Abstract
Primary glioblastomas are subdivided into several molecular subtypes. There is an ongoing debate over the cell of origin for these tumor types where some suggest a progenitor while others argue for a stem cell origin. Even within the same molecular subgroup, and using lineage tracing in mouse models, different groups have reached different conclusions. We addressed this problem from a combined mathematical modeling and experimental standpoint. We designed a novel mathematical framework to identify the most likely cells of origin of two glioma subtypes. Our mathematical model of the unperturbed in vivo system predicts that if a genetic event contributing to tumor initiation imparts symmetric self-renewing cell division (such as PDGF overexpression), then the cell of origin is a transit amplifier. Otherwise, the initiating mutations arise in stem cells. The mathematical framework was validated with the RCAS/tv-a system of somatic gene transfer in mice. We demonstrated that PDGF-induced gliomas can be derived from GFAP-expressing cells of the subventricular zone or the cortex (reactive astrocytes), thus validating the predictions of our mathematical model. This interdisciplinary approach allowed us to determine the likelihood that individual cell types serve as the cells of origin of gliomas in an unperturbed system.
Highlights
Glioblastomas (GBMs) are the most common primary brain tumors [1]
When comparing the relative importance of the three populations (SR, TA, and self-renewing TA (SRTA) cells) for cancer initiation, we found that the probability of cancer initiation from SRTA cells dominates the dynamics in the PDGF-induced case for almost all parameter choices (Figs. 3 and S3), while in the NF1-driven case, only SR cells can lead to cancer initiation (Fig. S4) if there is no appreciable gamma effect associated with either NF1 or TP53 loss
For the mathematical model of PDGF-driven gliomas, we found that using those parameter values that most accurately describe the human brain results in the probability of cancer initiation from SRTA cells dominating the dynamics for all times (Fig. 3A)
Summary
Our understanding of GBM biology has greatly improved, but the cell of origin for these tumors is still debated [2]. Some studies have demonstrated that neural stem cells (NSCs), located in the subventricular zone (SVZ), are a possible target for transformation [2]. NSCs in the SVZ and in the subgranular zone (SGZ) are capable of self-renewal and give rise to the three cell types in the central nervous system [3]. Several studies suggested that extracellular signals can affect glial cell specification and may convert specified precursors into multipotential stem cells [4]. The cerebral cortex contains many cell types including astrocytes and oligodendroglial progenitor cells (OPCs) that have been reported to behave stem-like under certain culture or pathologic conditions [4,5]. Several of the major genetic alterations associated with gliomas confer some of the properties of stem cells [6]
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