Abstract
Glioblastoma is the most common and aggressive malignant brain tumor in adults. The existence of glioblastoma stem cells (GSCs) or stem–like cells (stemloids) may account for its invasiveness and high recurrence. Rac proteins belong to the Rho small GTPase subfamily which regulates cell movement, proliferation, and survival. To investigate whether Rac proteins can serve as therapeutic targets for glioblastoma, especially for GSCs or stemloids, we examined the potential roles of Rac1, Rac2 and Rac3 on the properties of tumorspheres derived from glioblastoma cell lines. Tumorspheres are thought to be glioblastoma stem-like cells. We showed that Rac proteins promote the STAT3 and ERK activation and enhance cell proliferation and colony formation of glioblastoma stem-like cells. Knockdown of Rac proteins reduces the expression of GSC markers, such as CD133 and Sox2. The in vivo effects of Rac proteins in glioblastoma were further studied in zebrafish and in the mouse xenotransplantation model. Knocking-down Rac proteins abolished the angiogenesis effect induced by the injected tumorspheres in zebrafish model. In the CD133+-U373-tumorsphere xenotransplanted mouse model, suppression of Rac proteins decreased the incidence of tumor formation and inhibited the tumor growth. Moreover, knockdown of Rac proteins reduced the sphere forming efficiency of cells derived from these tumors. In conclusion, not only Rac1 but also Rac2 and 3 are important for glioblastoma tumorigenesis and can serve as the potential therapeutic targets against glioblastoma and its stem-like cells.
Highlights
IntroductionGlioblastoma multiforme (GBM) is the most common malignant primary brain tumor (classified as the grade IV astrocytoma), and one of the most aggressive cancers in humans
Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor, and one of the most aggressive cancers in humans
To investigate whether Rac proteins can serve as therapeutic targets for glioblastoma, especially for glioblastoma stem cells (GSCs) or stemloids, we examined the potential roles of Rac1, Rac2 and Rac3 on the properties of tumorspheres derived from glioblastoma cell lines
Summary
Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor (classified as the grade IV astrocytoma), and one of the most aggressive cancers in humans. The median survival rate of GBM is 10 to 14 months after diagnosis. Aberrant regulations are noted during glioblastoma progression, such as transformation of developing neural stem cells [1, 2], and accumulation of genetic mutations in mature brain cells [3,4,5]. Glioblastoma has been grouped into four subtypes: classical, neural, proneural, and mesenchymal [6]. Each type is defined by specific sets of aberration and expression levels of regulatory genes. The classical subtype responds positively to aggressive therapies, while the prognosis of proneural and mesenchymal subtypes are much poorer [6, 7]
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