Abstract
Recent studies report that STAT3 signaling is a master regulator of mesenchymal transformation of gliomas and that STAT3 modulated genes are highly expressed in the mesenchymal transcriptome of gliomas. A currently studied experimental treatment for gliomas consists of intratumoral injection of oncolytic viruses (OV), such as oncolytic herpes simplex virus type 1 (oHSV). We have described one particular oHSV (rQNestin34.5) that exhibits potent anti-glioma activity in animal models. Here, we hypothesized that alterations in STAT3 signaling in glioma cells may affect the replicative ability of rQNestin34.5. In fact, human U251 glioma cells engineered to either over-express STAT3 or with genetic down-regulation of STAT3 supported oHSV replication to a significantly higher or lesser degree, respectively, when compared to controls. Administration of pharmacologic agents that increase STAT3 phosphorylation/activation (Valproic Acid) or increase STAT3 levels (Interleukin 6) also significantly enhanced oHSV replication. Instead, administration of inhibitors of STAT3 phosphorylation/activation (LLL12) significantly reduced oHSV replication. STAT3 led to a reduction in interferon signaling in oHSV infected cells and inhibition of interferon signaling abolished the effect of STAT3 on oHSV replication. These data thus indicate that STAT3 signaling in malignant gliomas enhances oHSV replication, likely by inhibiting the interferon response in infected glioma cells, thus suggesting avenues for possible potentiation of oncolytic virotherapy.
Highlights
Malignant gliomas remain formidable cancers to treat and to palliate with conventional standard of care that includes neurosurgery, radiation and chemotherapy
There was an approximate 30 and 10 fold increase in titers of oncolytic HSV (oHSV) in HA STAT3 or FLAG STAT3 expressing glioma cells, respectively, when compared to control pCR/CMV transfectants (Figure 1c-black bars). This was confirmed by showing that expression of the late viral gene glycoprotein C was significantly increased in both STAT3 over-expressing transfectants (Figure 1d)
We show for the first time that STAT3 activation leads to enhanced replication of oHSV in glioma cells
Summary
Malignant gliomas remain formidable cancers to treat and to palliate with conventional standard of care that includes neurosurgery, radiation and chemotherapy. Several new therapeutic approaches have been attempted including the use of oncolytic viruses (OVs) [1] [2] [3]. These are naturally occurring or genetically engineered recombinant viruses that replicate in a relatively selective fashion in tumor cells. Several different engineered types of this OV have been tested in animal models and in one phase I clinical trial for MG there was reported evidence of a modest degree of replication of the oncolytic HSV (oHSV) in postinjection biopsies [7] [8]. Attempts in the laboratory to improve OV and oHSV replication have been the focus of recent research, including generating more potent OVs, combining OVs with pharmacologic modulators or immunomodulators, and understanding the tumor host response and barriers to OV efficacy in order to devise avenues to circumvent these
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