Brain-cancer stem cells may drive tumour formation
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Newsdesk http://neurology.thelancet.com Vol 4 January 2005 17 Experiments in mice suggest that the exact form of disease caused by infection with bovine spongiform encephalopathy (BSE)-derived or variant Creutzfeldt-Jakob disease (vCJD)-derived prions depends on the host’s genetic make-up. vCJD has so far only occurred in people homozygous for methionine at codon 129 of the human prion protein (MM homozygotes), explains John Collinge (Medical Research Council Prion Unit, University College London, UK). This has led researchers to suggest that MM homozygotes might have the shortest incubation for vCJD but that valine homozygotes (VV) and methionine-valine heterozygotes will eventually get the disease. Collinge’s new results suggest, however, that only MM homozygotes will get vCJD, and that people with one of the other prion genotypes may get another form of disease, perhaps more similar to classic CJD. Predictions that BSE will ultimately cause a massive epidemic of vCJD have so far not been realised. Nevertheless, recent reports of people contracting vCJD from blood transfusions have raised the spectre of a second wave of vCJD. Furthermore, notes Collinge, it is still early days for a family of diseases that can have incubation times of more than 40 years. To understand which prions cause which human disease, Collinge and his colleagues have been producing mice expressing different types of human prion protein and investigating their susceptibility to BSE, vCJD, and other human prion diseases. Infection of mice carrying VV homozygote human prion protein with BSE or vCJD produces a distinct molecular and neuropathological phenotype. Prions taken from these mice do not cause clinical disease in further VV hosts but do cause clinical disease in both wild- type mice and transgenic mice carrying the human MM prion protein (Science 2004; published online Nov 11, DOI: 10.1126/science.1103932). “We now have to consider the possibility that there may be carrier states of prion infection in people as there are in these animal models”, says Collinge. Given these results, comments Markus Glatzel (University of Zurich, Switzerland), “the only way to detect new forms of prion diseases that might be associated with exposure to BSE prions is by maintaining tight surveillance of human prion disease”. Neil Cashman (University of Toronto, Canada) agrees, noting that “human BSE may appear in different forms as the epidemic continues”. Monitoring the appearance of these forms, adds Collinge, will require their molecular classification “to see if there is any systematic change in particular subtypes”. Jane Bradbury Genetic susceptibility to prion disease: new phenotypes? Brain-cancer cells that express the cell- surface marker CD133 seem to exclusively initiate tumour formation. As few as 100 CD133 + cells had potent capabilities of self-renewal and prolifer- ation in vivo, and were able to generate tumours pathologically identical to the original tumour after engraftment (Nature 2004; 432: 396–401). “This is more definitive proof that brain-tumour growth is determined by small numbers of cells with stem-cell properties”, says author Peter Dirks (Hospital for Sick Children, Toronto, ON, Canada). To determine whether human brain- tumour cells were capable of tumour initiation in vivo, Dirks and colleagues compared the ability of both CD133 + and CD133 – tumour cells, which were isolated from human medullo- blastomas and glioblastomas, to initiate tumour formation. The cells were transplanted into the brains of non-obese diabetic, severe combined immunodeficient (NOD-SCID) mice. From 12 weeks to 24 weeks post- transplant, analysis showed that as few as 100 CD133 + cells were able to initiate growth of human brain tu- mours in NOD-SCID mice. Conversely, transplantation of as many as 50 000–100 000 CD133 – cells did not result in tumour formation, and histo- logical analysis at 12 weeks showed only a glial scar tract from the injection. “The two cell populations shared the same cytogenetic changes, but it is interesting that they exhibited such different behaviour”, says Dirks. “Even though the other cells were also cancer cells, they were not capable of tumour initiation.” The capacity for self-renewal was also assessed by serial passage. Serial retransplantation of CD133 + cells from xenografts were transplanted into secondary mice, and were assessed after 5 weeks. Tumours grew in all five of the secondarily xenografted mice, and all developed tumours with the phenotype of the original tumour and the primary xenograft. This research will not have an immediate clinical effect, commented Michael Clarke (University of Michigan Medical School, Ann Arbor, MI, USA), but “it will help to develop diagnostics and therapeutics, and the identi- fication of the cells can be compared to the identification of the mutations that cause cancer.” The first drugs specifically targeting cancer, such as imatinib mesilate (Gleevac), have only recently become available, he added. “Clearly, these new drugs are making an impact.” Roxanne Nelson Brain-cancer stem cells may drive tumour formation
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Transcript of Brain-cancer stem cells may drive tumour formation
Newsdesk
http://neurology.thelancet.com Vol 4 January 2005 17
Experiments in mice suggest that theexact form of disease caused byinfection with bovine spongiformencephalopathy (BSE)-derived orvariant Creutzfeldt-Jakob disease(vCJD)-derived prions depends on thehost’s genetic make-up.
vCJD has so far only occurred inpeople homozygous for methionine atcodon 129 of the human prion protein(MM homozygotes), explains JohnCollinge (Medical Research CouncilPrion Unit, University College London,UK). This has led researchers tosuggest that MM homozygotes mighthave the shortest incubation for vCJDbut that valine homozygotes (VV) andmethionine-valine heterozygotes willeventually get the disease. Collinge’snew results suggest, however, thatonly MM homozygotes will get vCJD,and that people with one of the otherprion genotypes may get anotherform of disease, perhaps more similarto classic CJD.
Predictions that BSE will ultimatelycause a massive epidemic of vCJD haveso far not been realised. Nevertheless,recent reports of people contractingvCJD from blood transfusions haveraised the spectre of a second wave ofvCJD. Furthermore, notes Collinge, it isstill early days for a family of diseasesthat can have incubation times ofmore than 40 years.
To understand which prions causewhich human disease, Collinge and hiscolleagues have been producing miceexpressing different types of humanprion protein and investigating theirsusceptibility to BSE, vCJD, and otherhuman prion diseases. Infection ofmice carrying VV homozygote humanprion protein with BSE or vCJDproduces a distinct molecular andneuropathological phenotype. Prionstaken from these mice do not causeclinical disease in further VV hosts butdo cause clinical disease in both wild-type mice and transgenic mice carrying
the human MM prion protein (Science2004; published online Nov 11, DOI:10.1126/science.1103932). “We nowhave to consider the possibility thatthere may be carrier states of prioninfection in people as there are inthese animal models”, says Collinge.
Given these results, commentsMarkus Glatzel (University of Zurich,Switzerland), “the only way to detectnew forms of prion diseases thatmight be associated with exposure toBSE prions is by maintaining tightsurveillance of human prion disease”.Neil Cashman (University of Toronto,Canada) agrees, noting that “humanBSE may appear in different forms asthe epidemic continues”. Monitoringthe appearance of these forms, addsCollinge, will require their molecularclassification “to see if there is anysystematic change in particularsubtypes”.
Jane Bradbury
Genetic susceptibility to prion disease: new phenotypes?
Brain-cancer cells that express the cell-surface marker CD133 seem toexclusively initiate tumour formation.As few as 100 CD133+ cells had potentcapabilities of self-renewal and prolifer-ation in vivo, and were able to generatetumours pathologically identical to theoriginal tumour after engraftment(Nature 2004; 432: 396–401).
“This is more definitive proof thatbrain-tumour growth is determined bysmall numbers of cells with stem-cellproperties”, says author Peter Dirks(Hospital for Sick Children, Toronto,ON, Canada).
To determine whether human brain-tumour cells were capable of tumourinitiation in vivo, Dirks and colleaguescompared the ability of both CD133+
and CD133– tumour cells, which wereisolated from human medullo-blastomas and glioblastomas, toinitiate tumour formation. The cells
were transplanted into the brains ofnon-obese diabetic, severe combinedimmunodeficient (NOD-SCID) mice.From 12 weeks to 24 weeks post-transplant, analysis showed that as fewas 100 CD133+ cells were able toinitiate growth of human brain tu-mours in NOD-SCID mice. Conversely,transplantation of as many as50 000–100 000 CD133– cells did notresult in tumour formation, and histo-logical analysis at 12 weeks showedonly a glial scar tract from the injection.
“The two cell populations shared thesame cytogenetic changes, but it isinteresting that they exhibited suchdifferent behaviour”, says Dirks. “Eventhough the other cells were also cancercells, they were not capable of tumourinitiation.”
The capacity for self-renewal wasalso assessed by serial passage. Serialretransplantation of CD133+ cells from
xenografts were transplanted intosecondary mice, and were assessedafter 5 weeks. Tumours grew in all fiveof the secondarily xenografted mice,and all developed tumours with thephenotype of the original tumour andthe primary xenograft.
This research will not have animmediate clinical effect, commentedMichael Clarke (University of MichiganMedical School, Ann Arbor, MI, USA),but “it will help to develop diagnosticsand therapeutics, and the identi-fication of the cells can be compared tothe identification of the mutationsthat cause cancer.”
The first drugs specifically targetingcancer, such as imatinib mesilate(Gleevac), have only recently becomeavailable, he added. “Clearly, these newdrugs are making an impact.”
Roxanne Nelson
Brain-cancer stem cells may drive tumour formation
