Editors' ChoiceCancer

Differentiation Block in Glioma

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Science Translational Medicine  26 May 2010:
Vol. 2, Issue 33, pp. 33ec85
DOI: 10.1126/scitranslmed.3001295

The cancer stem-cell theory, although controversial, postulates that tumor growth is driven by a small fraction of cells that, unlike the bulk of tumor cells, have the property of self-renewal, which is responsible for the relentless growth characteristic of malignant lesions. Self-renewal is also a characteristic of normal stem cells, which may suggest that normal stem cells within the tissue acquire mutations and become cancer stem cells that subsequently develop into a tumor. One of the less appreciated forms of cancer, glioblastoma multiforme (GBM)—the most aggressive type of glioma, affecting 1 in 100,000 individuals per year—is characterized by areas of aberrant differentiation within which the existence of cancer stem cells is well established. These “glioma-initiating cells,” or GICs, are isolated from human tumor samples by virtue of CD133 expression and are characterized by the ability to form tumors in immunodeficient mice.

Recently, studies using array comparative genomic hybridizationtechnology have revealed a previously unknown amplified region that contains seven genes on chromosome 20 in about 15% of human GBMs. Zheng and colleagues set out to determine which of these seven genes is responsible for the development of tumorigenesis. One of the seven, PLAGL2, a transcription factor, met all the criteria for an oncogene: PLAGL2 overexpression imparted anchorage-independent growth and increased invasiveness on mouse astrocytes and on human epithelial cells, whereas PLAGL2 depletion in glioma cell lines hindered growth. Further mechanistic investigation revealed that PLAGL2 overexpression blocked differentiation and promoted self-renewal of normal neural stem cells via the WNT signaling pathway, which is a well-known regulator of stem cell behavior. Therefore, these results highlight that PLAGL2 overexpression appears to be a critical event along the path from a normal neural stem cell to glioma formation, although the ways in which this factor is triggered and the therapeutic ways to fine-tune such triggers await further elucidation.

H. Zheng et al., PLAGL2 regulates Wnt signaling to impede differentiation in neural stem cells and gliomas. Cancer Cell. 17, 497–509 (2010).[Full Text]

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