Abstract
The dismal prognosis of glioblastoma multiforme (GBM) is mostly due to the high propensity of GBM tumor cells to invade. We reported an inverse relationship between GBM angiogenicity and expression of the DNA repair protein O(6)-methylguanine-DNA methyltransferase (MGMT), which has been extensively characterized for its role in resistance to alkylating agents used in GBM treatment. In the present study, given the major role of angiogenesis and invasion in GBM aggressiveness, we aimed to investigate the relationship between MGMT expression and GBM invasion. Stable overexpression of MGMT in the U87MG cell line significantly decreased invasion, altered expression of invasion-related genes, decreased expression of α(5)β(1) integrin and focal adhesion kinase, and reduced their spindle-shaped morphology and migration compared with the empty vector control. Conversely, short hairpin RNA-mediated stable knockdown of MGMT or its pharmacologic depletion in the MGMT-positive T98G cell line were required for increased invasion. The inverse relationship between MGMT and invasion was further validated in primary GBM patient-derived cell lines. Using paraffin-embedded tumors from patients with newly diagnosed GBM (n = 59), tumor MGMT promoter hypermethylation (MGMT gene silencing) was significantly associated with increased immunohistochemical expression of the proinvasive matricellular protein secreted protein acidic and rich in cysteine (SPARC; P = 0.039, χ(2) test). Taken together, our findings highlight for the first time the role of MGMT as a negative effector of GBM invasion. Future studies are warranted to elucidate the role of SPARC in the molecular mechanisms underlying the inverse relationship between MGMT and GBM invasion and the potential use of MGMT and SPARC as biomarkers of GBM invasion.
Highlights
The lethality of glioblastoma multiforme (GBM) stems from its pronounced infiltrative potential, as cells can diffusely invade beyond the margin of therapeutic resection [1]
Because angiogenesis and invasion are critical in glioma aggressiveness and share common molecular effectors [16, 17], we sought to determine whether methylguanine-DNA methyltransferase (MGMT) expression affects GBM invasive potential
To assess the relationship between MGMT and GBM invasiveness, we investigated in vitro invasion of a panel of 6 established cell lines, as well as the MGMT(–) cell line U87MG stably transfected with a vector encoding for MGMT (U87/ MGMT) or the control empty vector (U87/EV; 15, 21)
Summary
The lethality of glioblastoma multiforme (GBM) stems from its pronounced infiltrative potential, as cells can diffusely invade beyond the margin of therapeutic resection [1]. The prognosis of GBM remains poor, with a median survival of only 15 months following standard of care therapy involving surgery, radiotherapy, and chemotherapy with the alkylating agent temozolomide (TMZ; 2). Authors' Affiliations: 1Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton; 2Department of Oncology, Tom Baker Cancer Centre, Calgary, Alberta; 3Department of Oncology, Research Institute of the McGill University Health Centre; and 4Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada. Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).
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