Mouse Induced Glioma-Initiating Cell Models and Therapeutic Targets

Toru      Kondo

Abstract

Both stem cells and cancer cells are thought to be capable of unlimited self-renewal. Moreover, a small number of cancer cells express stem cell markers, including CD133 and ATP-binding cassette transporters through which the cells can pump out anti-cancer drugs or specific fluorescence dyes such as Hoechst33342, suggesting that either cancer cells resemble stem cells or that cancers contain stem cell-like cancer cells, called cancer-initiating cells (CICs) or cancer stem cells. Using the common characteristics of tissue-specific stem cells, malignant tumors and cancer cell lines were shown to contain CICs, which self-renew and are tumorigenic. CICs are also resistant to both irradiation and chemotherapy. These findings suggest that CICs are critical targets for successful therapy. However, CICs have not been well characterized, due to a lack of specific markers. We recently established mouse glioma-initiating cell (GIC) lines by overexpressing oncogenic HRasL61 in p53-deficient neural cells. These cells form transplantable glioblastoma multiforme (GBM) with features of human GBM when as few as 10 cells are transplanted in vivo, suggesting that these GIC-like cells are enriched in CICs. Characterization of these GICs showed that they expressed little or no Sox11. The overexpression of exogenous Sox11 in GICs blocked their tumorigenesis by inducing their neuronal differentiation, which was accompanied by decreased levels of a novel oncogene, plagl1. These findings suggest that Sox11 and Plagl1 work as a tumor suppressor and oncogene, respectively, in GBM and are potential therapeutic targets.

Keywords: Glioblastoma multiforme (GBM), glioma-initiating cells (GIC), neural stem cells (NSC), p53, Plagl1, Ras, Sox11, stem cells, cancer cells, CD133, ATP-binding cassette transporters, cancer-initiating cells, p53-deficient neural cells, exogenous Sox11, tumor suppressor, oncogene, homeostasis, central nervous system, neurons, astrocytes, oligodendrocyte, NSC-like cancer, oligodendrocyte precursor cells, anti-cancer drugs, multi-drug resistance gene, multi-drug resistance protein, breast cancer resistance protein, leukemic stem cell-like cells, p53-deficient NSCs, NSCL61s, cancer therapy, tissue- specific stem cells, TSC markers, oncogenic mutations, ventricular zone, oligodendrocyte marker GC, gliomagenesis, avian leukosis virus, topoisomerase II, O6-methylguanine-DNA-methyltransferase, dihydrofolate reductase, metallothioneins, CXCR4, beta1-integrin, N-cadherin, aldehyde dehydrogenase activity, acute myeloid leukemia, ALDH, p53 Pathway, cyclin-dependent kinase (cdk) inhibitor, Retinoblastoma, Tyrosine Kinase