Abstract
Aberrant c-Met has been implicated in the development of many cancers. The objective of this study was to identify an unfavorable prognostic marker that might guide decisions regarding clinical treatment strategies for high-grade gliomas. C-Met expression was measured using immunohistochemistry in 783 gliomas, and we further analyzed c-Met mRNA levels using the Agilent Whole Genome mRNA Microarray in 286 frozen samples. In vitro, we performed cell migration and invasion assays. Cell sensitivity to temozolomide (TMZ) chemotherapy was determined using MTT assays. Both mRNA and protein levels of c-Met were significantly associated with tumor grade progression and inversely correlated with overall and progression-free survival in high-grade gliomas (all P < 0.0001). These findings were nearly consistent at the mRNA level across 3 independent cohorts. Multivariable analysis indicated that c-Met was an independent prognostic marker after adjusting for age, preoperative Karnofsky Performance Status (KPS) score, the extent of resection, radiotherapy, TMZ chemotherapy, and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status. Further analysis in vitro revealed that downregulating the expression of c-Met dramatically inhibited cell migration and invasion capacities, enhanced sensitivity to TMZ chemotherapy in H4 and U87 glioma cells. Our results suggest that c-Met may serve as a potential predictive maker for clinical decision making.
Highlights
It is widely accepted that the most consistent abnormalities associated with well-known molecular aberrations of aggressive gliomas, such as chromosome 7 amplification and chromosome 10 deletion, are present in 80% to 90% of cases[2,3,4]
We found that the patients in the low-expression group were perfectly separated, which indicates that the patients who accepted aggressive therapy experienced longer Overall survival (OS) (Fig. 3B, P < 0.0001) and Progression-free survival (PFS) (Fig. 3E, P < 0.0001) than the patients who received only radiotherapy but that the same phenomenon was not observed in the high-expression group (Fig. 3C, P = 0.2833; Fig. 3F, P = 0.0687)
Nabeshima et al concluded that the expression of c-Met is correlated with the grade of malignancy in human astrocytic tumors[27], Lee et al found that the overexpression of c-Met is associated with the survival of patients with colorectal cancer[28], and Kong et al and Petterson et al came to similar conclusions for patients who have GBMs29,30
Summary
It is widely accepted that the most consistent abnormalities associated with well-known molecular aberrations of aggressive gliomas, such as chromosome 7 amplification and chromosome 10 deletion (which were the primary concerns of our present study), are present in 80% to 90% of cases[2,3,4]. Proto-oncogenes and markers of metastatic propensity and proliferation are some of the different research tools that have been used Among these tools, the most interesting tumor marker is Met (a hepatocyte growth factor receptor), which is a transmembrane receptor protein that has been implicated in the pathogenesis of glioblastomas (GBMs) through autocrine and/or paracrine mechanisms that potentially affect tumor cell growth, survival, invasion, migration, and angiogenesis[5,6,7,8]. A prognostic and/or predictive marker of the effects of anti-MET/HGF therapeutics in a large high-grade glioma population Based on this background information, the objective of this study was to identify a molecular marker that can predict the effect of treatment and may be used as a prognostic marker for unfavorable outcomes in patients with highly diffuse astrocytomas. We selected c-Met as the molecular target and evaluated the significance of the correlations of this marker with overall survival, progression-free survival and therapy outcomes in a large-scale study of high-grade tumor specimens
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