Association of Notch-1, osteopontin and stem-like cells in ENU-glioma malignant process

Abstract

Notch-1 and osteopontin (OPN) mediate angiogenesis and glioma stem-like cell (GSLC) maintenance. However, the relationship between these molecules and GSLCs during the development of glioma is unknown. We investigate the expression of Notch-1, OPN and vascular endothelial growth factor (VEGF) associated to the stemness markers nestin and CD133 in three stages of murine gliomas induced by N-ethyl-N-nitrosourea (ENU).Notch-1 and OPN overexpress in the intermediate stage (II), which corresponds to the “angiogenesis switch”. Nestin+ cells appear in all stages of ENU-glioma but CD133 only from stage II on. In stage III, neoplastic cells expressing nestin, CD133 and nestin/CD133 reside in spheroid-like aggregates (SAs) and in the neoangiogenic border. These aggregates show Notch-1 and VEGF+ surrounding cells and a significant size and density increase with respect to stage I (3.3 ± 1.5 to 22.4 ± 6.3 µm2, n° = 0.3 ± 0.1 to 4.2 ± 0.9, from stage I to stage III, respectively).OPN expression increases in correlation to the glioma malignancy from 4.5 ± 1.8% (I) to 12.3 ± 1.2% of OPN+ cells (III). It predominates in astrocyte-like cells of the neoangiogenic border, displaying co-location with VEGF and CD133. The OPN immunopositivity distribution correlates with the CD133 distribution.In conclusion, OPN co-expressing with CD133 contributes to the identification of GSLCs in the neoangiogenic border, while Notch-1 is present around SAs in advanced stages. The ENU-glioma, mainly in stage II, is a useful tool for assessing new antitumour therapies against these molecules.

N-Ethyl-N-Nitrosourea Induced Leukaemia in a Mouse Model: Protective Effect of Icaritin via Inhibition of IL-6/JAK2/STAT3 Pathway Causes Apoptosis

“…7 In experiments with pregnant Sprague Dawley rats, a dose of 80 mg/ kg ENU was administered on embryonic day 15, resulting in the induction of gliomas and schwannomas. 8 It is important to consider that the specific dosage, frequency of administration, and treatment technique employed can significantly influence leukemia induction and impact the target cell and affected organ. 9 Inflammatory reactions and leukemia both include the IL-6/JAK2/STAT3 signaling pathway, which has recently become prominent.…”