Abstract BACKGROUND Recent clinical studies suggest beneficial effects of propofol anesthesia on tumor progression and patient survival in solid tumors but reported benefits are modest. One potential reason is the relatively short, single exposure to propofol, limited to the surgical period. Brain metastases (BM) are the most common brain tumors in adults. Metastatic tumors develop following infiltration of the brain from primary tumors such as lung, breast, melanoma, and colorectal cancers. BM are treated with combination therapies, including surgery, radiotherapy, chemotherapy, and immunotherapy, however the prognosis of most patients with BM remains dismal. In this report we investigated the effects of propofol plus radiation on cancer stem cells derived from human lung cancer brain metastases (BM-CSCs) and their cross-talk with microglia. OBJECTIVES Our hypothesis is that propofol can be repurposed as a treatment of BM in addition to its anesthetic uses. To test this, we first examined the cytotoxic effects of propofol on cancer stem cells established from BM-CSCs alone and with radiation. Also, we studied the effects of propofol on the cross-talk of BM-CSCs and microglia. RESULTS We found that propofol 1) exerted inhibitory effect on BM-CSCs self-renewal, stemness and cell proliferation; 2) increased cell death of cancer cells but not normal neural elements; 3) sensitized BM-CSCs to radiation; 4) inhibited the pro-tumorigenic BM-CSCs/ microglia cross-talk by promoting M1 phenotypes of co-cultured microglia. CONCLUSIONS Propofol exerted anti-tumor effects on BM-CSCs including inhibition of cell renewal, proliferation, and mesenchymal transition. Propofol at sensitized BM-GSCs to radiation and at higher concentrations induced cell death. Propofol exerted anti-tumor cytotoxicity also by inhibiting the pro-tumorigenic CSC-microglia cross-talk via secreted extracellular vesicles (EVs). Propofol effects can be exploited as a general anesthetic of choice during tumor resection and should be examined as an anti-tumor agent in sub-anesthetic doses either alone or in combination with radiation.
Abstract BACKGROUND Glioblastoma (GBM), is the most common primary brain tumor. GBM contains a small subpopulation of glioma stem cells (GSCs) that are implicated in tumor recurrence and treatment resistance and therefore represent important therapeutic targets. Recent clinical studies suggest propofol impacts subsequent tumor response to treatments and patient prognosis. The effects of propofol on patient derived GSCs alone and in combination with radiation and temozolomide, (TMZ) have not been reported. Objectives: The molecular mechanisms underlying propofol’s anti-tumor effects on GSCs and its effect on cellular communication with microglia was studied. Using GSC spheroids, differentiated glioma and tumor cells on a microfluid chip, effects of propofol alone and together with radiation and TMZ on the self-renewal and stemness of GSCs, their mesenchymal transit and the proliferation and apoptosis of differentiated glioma cells was analyzed. Using transwell plates, the effects of propofol on the cross-talk of GSCs with human microglia cells was examined. RESULTS Propofol exerted a dose-dependent inhibitory effect on the self-renewal, expression of mesenchymal markers and migration of GSCs and sensitized them to both temozolomide (TMZ) and radiation. At higher concentrations propofol induced a large degree of cell death as demonstrated using microfluid chip. Propofol increased the expression of the lncRNA BDNF-AS, which acts as a tumor suppressor in GBM and silencing of this lncRNA partially abrogated propofol’s anti-tumor effects. Propofol also inhibited the pro-tumorigenic GSC-microglia cross talk via extracellular vesicles (EVs) and delivery of BDNF-AS. CONCLUSIONS Propofol exerted anti-tumor effects on GSCs and differentiated glioma cells by inhibiting cell renewal, proliferation, and mesenchymal transition and by inducing cell death at higher concentration. Propofol also sensitized GSCs to radiation and TMZ. Propofol, which is widely used in GBM surgeries, should be further explored as a potential repurposed drug during resection and an effective adjunct to radiation and TMZ.
Glioblastoma (GBM) is a highly aggressive tumor with poor prognosis. A small subpopulation of glioma stem cells (GSCs) has been implicated in radiation resistance and tumor recurrence. In this study we analyzed the expression of miRNAs associated with the functions of GSCs using miRNA microarray analysis of these cells compared with human neural stem cells. These analyses identified gene clusters associated with glioma cell invasiveness, axonal guidance, and TGF-β signaling. miR-504 was significantly downregulated in GSCs compared with NSCs, its expression was lower in GBM compared with normal brain specimens and further decreased in the mesenchymal glioma subtype. Overexpression of miR-504 in GSCs inhibited their self-renewal, migration and the expression of mesenchymal markers. The inhibitory effect of miR-504 was mediated by targeting Grb10 expression which acts as an oncogene in GSCs and GBM. Overexpression of exogenous miR-504 resulted also in its delivery to cocultured microglia by GSC-secreted extracellular vesicles (EVs) and in the abrogation of the GSC-induced polarization of microglia to M2 subtype. Finally, miR-504 overexpression prolonged the survival of mice harboring GSC-derived xenografts and decreased tumor growth. In summary, we identified miRNAs and potential target networks that play a role in the stemness and mesenchymal transition of GSCs and the miR-504/Grb10 pathway as an important regulator of this process. Overexpression of miR-504 exerted antitumor effects in GSCs as well as bystander effects on the polarization of microglia via delivery by EVs.
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