Abstract
Glioblastoma multiforme (GBM) recurrences after temozolomide (TMZ) treatment result from the expansion of drug-resistant and potentially invasive GBM cells. This process is facilitated by O6-Methylguanine-DNA Methyltransferase (MGMT), which counteracts alkylating TMZ activity. We traced the expansion of invasive cell lineages under persistent chemotherapeutic stress in MGMTlow (U87) and MGMThigh (T98G) GBM populations to look into the mechanisms of TMZ-induced microevolution of GBM invasiveness. TMZ treatment induced short-term, pro-invasive phenotypic shifts of U87 cells, in the absence of Snail-1 activation. They were illustrated by a transient induction of their motility and followed by the hypertrophy and the signs of senescence in scarce U87 sub-populations that survived long-term TMZ stress. In turn, MGMThigh T98G cells reacted to the long-term TMZ treatment with the permanent induction of invasiveness. Ectopic Snail-1 down-regulation attenuated this effect, whereas its up-regulation augmented T98G invasiveness. MGMTlow and MGMThigh cells both reacted to the long-term TMZ stress with the induction of Cx43 expression. However, only in MGMThigh T98G populations, Cx43 was directly involved in the induction of invasiveness, as manifested by the induction of T98G invasiveness after ectopic Cx43 up-regulation and by the opposite effect after Cx43 down-regulation. Collectively, Snail-1/Cx43-dependent signaling participates in the long-term TMZ-induced microevolution of the invasive GBM front. High MGMT activity remains a prerequisite for this process, even though MGMT-related GBM chemoresistance is not necessary for its initiation.
Highlights
Introduction iationsThe phenotypic microevolution of tumor cells determines the promotion and progression of tumors, and it is crucial for their lethality
Our study is probably the first to discuss the function of Snail-1 in terms of TMZ stress-induced microevolution of Glioblastoma multiforme (GBM) invasiveness. These in vitro data need to be verified in vivo; at the current stage of the research, they illustrate the mechanistic link between Snail-1 signaling and chemotherapy-induced microevolution of Numerous co-factors participate in Snail-1-dependent epithelial-mesenchymal transition (EMT)/glial-to-mesenchymal transition (GMT) of tumor cells
Our current data indicate that Methylguanine-DNA Methyltransferase (MGMT) activity can be a prerequisite for the selective expansion of invasive GBM lineages, even though MGMT-related GBM chemoresistance is not necessary for its initiation
Summary
Introduction iationsThe phenotypic microevolution of tumor cells determines the promotion and progression of tumors, and it is crucial for their lethality. Multiple signaling pathways that govern this process depend on intercellular communication systems established within the tumor cell populations and between tumor and “stromal” cells [1]. (i) “endo/paracrine” or humoral factors; (ii) juxtacrine signals/exchange of mechanical stimuli via membrane receptors [2,3,4]; and, (iii) direct exchange of metabolites/organelles via gap junctions/nanotunnels [5,6,7]. These signaling systems can trigger secular and/or heritable phenotypic switches in “metastable” cells that potentially enhance cell invasiveness and resistance to chemotherapeutic stress.
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