Abstract 2367A: Understanding the role of stem-like tumor cells in mouse models of high-grade gliomas

Abstract

Abstract High-grade gliomas (WHO grade III-IV) are typified by poor therapeutic response and rapid lethality. Since the discovery of glioma cells with properties reminiscent of neural stem cells, there has been a great deal of interest in understanding their contributes to tumor growth and therapeutic resistance. Self-renewal is the defining characteristic of both normal and cancer stem cells, and it has been hypothesized that glioma cells with self-renewal capacity contribute disproportionately to tumor growth compared to other, more differentiated lineages. However, analyses are complicated by the lack of reliable markers to definitively identify and functionally characterize each distinct cell lineage. In the normal neurogenic niche, ID (Inhibitor of DNA-binding) genes regulate self-renewal and multipotency of adult neural stem cells. Here, using mouse models of high-grade glioma driven by PDGF- or mutKRAS, we show that high Id1 expression (Id1high) identifies self-renewing, multipotent tumor cells. By contrast, low Id1 expression (Id1low) identifies progenitor-like cells with proliferative potential but limited self-renewal capacity. While Id1high cells generate tumors upon orthotopic transplantation, Id1low cells do so with shorter latency and higher penetrance. Further, eliminating tumor cell self-renewal through targeted deletion of ID genes has modest effects on overall survival, while knockdown of the bHLH transcription factor, Olig2, within the Id1low population, results in a significant survival benefit. Together, these data highlight an important distinction between self-renewal capacity and tumor growth potential in two mouse models of gliomagenesis, underscoring the importance of non-stem cell lineages in disease progression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2367A. doi:1538-7445.AM2012-2367A