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Logo of neuroncolAboutAuthor GuidelinesEditorial BoardNeuro-Oncology
Neuro Oncol. 2010 June; 12(6): 519.
PMCID: PMC2940644

Tumor-Initiating Cells: An Influential Paradigm for Xenograft Research

C. David James, Executive Editor, SNO

Xenograft-associated brain tumor studies have been performed for as long as neuro-oncology has been a definable field of cancer research. The earliest studies involved heterotransplantation of human brain tumor cells into immunocompetent hosts1 and subsequently the still-popular athymic nude mouse hosts.2 Identifying rodent hosts that maximize our ability to study a variety of brain tumor subtypes in vivo continues to see substantial research activity, as indicated by the study by Yu et al4 published in the current issue of Neuro-Oncology. In the associated investigation, Rag2 mice, which lack B and T cell function, were used as hosts for engrafting and propagating an ependymoma—a central nervous system tumor subtype whose degree of malignancy is generally insufficient for successful propagation using the conventional athymic mouse model.

The mouse host used in the current study, although significant, does not represent the major subject of this editorial. Rather, this editorial focuses on primary tumor and derivative xenograft cancer stem cell, or tumor-initiating cell, composition. In 2004, results presented by Singh et al3 supported the importance of the CD133+ fraction of patient brain tumors in tumorigenicity in NOD-SCID mice. The pervasive influence of this report has been evident ever since, and the characterization of brain tumors, especially gliomas, and corresponding derivatives for CD133 composition has been a consistent feature of published studies over the past 6 years. In fact, as of April 5, 2010, the manuscript by Singh et al3 has been cited 1144 times, with one more acknowledgement by Yu et al4 in the current issue of Neuro-Oncology. One wonders whether the referees realized the likely impact of the 2004 publication at the time of its review.

The idea of CD133 expression as a key determinant of brain tumor tumorigenicity has proven to be contentious, as there now exist a substantial number of studies that support or oppose it. Rather than taking a side on this controversial issue, taking a step back to “see the forest for the trees” may be a more appropriate as well as diplomatic course of action. Specifically, one could and perhaps should consider that CD133-related research and observations have substantially increased our appreciation of the importance of tumor heterogeneity in the biology of malignant glioma. In particular, there exist subsets of tumor cells that are especially important to the aggressive and therapy-resistant5 nature of glioma. Because mouse host tumorigenicity is the gold standard for evaluating tumor-initiating cell “stemness,” cancer stem cell research is intimately and perhaps inextricably associated with xenograft research. The study by Yu et al4 takes into account these various interrelated matters and reminds us that the cancer stem cell hypothesis continues to be a major influence in the field of neuro-oncology.

C. David James, Executive Editor, SNO


1. Krigman MR, Manueldis EE. Distribution of fluorescent tracers in heterologously transplanted intracerebral tumors. Cancer Res. 1964;24:1749–1759. [PubMed]
2. Rana MW, Pinkerton H, Thornton H, Nagy D. Heterotransplantation of human glioblastoma multiforme and meningioma to nude mice. Proc Soc Exp Biol Med. 1977;155:85–88. [PubMed]
3. Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD, Dirks PB. Identification of human brain tumour initiating cells. Nature. 2004;432:396–401. [PubMed]
4. Yu L, Baxter PA, Voicu H, Gurusiddappa S, Zhao Y, Adesina A, Man TK, Shu Q, Zhang Y-J, Zhao X-M, Su JM, Perlaky L, Dauser R, Chintagumpala M, Lau CC, Blaney SM, Rao PH, Leung H-CE, Li XN. A clinical relevant orthotopic xenograft model of ependymoma that maintains the genomic signature of the primary tumor and preserves cancer stem cells in vivo. Neuro-Oncology. 2010;12:580–594. [PMC free article] [PubMed]
5. Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, Dewhirst MW, Bigner DD, Rich JN. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 2006;444:756–760. [PubMed]

Articles from Neuro-Oncology are provided here courtesy of Society for Neuro-Oncology and Oxford University Press