Developmental origins of brain tumors

Abstract

Brain tumors are devastating owing to the high fatality rate and the devastating impact on life qualities of patients. Recent advancement of comparative transcriptome profiling tools and mouse genetic models has greatly deepened our understanding of the developmental origins of these tumors, which could lead to effective therapeutic strategies. We review recent progresses in three types of brain tumors: ependymoma, medulloblastoma, and malignant glioma. The conceptual framework established by these studies converged on three important aspects. First, subtypes in each tumor group originate from distinct cell types. Second, each cell-of-origin is uniquely susceptible to some but not other genetic mutations. Lastly, mutant stem cells may not transform until they differentiate into more restricted progenitor cell type. Overall, these findings indicate the existence of intricate interactions between gene mutations and developmental program for the formation of brain tumors.

Figure 1. MADM, a mouse genetic mosaic model, can be used for identifying tumor cell of origin and evaluating novel targets against such cells for tumor prevention or treatment

(A) Scheme that shows how MADM can concurrently mutate and label cells via a Cre/loxP-mediated inter-chromosomal mitotic recombination event. Green cells are homozygous null for the gene-of-interest that is distal to the MADM cassette on the same chromosome; red cells are WT cells. For details, see Zong et al 2005. (B) Scheme that illustrates how to use MADM-based cancer model to identify cell of origin by analyzing the aberrant growth of all progeny lineages derived from mutant stem/progenitor cells in a defined organ. Although we use the brain as an example here, the same principle should be applicable to tumors in other organs. For details, see Liu et al 2011. (C) The MADM system can be further modified by incorporating the Tet-ON system to investigate the effects of further genetic manipulation on the cell of origin. With the temporal control of the intervention, one could model the treatment effects of any gene on tumor initiation, progression, and malignancies.