In recent years, cancer biologists have shown that the growth of solid tumors may be driven by a minor subpopulation of cells that behave as stem cells. The identification of these cells in tumors has fueled the search for underlying growth regulatory mechanisms in normal stem cells whose misregulation might cause cancerous transformation. One such study conducted by researchers from Dana–Farber Cancer Institute has succeeded in identifying a transcription factor, previously known as a vital component of normal brain development, to be critical for brain tumor formation. The work was conducted in the labs of Charles Stiles, HMS professor of microbiology and molecular genetics, and David Rowitch, formerly an HMS associate professor of pediatrics. Postdocs Keith Ligon, Emmanuelle Huillard, and Shwetal Mehta contributed equally to this work, which appears in the Feb. 15 Neuron.
The researchers studied Olig2, a transcription factor that is specifically expressed in multipotent neural progenitor cells (stem cells) of the developing central nervous system. During normal development, a key function of Olig2 is to prevent differentiation and maintain neural stem cells in a replication-competent state until a sufficient number of cells are available to undergo differentiation and assemble an intact brain.
Human glioblastoma samples show the presence of tumor progenitor cells, which bear similarities to normal neural stem cells and are likely derived from them. Ninety-eight percent of these cells, named CD133, express Olig2. This observation motivated the researchers to interrogate the role of Olig2 in tumor development.
The authors showed that Olig2 function is crucial for tumor development in a mouse model of malignant glioma that emulates the genetic mutations seen commonly in human malignant gliomas. The absence of Olig2 in the context of an otherwise tumor-promoting genetic background prevented the growth of tumors in the brains of immunocompromised mice; the ability to form tumors was rescued by reintroduction of the Olig2 gene. On a mechanistic level, the research team identified a cell cycle inhibitor molecule, p21, whose expression is repressed by Olig2, which may be a key event allowing uncontrolled proliferation of tumor cells.
This research highlights the role of developmental regulators in facilitation, if not initiation, of cancer progression. Whereas loss of tumor suppressors such as p53 is a familiar feature in cancers of most tissue types, knowledge about tissue-specific factors that are critical for tumorigenesis is still lacking. The current study fills this gap with the identification of Olig2 as a lineage-specific transcription repressor whose aberrant expression in neural stem cells can be a precursor to malignancy.
