In spite of intense research, what exactly triggers the formation of a glioblastoma cancer stem cell remains elusive. Further, most researchers believe that these cancer stem cells originate from either normal neural stem cells or early progenitor cells. However, in a recent study, researchers at The Salk Institute for Biological Studies (La Jolla CA) challenge this dogma and show that cortical neurons in the brain can “go back in time”, revert to a stem cell-like state and in turn produce tumors. This study represents a paradigm shift in our understanding of glioblastoma because of two main reasons:
Mature neurons were thought to be terminally differentiated and incapable of any further transformation. Glioblastomas were never before shown to arise from neuronal cells. The approach taken by these researchers in their study was to genetically turn off the expression of two tumor suppressor proteins, p53 and neurofibromatosis type I (NF1) in the mouse central nervous system. The knockdown of these two proteins caused cortical neurons in the mouse brain to reprogram back to an immature or stem cell-like state. These cells now had a high expression of stem cell markers and a decreased expression of differentiation markers. This indicates that the cortical neurons underwent transformation to a more primitive phenotype.
More importantly, they were able to produce tumors in mouse brains. Thus, following knockdown of p53 and NF1, cortical neurons regressed developmentally and formed glioblastoma cancer stem cells capable of tumorigenesis. Apart from neurons, glial cells and neural stem cells were also able to produce tumors following p53 and NF1 knockdown.
The prevalent view on glioblastoma formation is that normal neural stem cells in the brain undergo malignant transformation and produce tumors. Hence, this is a landmark study that demonstrates how existing populations of mature brain cells, including neurons and glial cells can “enter a time machine and travel back to their developmental past” to a more primitive, stem-like state (a process called dedifferentiation) and eventually lead to tumor formation. Of course, the findings from this study need to be validated in human cells. But this study offers a possible explanation of the recurrence of glioblastomas following conventional therapy.
In the same study, when mouse tumors generated were analyzed, their molecular profiles resembled a highly aggressive variant of glioblastomas observed clinically, designated as the mesenchymal subtype. Apart from this subtype, a previous study has described three other variants, each with its distinct molecular signature. It is very likely that each of these subtypes originates from a distinct cancer stem cell type, which in turn may be produced by dedifferentiation of different cell populations in the central nervous system.
The implication of this complexity is that an effective treatment strategy against this disease would need to include detailed molecular analyses of tumor signatures in order to personalize therapy. Findings from this study are important to understand the pathogenesis of glioblastoma and to design more effective treatment options. If a therapeutic agent can block dedifferentiation of cells, it may effectively get rid of cancer stem cell populations and prove to be a highly valuable adjunct to current therapies against glioblastoma.