To investigate the tumor-initiating cells (TICs) in rhabdoid meningioma (RM), a population of CD105-positive cells isolated from a fresh RM surgical sample was analyzed for proliferative activity, self-renewal ability, tumorigenic ability, multilineage differentiation potential, as well as chromosomal aberrations. The results showed that isolated CD105-positive cells could be maintained for more than 50 generations in vitro. These cells exhibited increased proliferative activity and single-cell tumor sphere-formation ability compared with CD105-negative cells. In vivo experiments showed that CD105-positive cells possessed much greater potential to reconstitute the original human RM in nude mice as compared with CD105-negative cells. Phenotypically, CD105-positive cells shared some surface markers with mesenchymal progenitor cells (MPCs), but karyotype analysis showed chromosomal abnormalities characteristic of malignant meningioma, thus distinguishing them from supportive stroma-derived MPCs. In addition, in contrast to CD105-negative cells, CD105-positive cells could differentiate into adipocytes and osteocytes in response to specific induction agents. Finally, CD105-positive cells with stem-like features were also isolated from xenograft tumors. In conclusion, a population of CD105-positive TICs with some traits of MPCs was identified in RM and might provide a promising therapeutic target in management of malignant meningioma.

BackgroundThe human apurinic/apyrimidinic endonuclease 1/Redox effector factor-1 (APE1/Ref-1) is implicated in tumor development and progression. Recently, the APE1/Ref-1 promoter -141T/G variant (rs1760944) has been reported to be associated with lung cancer risk. Given the importance of APE1/Ref-1 in both DNA repair and redox activity, we speculate that the -141T/G polymorphism may confer individual susceptibility to gliomas or its subtypes.MethodsThe APE1/Ref-1 -141T/G polymorphism was analyzed in a case-control study including 766 glioma patients (among them 241 glioblastoma, 284 astrocytomas except for glioblastoma and 241 other gliomas) and 824 cancer-free controls from eastern China. Genotyping was performed with Sequenom MassARRAY iPLEX platform by use of allele-specific MALDI-TOF mass spectrometry assay. We estimated odds ratios (ORs) and 95% confidence intervals (95% CIs) using unconditional logistic regression. A test of trend was calculated using the genotype as an ordinal variable in the regression model. For each statistically significant association identified, we estimated the false positive reporting probability (FPRP). FPRP values less than 0.2 were consider to indicate robust associations.ResultsThe significant association between the APE1/Ref-1 promoter -141T/G polymorphism and glioma risk was not observed. However, the stratified analysis by histology revealed the variant allele G significantly decreased glioblastoma risk (OR = 0.80, 95% CI = 0.65-0.98, P = 0.032). Individuals with the homozygous -141GG genotype exhibited 46% reduced risk of glioblastoma (adjusted OR = 0.54, 95% CI 0.34-0.87, P = 0.012), compared with the TT homozygote. This result remained robust given the prior probabilities of 25% (FPRP = 0.052) and 10% (FPRP = 0.140), but not with a prior probability of 1% (FPRP = 0.643). The P-associated with the trend test was 0.014.ConclusionsOur results suggest that a specific genetic variant located in the APE1/Ref-1 promoter may modulate risk of glioblastoma, but not for other histological gliomas. Larger studies with more APE1 polymorphisms are required to validate these preliminary findings.

Matrix metallopeptidases (MMPs) play an important role in central nervous system tumor growth, invasion and spreading. The currently available data provide clear evidence for the involvement of MMP3 in the pathophysiology of glioma. The study aims to explore the association of single nucleotide polymorphisms (SNPs) across the MMP3 gene with glioma risk. Three haplotype tagging and additional two promoter SNPs were genotyped among 766 glioma patients and 824 cancer-free controls from East China. None of these polymorphisms alone had a significant effect on risk of gliomas. However, when three promoter polymorphisms were evaluated together by the number of putative risk of genotypes (i.e., rs645419AA, 632478CA+AA, rs522616AA), a statistically significantly increased risk of gliomas was associated with the combined genotypes with two to three risk genotypes, compared with those with zero to one risk genotypes (adjusted odds ratio (OR) = 1.32; 95% confidence interval (CI) = 1.03-1.68). This increased risk was also more pronounced among adults (adjusted OR = 1.14, 95%CI = 1.02-1.27), males (adjusted OR = 1.19, 95%CI = 1.05-1.36), smokers (adjusted OR = 1.28, 95%CI = 1.07-1.52), subjects with no family history of cancer (adjusted OR = 1.21, 95%CI = 1.07-1.37), and patients with nonastrocytic gliomas (adjusted OR = 1.23, 95%CI = 1.06-1.43). In summary, our results suggest that any one of MMP3 variants may not have a substantial effect on glioma risk, but a joint effect of MMP3 promoter polymorphisms may contribute to risk of gliomas, particularly for adult gliomas.