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Abstract: Matrix metalloproteinases (MMPs) play an important role in glioma infiltration, facilitating cell migration and tumor invasion through their ability to degrade the extracellular matrix. Therefore, the inhibition of MMPs has been suggested to be a promising therapeutic strategy for brain tumors. This study examined the effect of ginsenoside Rh2 on the expression of MMPs in human astroglioma cells. Rh2 inhibited the PMA-induced mRNA expression of MMP-1, -3, -9, and -14, suggesting that Rh2 has a broad-spectrum inhibitory effect on MMPs. The molecular mechanism underlying MMP-9 inhibition was further investigated because MMP-9 plays a major role in the invasiveness of glioma. It was found that Rh2 inhibited the secretion and protein expression of MMP-9 induced by PMA in human astroglioma cells. The Rh2-mediated inhibition of MMP-9 gene expression appears to occur through NF-κB and AP-1 because their DNA binding and transcriptional activities were suppressed by the agent. Furthermore, Rh2 significantly repressed the PMA-mediated activation of p38 MAPK, ERK and JNK, which are upstream modulators of NF-κB and AP-1. Finally, Rh2 inhibited the in vitro invasiveness of glioma cells, which might be attributed to the broad-spectrum inhibition of MMPs by Rh2. Overall, the strong inhibition of MMP expression by Rh2 might provide a potential therapeutic modality for brain tumors. [Copyright &y& Elsevier]

We present a 59-year-old woman who noted an enlarging lump on her forehead 6 months after a left frontotemporal craniotomy for tumor resection and chemoradiation of her primary glioblastoma multiforme (GBM). GBM is a highly aggressive intracranial neoplasm associated with the shortest survival time of any primary central nervous system malignancy. Extracranial metastasis is rare, especially without previous surgical disruption of the dura and calvarium, which has been postulated to cause seeding of the extracranial space with tumor cells. This patient’s MRI revealed tumor recurrence for which she underwent repeat resection. Histopathology confirmed GBM with unmethylated O-6-methylguanine-DNA methyltransferase and wildtype isocitrate dehydrogenase 1 status, as well as tumor invasion through the bone and subdermal space. The genetic and molecular factors that predict extracranial invasion remain unclear and require further investigation. Emerging data on circulating tumor cells in GBM patients indicate that extraaxial metastasis may be part of the disease course in some, particularly in long term survivors. Furthermore, the proximity of calvarial and scalp lesions to previous surgical sites and the time course in which they emerge after surgery suggests that iatrogenic seeding may also play a role in metastasis. With heightened awareness of the phenomenon, surgical strategies such as watertight approximation of the dura, bone flap replacement, or changing surgical instruments once the intradural component is complete may prove useful to prevent seeding. Prophylactic craniospinal irradiation may also be an appropriate tool in patients at high risk for metastasis, although this population is difficult to identify. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) possesses glioma stem cells (GSCs) that exhibit aggressive invasion behavior in the brain. Current preclinical GBM invasion assays using mouse brain xenografts are time consuming and less efficient. Here, we demonstrate an array of methods that allow rapid and efficient assaying of GSCs invasion in human brain organoids. The assays are versatile to characterize various aspects of GSCs, such as invasion, integration, and interaction with mature neurons of brain organoids. Tissue clearing and quantitative 3D imaging of GSCs in host organoids reveal that invasiveness is inversely correlated with the organoids' age. Importantly, the described invasion assays can distinguish the invasive behaviors of primary and recurrent GSCs. The assays are also amenable to test pharmacological agents. As an example, we show that GI254023X, an inhibitor of ADAM10, could prevent the integration of GSCs into the organoids. • Controlled and efficient assays characterize GSCs invasions in human brain organoids • GSCs interact with mature neurons and establish hemisynapses in human brain organoids • Assay 2 resembles the invasion behavior of GSCs in clinical samples of brain tissues • Assay 3 is preferentially suitable for drug screening For an improved versatility and reliability of 3D human brain organoids in modeling GBM, Goranci-Buzhala et al. established an array of methods that allow rapid and efficient assaying of glioma stem cell (GSC) invasion. Readouts described here can be used to study GSC invasion, integration, interaction with mature neurons, and drug screening. [ABSTRACT FROM AUTHOR]