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Subtypes Of Ependymomas Arise From Rare Stem Cells In The Nervous System

Date:
October 18, 2005
Source:
St. Jude Children's Research Hospital
Summary:
Finding suggests that new drugs to treat ependymoma and other types of solid tumors should be designed to target the specific signal pathways that cause uncontrolled replication of cancer stem cells, according to St. Jude Children's Research Hospital.
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Brain tumors called ependymomas that occur in different parts of thecentral nervous system appear to arise from subpopulations of stemcells called radial glia cells (RGCs), according to investigators atSt. Jude Children's Research Hospital. The discovery explains why someidentical-looking ependymomas are actually distinctly differentdiseases, the researchers said.

This new information, in combination with the techniques used toconduct the study, holds promise for designing more effectivetreatments for ependymomas as well as for other solid tumors. A reporton this work appears in the October issue of Cancer Cell.RGCs are unspecialized cells that line the surface of the ventricles(fluid-filled spaces in the brain) and the spinal cord, and give riseto normal mature cells in the nervous system. The St. Jude study foundstrong evidence that when rare populations of RGCs acquire mutationsthat disrupt the cell signaling pathways controlling growth anddifferentiation, these cells reproduce continually and give rise to anependymoma.

The St. Jude finding that RGCs can give rise to these tumors isconsistent with evidence from a variety of researchers that cancersarise from, and are maintained by, a rare number of mutated stem cellscalled cancer stem cells, according to Richard Gilbertson, M.D., Ph.D.,associate member in the Developmental Neurobiology and theHematology-Oncology departments. Gilbertson is senior author of theCancer Cell paper.

The current discovery at St. Jude explains why ependymomas arising invarious parts of the central nervous system are clinically different,even though they look the same histologically (as seen under amicroscope), the St. Jude researcher said. For example, although allependymomas look alike, supratentorial ependymomas arise in the toppart of the brain in both adults and children; often cause weakness inthe arms and legs, visual problems and seizures; and have a survivalrate of 50-60 percent. Posterior fossa ependymomas arise in the back ofthe brain and cause patients to have an unsteady walk and neck pain;and they occur mainly in children and have a slightly worse prognosisthan do surpratentorial tumors. A spinal ependymoma occurs mainly inadults, and more than 70 percent of patients who undergo surgery toremove this tumor survive.

"Historically, physicians based their diagnosis and treatment of cancerprimarily on the histology of tumors," Gilbertson said. "So ourdemonstration that identical-looking ependymomas that arise indifferent regions of the central nervous system are distinct diseasesat the cellular and molecular level is an important insight. Thissuggests that treatments should be designed to kill the cancer stemcells. If you kill only the cells making up the bulk of the tumor, thedisease will likely return because you haven't eliminated the stemcells that are the source of the tumor."

The St. Jude study is also important because ependymomas are the thirdmost common central nervous system tumor in children and no effectivechemotherapy exists for them. "If surgery and radiation doesn't treatthe entire tumor, then resistant stem cells left behind might re-growthe cancer," Gilbertson said. "And since children don't tolerateradiation treatment well, we need new treatments that completelyeliminate cells that produce the tumors."

The researchers made their discovery by first determining the patternsof gene expression in more than 100 tumor samples from patients withdifferent types of ependymoma. Gene expression patterns, calledsignatures, reflect the specific genes that have been activated in thetumors. The signatures that distinguished supratentorial, posteriorfossa and spinal ependymomas included genes that regulate theproliferation and differentiation of normal primitive cells in thecorresponding region of the embryonic nervous system. For example, theSt. Jude team showed that more than 80 percent of genes expressed athigh levels in the supratentorial and spinal ependymomas are alsoexpressed in the corresponding regions of the nervous system duringdevelopment.

The team also demonstrated that each subtype of ependymoma containsrare populations of cells that resemble RGCs. Moreover, when theseRGC-like ependymoma cancer stem cells were inserted into laboratorymodels that lacked protective immune systems, the stem cells formedtumors. This was additional strong evidence that mutated RGCs can giverise to ependymomas.

The different genetic signatures found in each subtype of ependymomarepresent potential targets for new drugs designed to kill RGCs thatgive rise to each subtype of this tumor, said Gilbertson. Suchindividualized treatment might allow physicians to prevent therecurrence of ependymoma following treatment to remove the primary(original) tumor by eliminating the cancer stem cells that give rise tothe tumor.

The technique the St. Jude team used to identify populations of RGCs ascells of origin of ependymoma could also be used to identify cancerstem cells for other solid tumors, according to Helen Poppleton, PhD,an associate scientist. "That new knowledge could lead to thedevelopment of new drugs that significantly improve the outcomes of avariety of cancers," Poppleton said. One of the authors of the paper,Poppleton did much of the work on this project.

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Other authors of this paper include Michael D. Taylor, ChristineFuller, Xiaoping Su, Xiaong Liu, Patrician Jensen, Susan Magdelano,James Dalton, Julian Board, Amar Gajjar and Tom Curran (St. Jude);Tobey MacDonald (Children's National Medical Center; Washington, DC);Jim Rutka (Hospital for Sick Children; Toronto, Canada); and AbhijitGuha (Toronto Western Hospital; Canada).

This work was supported in part by the National Institutes of Health,the V Foundation for Cancer Research, the Sontag Foundation and ALSAC.

St. Jude Children's Research Hospital
St. Jude Children'sResearch Hospital is internationally recognized for its pioneering workin finding cures and saving children with cancer and other catastrophicdiseases. Founded by late entertainer Danny Thomas and based inMemphis, Tenn., St. Jude freely shares its discoveries with scientificand medical communities around the world. No family ever pays fortreatments not covered by insurance, and families without insurance arenever asked to pay. St. Jude is financially supported by ALSAC, itsfund-raising organization. For more information, please visit www.stjude.org.


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St. Jude Children's Research Hospital. "Subtypes Of Ependymomas Arise From Rare Stem Cells In The Nervous System." ScienceDaily. ScienceDaily, 18 October 2005. <www.sciencedaily.com/releases/2005/10/051018073311.htm>.
St. Jude Children's Research Hospital. (2005, October 18). Subtypes Of Ependymomas Arise From Rare Stem Cells In The Nervous System. ScienceDaily. Retrieved May 22, 2024 from www.sciencedaily.com/releases/2005/10/051018073311.htm
St. Jude Children's Research Hospital. "Subtypes Of Ependymomas Arise From Rare Stem Cells In The Nervous System." ScienceDaily. www.sciencedaily.com/releases/2005/10/051018073311.htm (accessed May 22, 2024).

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