Glioblastoma cells: A heterogeneous and fatal tumor interacting with the parenchyma

Alves, Tércia; Lima, Flávia Regina Souza; Kahn, Suzana Assad; Lobo, Denise S.; Dubois, Luiz Gustavo; Soletti, Rossana C.; Borges, Helena L.; Neto, Vivaldo Moura

doi:10.1016/j.lfs.2011.04.022

Cited by 123 publications

(98 citation statements)

References 106 publications

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“…Due to the diffuse infiltration of glioblastoma cells into the brain tissues, resection of the bulk tumor is typically followed by tumor reinitiation at the resection site or at another location in the brain. The highly aggressive and invasive properties of glioblastoma cells contribute significantly to the poor prognosis of cases involving this type of tumor (3). Therefore, it has been proposed that anti-invasion agents may play a crucial role in the treatment of glioblastoma (4).…”

Section: Introductionmentioning

confidence: 99%

Resveratrol suppresses human glioblastoma cell migration and invasion via activation of RhoA/ROCK signaling pathway

et al. 2015

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Abstract. Numerous studies have demonstrated that resveratrol has a potential use in cancer prevention and treatment. However, the effects of resveratrol on cancer cell motility and invasiveness remain unclear. The current study aimed to examine the effects of resveratrol on cell migration and invasion in human glioblastoma cells, and to explore the underlying molecular mechanisms. In wound-healing and Matrigel transwell assays, resveratrol was found to significantly inhibit the migration and invasion of U87MG, T98G and U251 glioblastoma cells in vitro. Results from western blot analysis and gelatin zymography revealed that resveratrol also suppressed the expression and activity of matrix metalloproteinase 2 (MMP-2; P<0.05), an important mediator of cell migration and invasion. Furthermore, using a pull-down assay, increased activation of RhoA was observed in glioblastoma cells treated with resveratrol vs. controls (P<0.05). Notably, inhibition of the RhoA/Rho-associated kinase (ROCK) pathway by C3 transferase or Y-27362 was found to attenuate the resveratrol-induced reductions in cell migration and invasion (P<0.05), and also partially rescued the decreased expression and activity of MMP-2 induced by resveratrol (P<0.05). Taken together, the results suggest that resveratrol may inhibit glioblastoma cell motility and invasiveness via activating the RhoA/ROCK signaling pathway. IntroductionGlioblastoma is the most common and lethal intracranial malignant tumor with a yearly incidence of 3-4 per 100,000 (1). Despite the use of multimodal treatments, the prognosis of glioblastoma has been little improved, with a typical median survival time of only 12-15 months (2). Due to the diffuse infiltration of glioblastoma cells into the brain tissues, resection of the bulk tumor is typically followed by tumor reinitiation at the resection site or at another location in the brain. The highly aggressive and invasive properties of glioblastoma cells contribute significantly to the poor prognosis of cases involving this type of tumor (3). Therefore, it has been proposed that anti-invasion agents may play a crucial role in the treatment of glioblastoma (4).The invasion of malignant cancer cells is favored by degradation of the extracellular matrix (ECM), upregulation of proteolytic enzyme activity and an increase in tumor cell motility and invasive ability (5,6). Accumulating evidence has suggested that matrix metalloproteinases (MMPs) are capable of promoting tumor invasion and metastasis via degradation of the ECM (7), among which two gelatinases, MMP-2 and MMP-9, have attracted the most attention (8). Rho GTPases are a family of small GTP-binding proteins that serve as molecular switches in a wide variety of cellular signaling pathways, ultimately inducing changes in the organization of the actin cytoskeleton and regulating cell motility (9). It has been reported that RhoA activity is significantly reduced in astrocytic tumors (10-12), and increased RhoA activity in glioblastoma cells has been associated with impaired cell mi...

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Section: Introductionmentioning

confidence: 99%

Resveratrol suppresses human glioblastoma cell migration and invasion via activation of RhoA/ROCK signaling pathway

et al. 2015

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“…Until now, little was known about the genetic mechanisms involved in gliomagenesis. [1][2][3][4] A positive association between the overexpression of stem cell marker genes and progression/metastasis of tumors triggered the idea that targeting of self-renewal pathways can be applied as a powerful approach in cancer treatment.…”

Section: Introductionmentioning

confidence: 99%

Dendrosomal curcumin nanoformulation downregulates pluripotency genes via miR-145 activation in U87MG glioblastoma cells

Mirgani¹,

Isacchi²,

Sadeghizadeh³

et al. 2014

IJN

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Glioblastoma is an invasive tumor of the central nervous system. Tumor recurrence resulting from ineffective current treatments, mainly due to the blood–brain barrier, highlights the need for innovative therapeutic alternatives. The recent availability of nanotechnology represents a novel targeted strategy in cancer therapy. Natural products have received considerable attention for cancer therapy because of general lower side effects. Curcumin is a new candidate for anticancer treatment, but its low bioavailability and water solubility represent the main disadvantages of its use. Here, curcumin was efficiently encapsulated in a nontoxic nanocarrier, termed dendrosome, to overcome these problems. Dendrosomal curcumin was prepared as 142 nm spherical structures with constant physical and chemical stability. The inhibitory role of dendrosomal curcumin on the proliferation of U87MG cells, a cellular model of glioblastoma, was evaluated by considering master genes of pluripotency and regulatory miRNA (microribonucleic acid). Methylthiazol tetrazolium assay and flow cytometry were used to detect the antiproliferative effects of dendrosomal curcumin. Annexin-V-FLUOS and caspase assay were used to quantify apoptosis. Real-time polymerase chain reaction was used to analyze the expression of OCT4 (octamer binding protein 4) gene variants ( OCT4A , OCT4B , and OCT4B1 ), SOX-2 (SRY [sex determining region Y]-box 2) , Nanog , and miR-145 . Dendrosomal curcumin efficiently suppresses U87MG cells growth with no cytotoxicity related to dendrosome. Additionally, the accumulation of cells in the SubG 1 phase was observed in a time- and dose-dependent manner as well as higher rates of apoptosis after dendrosomal curcumin treatment. Conversely, nonneoplastic cells were not affected by this formulation. Dendrosomal curcumin significantly decreased the relative expression of OCT4A , OCT4B1 , SOX-2 , and Nanog along with noticeable overexpression of miR-145 as the upstream regulator. This suggests that dendrosomal curcumin reduces the proliferation of U87MG cells through the downregulation of OCT4 (octamer binding protein 4) variants and SOX-2 (SRY [sex determining region Y]-box 2) in an miR-145 -dependent manner.

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“…Tumoral heterogenic patterns might stratify patients individually, enabling the selection of appropriate therapeutics. Hence, intra-tumoral heterogeneity significantly contributes to the development of prognostic/predictive biomarkers and personalized treatment regimens [42][43][44][45][46] .…”

Section: Role Of Infections In Gliomagenesismentioning

confidence: 99%

Insights into molecular therapy of glioma: current challenges and next generation blueprint

et al. 2017

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Glioma accounts for the majority of human brain tumors. With prevailing treatment regimens, the patients have poor survival rates. In spite of current development in mainstream glioma therapy, a cure for glioma appears to be out of reach. The infiltrative nature of glioma and acquired resistance substancially restrict the therapeutic options. Better elucidation of the complicated pathobiology of glioma and proteogenomic characterization might eventually open novel avenues for the design of more sophisticated and effective combination regimens. This could be accomplished by individually tailoring progressive neuroimaging techniques, terminating DNA synthesis with prodrug-activating genes, silencing gliomagenesis genes (gene therapy), targeting miRNA oncogenic activity (miRNAmRNA interaction), combining Hedgehog-Gli/Akt inhibitors with stem cell therapy, employing tumor lysates as antigen sources for efficient depletion of tumor-specific cancer stem cells by cytotoxic T lymphocytes (dendritic cell vaccination), adoptive transfer of chimeric antigen receptor-modified T cells, and combining immune checkpoint inhibitors with conventional therapeutic modalities. Thus, the present review captures the latest trends associated with the molecular mechanisms involved in glial tumorigenesis as well as the limitations of surgery, radiation and chemotherapy. In this article we also critically discuss the next generation molecular therapeutic strategies and their mechanisms for the successful treatment of glioma.

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Glioblastoma cells: A heterogeneous and fatal tumor interacting with the parenchyma

Cited by 123 publications

References 106 publications

Resveratrol suppresses human glioblastoma cell migration and invasion via activation of RhoA/ROCK signaling pathway

Resveratrol suppresses human glioblastoma cell migration and invasion via activation of RhoA/ROCK signaling pathway

Dendrosomal curcumin nanoformulation downregulates pluripotency genes via miR-145 activation in U87MG glioblastoma cells

Insights into molecular therapy of glioma: current challenges and next generation blueprint

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