older than 40 have the tests every 1–2 years. ORIGINAL RESEARCH PAPER Nystrom, L. et al. Long-term effects of mammography screening: updated overview of the Swedish randomised trials. Lancet 359, 909–919 (2002) FURTHER READING Olson, O. & Gotzsche, P. C. Cochrane review on screening for breast cancer with mammorgraphy. Lancet 358, 1340–1342 (2001) | Gelmon, K. A. & Olivotto, I. The mammography screening debate: time to move on. Lancet 359, 904–905 (2002) WEB SITE NCI statement on mammography screening: http://newscenter.cancer.gov/pressreleases/mammstatement31jan02.html TRIAL WATCH
Transcript of TUMOUR REGRESSIONRAS, the magician
NATURE REVIEWS | CANCER VOLUME 2 | APRIL 2002 | 249
H I G H L I G H T S
RAS, the magician
T U M O U R R E G R E S S I O N
Spontaneous disappearance is,unfortunately, a rare event inoncology, but neuroblastomas aremore likely to play this trick thanother tumours. What makes themregress? Paradoxically, theoverexpression of two oncogenes— HRAS and TRKA — has beenassociated with a good prognosis,but the mechanism of regressionhas remained a mystery.Possibilities include apoptosis anddifferentiation, but ChifumiKitanaka and colleagues now bringa third possibility onto the scene:non-apoptotic cell death.
Japan has a population-screeningprogramme for neuroblastoma ininfants, which permits the detectionof neuroblastomas that mightotherwise spontaneously regress.The authors first compared tumoursamples from mass-screenedpatients with clinically detectedtumours from older children whohad advanced-stageneuroblastomas. Patches of HRASstaining occurred more frequentlyin mass-screened tumours than inclinically detected tumours, andthese patches frequently colocalizedwith areas of degenerating cells.However, these regions did not stainfor two classical apoptotic markers— active caspase-3 or fragmented 3′DNA ends (TUNEL assay). Instead,staining with the periodic-acid–Schiff reagent and electron-microscopic analysis hinted that thecells might be eating themselves(autophagy).
The authors then turned toneuroblastoma cell lines todetermine whether HRASexpression could kill these cells by anon-apoptotic mechansism.Expression of either wild-typeHRAS or RASV12, a constitutivelyactive HRAS mutant, caused thecells to round up and fragment,whereas expression of an inactiveHRAS mutant had no effect.Furthermore, the degenerating cellslooked quite different from thosethat were induced to apoptose bystauropsorine or serum withdrawal.
Again, no DNA fragmentation wasapparent in TUNEL assays, andelectron microscopy revealedincreased numbers of lysosomes,characteristic of autophagicdegeneration.
Is caspase activation requiredfor this peculiar form of HRAS-mediated cell death? Caspaseinhibitors did not prevent HRAS-induced cell death, but did blockstaurosporine-mediated apoptosis.Furthermore, poly(ADP-ribosyl)transferase (PARP), which isinvariably attacked by activecaspases, was not fragmented inRAS-expressing neuroblastomacells. Finally, overexpression of theanti-apoptotic protein BCL-X
Ldid
not block HRAS-mediated celldeath, but did preventstaurosporine-mediated death.Active HRAS, then, can kill cells bya mechanism that is distinct fromapoptosis.
Expression of both HRAS andthe gene for the nerve growth factor(NGF) receptor TRKA is a betterindicator of good prognosis thaneither gene alone, so the authorswanted to know whether TRKAcould augment HRAS-mediated celldeath. NGF increased theproportion of HRAS-mediated celldegeneration, but only when TRKAwas overexpressed.
Can we learn some magic tricksfrom this study? If there are otherways to activate this apparentlyautophagic pathway, perhaps oneday we’ll be able to makeneuroblastomas — and maybeother tumours, too — disappeareven if they don’t expressfavourable markers.
Cath Brooksbank
References and linksORIGINAL RESEARCH PAPER Kitanaka, C. et al. Increased Ras expression and caspase-independent neuroblastoma cell death: possiblemechanism of spontaneous neuroblastomaregression. J. Natl Cancer Inst. 94, 358–368(2002) FURTHER READING Reynolds, C. P. Ras andseppuku in neuroblastoma. J. Natl Cancer Inst.94, 319–321 (2002)WEB SITEThe Neuroblastoma Hope Foundation:http://www.acor.org/diseases/cns/nblastoma/
Mammography moves onA new analysis of data from four Swedish randomized controlledtrials might finally bring an end to the debate surrounding thebenefits of mammography screening. In the 16 March issue ofThe Lancet, Lennarth Nystrom and colleagues report thatmammography screening for breast tumours does lead to astatistically significant reduction in cancer mortality in womenaged 55 years or over. The study is an updated analysis of the largeSwedish clinical trials that have been at the centre of thatcontroversy. In a study published in 2001, Ole Olsen and PeterGotzsche raised concern that mammography randomized trials— including the Swedish trials — were flawed, and did notprovide reliable evidence to support the benefit of this screeningprocedure. Nystrom et al. therefore extended their analysis,performing a long-term follow-up study of the outcomes of247,000 women over almost 16 years. They also determined theage-specific and trial-specific effects of mammography on breastcancer mortality, and re-examined their earlier data in light ofOlsen and Gotzsche’s critiques of their randomizationprocedures. In comparing the relative risks for breast cancer death(and death from all causes) between women who receivedmammography screening and controls, the authors reported 584breast cancer deaths among the 1,688,440 women in controlgroups, but only 511 breast cancer deaths in 1,864,770 womenwho were invited for mammography screening. This represents astatistically significant overall reduction in breast cancer mortalityof 21%. The reduction was greatest (33%) in the age group 60–69years at entry to the trials. Nystrom et al. also report statisticallysignificant effects in the age groups 55–59, 60–64 and 65–69 years,but only a small relative risk reduction (5%) in women aged50–54 years. So, the benefits of mammography increase with age.
In an editorial accompanying the research, Karen Gelmon claimsthat the study shows “real but modest” benefits for screening, andstates that the new analysis “reassures us that the Swedish data arebelievable”. Hopefully, the research will settle the debate amongscientists and statisticians over the value of mammograms, andlend credence to the US government’s recent recommendationthat women older than 40 have the tests every 1–2 years.ORIGINAL RESEARCH PAPER Nystrom, L. et al. Long-term effects of mammographyscreening: updated overview of the Swedish randomised trials. Lancet 359, 909–919 (2002)FURTHER READING Olson, O. & Gotzsche, P. C. Cochrane review on screening for breastcancer with mammorgraphy. Lancet 358, 1340–1342 (2001) | Gelmon, K. A. & Olivotto, I.The mammography screening debate: time to move on. Lancet 359, 904–905 (2002)WEB SITENCI statement on mammography screening:http://newscenter.cancer.gov/pressreleases/mammstatement31jan02.html
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