Mouse Low-Grade Gliomas Contain Cancer Stem Cells with Unique Molecular and Functional Properties

Abstract

Summary The availability of adult malignant glioma stem cells (GSCs) has provided unprecedented opportunities to identify the mechanisms underlying treatment resistance. Unfortunately, there is a lack of comparable reagents for the study of pediatric low-grade glioma (LGG). Leveraging a neurofibromatosis-1 (Nf1) genetically-engineered mouse LGG model, we report the isolation of CD133+ multi-potent low-grade glioma stem cells (LG-GSCs), which generate glioma-like lesions histologically similar to the parent tumor following injection into immunocompetent hosts. In addition, we demonstrate that these LG-GSCs harbor selective resistance to currently-employed conventional and biologically-targeted anti-cancer agents, which reflect the acquisition of new targetable signaling pathway abnormalities. Using transcriptomal analysis to identify additional molecular properties, we discovered that mouse and human LG-GSCs harbor high levels of Abcg1 expression critical for protecting against endoplasmic reticulum (ER) stress-induced mouse LG-GSC apoptosis. Collectively, these findings establish that LGG cancer stem cells have unique molecular and functional properties relevant to brain cancer treatment.

Challenges in Drug Discovery for Neurofibromatosis Type 1-Associated Low-Grade Glioma

“…Using Nf1 optic glioma GEM models, LGG CSCs have been isolated, which were capable of self-renewal, long-term passage, and multilineage differentiation (56). Importantly, these CSCs formed LGG-like lesions when injected into the brainstems of immunocompetent, but not immunocompromised (athymic), mice.…”

“…Importantly, these downstream effectors converge on the mTOR complex to regulate astrocyte growth in vitro and Nf1 optic glioma proliferation in vivo (9). Future laboratory investigations will be required to define the RAS effector signaling networks required for optic glioma maintenance relevant to adaptive and potential escape mechanisms from targeted therapies that might be operative in these tumors (56). …”

“…Current xenograft methodologies developed using HGG cells may not be suitable for generating LGG PDX due to the relative stromal independence of HGG cells. The methodologies for future PA PDX studies can be tested and optimized using xenografts developed from mouse NF1-LGG cells (56). Current mouse xenograft methodologies involve the isolation of single cells (CD133+) from the optic nerves of 3-month-old mice with NF1-LGG ( Nf1 +/− GFAP CKO mice) (56).…”

“…The methodologies for future PA PDX studies can be tested and optimized using xenografts developed from mouse NF1-LGG cells (56). Current mouse xenograft methodologies involve the isolation of single cells (CD133+) from the optic nerves of 3-month-old mice with NF1-LGG ( Nf1 +/− GFAP CKO mice) (56). The resulting glioma stem cells express several stem cell markers and a response to therapeutic treatments similar to that observed in humans.…”

STEM CELL AND CANCER STEM CELL: A Tale of Two Cells

“…In some malignant melanoma, keratinocytes also contribute as microenvironmental factor (Lacina et al, 2015). Many studies reported that Glioma stem cells (GSCs) reside in particular niches to maintain their behavior (Chen et al, 2015;Lathia et al, 2015). A hypoxic microenvironment has been reported to be important in regulating GSC molecular and phenotypic features through the recruitment of vascular and stromal cells (Persano et al, 2013).…”