Jin-xiang Cheng

How powerful is CD133 as a cancer stem cell marker in brain tumors

Cancer stem cells (CSCs) have been identified in a growing number of hematopoietic and solid tissue malignancies and are typically recognized by virtue of the expression of cell surface markers. CD133, a stem cell marker, is now extensively used as a surface marker to identify and isolate brain tumor stem cells (BTSCs) in malignant brain tumors. However, CD133 as the marker to sort BTSCs suffered some controversies. In this review, we reviewed the rise of CD133, analyzed the efficiency of CD133 on identification and isolation of BTSCs, explained some controversial study results and summed up the role of CD133 and other effective CSCs markers in sorting CSCs in other tumors. We analyzed current limited reports and found that the expression of CD133 was correlated with poor clinical prognosis in brain tumors. Finally, we summarized the mechanisms of chemo- and radio- resistance of CD133+ brain tumor cell, especially emphasized that the aberrant activation of development pathways in BTSCs can be potential targets to BTSCs, and outlined current preclinical studies on killing BTSCs or sensitizing BTSCs to chemo- and radio-therapies.

Health-related quality of life in patients with high-grade glioma

Health-related quality of life (HRQOL) has become an increasingly important endpoint in cancer studies; however, the research into the HRQOL of patients with high-grade glioma (HGG) is sparse compared with that for patients with other neoplasms. Owing to the specific location and poor prognosis, it is more important and difficult to study HRQOL in patients with HGG than in those with other tumors; furthermore, the study of HRQOL in patients with HGG differs from that for patients with other tumors. In this review, we identified and compared the most frequently used instruments to assess HRQOL; analyzed specific facets and determinants of HRQOL (such as sex, tumor location and histological classification, depression, and cognitive function), as well as the association between HRQOL and survival; and appraised the effects of new treatments on HRQOL in patients with HGG from randomized controlled trials. Furthermore, we detected broadly existing problems and many contradictory outcomes and gave some proper interpretation and suggestions regarding them.

Radiotherapy Plus Concurrent or Sequential Temozolomide for Glioblastoma in the Elderly: A Meta-Analysis

Background Many physicians are reluctant to treat elderly glioblastoma (GBM) patients as aggressively as younger patients, which is not evidence based due to the absence of validated data from primary studies. We conducted a meta-analysis to provide valid evidence for the use of the aggressive combination of radiotherapy (RT) and temozolomide (TMZ) in elderly GBM patients. Methods A systematic literature search was conducted using the PubMed, EMBASE and Cochrane databases. Studies comparing combined RT/TMZ with RT alone in elderly patients (≥65 years) with newly diagnosed GBM were eligible for inclusion. Results No eligible randomized trials were identified. Alternatively, a meta-analysis of nonrandomized studies (NRSs) was performed, with 16 studies eligible for overall survival (OS) analysis and nine for progression-free survival (PFS) analysis. Combined RT/TMZ was shown to reduce the risk of death and progression in elderly GBM patients compared with RT alone (OS hazard ratio [HR] 0.59, 95% confidence interval [CI] 0.48–0.72; PFS: HR 0.58, 95% CI 0.41–0.84). Evaluable patients were reported to tolerate combined treatment but certain toxicities, and especially hematological toxicities, were more frequently observed. Limited data on O6-methylguanine-DNA methyltransferase (MGMT) promoter status and quality of life were reported. Conclusion The meta-analysis of NRSs provided level 2a evidence (Oxford Centre for Evidence-Based Medicine) that combined RT/TMZ conferred a clear survival benefit on a selection of elderly GBM patients who had a favorable prognosis (e.g., extensive resection, favorable KPS). Toxicities were more frequent but acceptable. Future randomized trials are warranted to justify a definitive conclusion.

Association of elevated GRP78 expression with increased astrocytoma malignancy via Akt and ERK pathways.

Unlike other members of HSP70 family, GRP78 manifests multifaceted subcellular distribution and forms complex with different signals, resulting in its close correlation with various tumors. However, its expression profile and function in glioma remain less well defined. In this study, normal brain tissue and astrocytic tumor specimens were evaluated for GRP78 expression, which was shown to be up-regulated in astrocytoma compared with normal tissue, increased markedly as astrocytoma pathologic grade escalates, and can still be enhanced for disease recurrence. By employing Cox regression analyses, high GRP78 expression was correlated with a poorer outcome for recurrent glioblastoma patients. In addition, immunofluorescence microscopy detected cell surface positioning of GRP78 on human glioma cells. After transfection with siRNA or antibody ligation of surface GRP78, phosphorylation of Akt and ERK was attenuated. These findings indicate that GRP78 plays an important role in astrocytoma malignancy, whereas its cell surface localization may be attractive for clinical utilization.

Quantitative detection of multiple gene promoter hypermethylation in tumor tissue, serum, and cerebrospinal fluid predicts prognosis of malignant gliomas.

Aberrant promoter hypermethylation of several known or putative tumor suppressor genes occurs frequently during the malignant transformation in gliomas. We hypothesized that quantitative analysis of methylated genes will provide prognostic values in malignant glioma patients. We used an immunocapturing approach followed by real-time polymerase chain reaction analysis to detect altered patterns of promoter methylation in O-6-methylguanine-DNA methyltransferase (MGMT), p16INK4a, tissue inhibitor of metalloproteinase-3 (TIMP-3), and thrombospondin 1 (THBS1). The tumor tissue and paired serum as well as cerebrospinal fluid (CSF) from 66 patients with malignant gliomas were studied. Serum and CSF from 20 age-matched noncancer individuals were used as control. Promoter hypermethylation in MGMT, p16INK4a, TIMP-3, and THBS1 was detected at high frequencies in tumor tissue, serum, and CSF. None of the control serum or CSF showed aberrant methylation. Hypermethylation in serum and CSF DNA was all accompanied with methylation in the corresponding tumor tissues with 100% specificity. Highly elevated MGMT, p16INK4a, and THBS1 methylation levels in gliomas serum were the sole independent factors predicting inferior overall survival in this cohort. For progression-free survival, hypermethylation of MGMT and THBS1 in CSF were the independent prognostic factors. Multiple gene promoter hypermethylation analysis appears to be promising as a prognostic factor in glioma and as a mini-invasive tumor marker in serum and/or CSF DNA. Evaluation of these changes may help in selecting glioma patients for optimal adjuvant treatments and modifying chemotherapy.

Global Histone Modification Patterns as Prognostic Markers to Classify Glioma Patients

Background: An altered pattern of epigenetic modifications is central to the development and progression of various tumors. We studied epigenetic changes involving multiple modifications of histones to better predict prognosis of glioma patients. Methods: Immunohistochemistry was done to investigate global histone modification expression of histone 3 lysine 4 dimethylation (H3K4diMe), histone 4 arginine 3 monomethylation (H4R3monoMe), histone 4 lysine 20 trimethylation (H4K20triMe), and acetylation of histone 3 lysine 9 (H3K9Ac), histone 3 lysine 18 (H3K18Ac), histone 4 lysine 12 (H4K12Ac), and histone 4 lysine 16 (H4K16Ac) in resected tumor samples of 230 glioma patients. Data were analyzed using a recursive partitioning analysis (RPA). Results: RPA classified the patients into 10 distinct prognostic groups based on WHO grade, histology, and histone modifications: H3K9Ac (<88% or ≥88% tumor cells), H3K4diMe (<64% or ≥64% tumor cells), H3K18Ac (<74% or ≥74% tumor cells), and H4K20triMe (<75% or ≥75% tumor cells). The 10 groups were associated with significantly different progression-free (P < 0.0001) and overall survival (P < 0.0001). Cox proportional hazards models including age, sex, WHO grade, histology, extent of tumor resection, Karnofsky performance status score, and RPA groups retained age and RPA groups as the sole independent factors significantly influencing overall survival. For progression-free survival, RPA grouping was the only independent prognostic factor. Conclusions: Multiple histone modifications seem to have prognostic relevance in glioma. Impact: Further evaluation of histone modifications as prognostic markers of treatment and predictors of chemotherapy response using histone deacetylase inhibitors is warranted. Cancer Epidemiol Biomarkers Prev; 19(11); 2888–96. ©2010 AACR.

Notch-1 activation-dependent p53 restoration contributes to resveratrol-induced apoptosis in glioblastoma cells

Glioblastoma is the most malignant form of adult brain tumor and is associated with a dismal prognosis. Emerging data suggest that Notch signaling participates principally in the formation and malignant progression of glioblastoma. Resveratrol is a terpenoid that exhibits broad pro-apoptotic activity in various types of cancers, including glioblastoma. However, the effects of resveratrol on Notch signaling in glioblastomas have not yet been fully elucidated. We demonstrated that resveratrol strongly suppressed cell growth and induced apoptosis in A172 and T98G glioblastoma cells, which have low active Notch-1 expression and a heterozygous p53 mutation. Our results suggest that resveratrol significantly activates intracellular Notch-1 and restores wild-type p53 expression in a time-dependent manner. Significant de-phosphorylation of Akt, increased Bax expression, decreased Bcl-2 expression and cleavage of caspase-3 were also observed in resveratrol-induced apoptosis in glioblastoma cells. Moreover, simultaneous treatment with resveratrol and a Notch-1 inhibitor (MRK-003) partially attenuated the apoptosis and completely blocked the activation of Notch-1 and the increase in wild-type p53. This suggests that restoration of wild-type p53 expression depends on Notch-1 activation. In addition, the de-phosphorylation of Akt, increased expression of Bax and cleavage of caspase-3 were not fully reversed by MRK-003 treatment, suggesting that p53 restoration is not the only mechanism underlying resveratrol-induced apoptosis. Taken together, we confirmed the anti-proliferative and pro-apoptotic effects of resveratrol on glioblastoma cells and revealed Notch-1 activation-dependent restoration of p53 as an important causative mechanism.

The treatment of glioblastomas: A systematic update on clinical Phase III trials

Glioblastomas (GBMs) are invariably associated with unavoidable tumor recurrence and overall poor prognosis. The present study is to summarize the results of clinical Phase III studies on GBMs over the past seven years. A systematic literature search was performed using major electronic databases and by screening meeting abstracts. Totally, 16 studies of patients with newly diagnosed GBMs, recurrent GBMs, and elderly patients with GBMs were selected for this review. Although the outcomes of the experimental therapies were not encouraging, these studies produced a considerable amount of potentially clinically relevant information. Such aspects as surgical outcomes, radiation schedules, temozolomide (TMZ) schedules, methylation status of the O6-methylguanine DNA methyltransferase (MGMT) gene, combination of therapies, novel drug delivery methods and use of targeted agents have come to light and are being addressed here. In addition, we discuss the existing controversies of (1) surgical studies, (2) evaluations of recurrence, (3) salvage treatment bias, and (4) studies on elderly patients.

Controversies concerning the application of brachytherapy in central nervous system tumors

IntroductionBrachytherapy (BRT) is defined as a therapy technique where a radioactive source is placed a short distance from or within the tumor being treated. Much expectation has been placed on its efficacy to improve the outcome for patients with central nervous system (CNS) tumors due to the initial promising results from single institution retrospective studies. However, these optimistic findings have been highly debated since the selection criteria itself is preferable to other therapeutic modalities. The fact that BRT demonstrated no significant survival advantage in two prospective studies, together with the emerging role of stereotactic convergence therapy as a promising alternative, has further decreased the enthusiasm for BRT. Despite all the negative aspects, BRT continues to be conducted for the management of CNS tumors including gliomas, meningiomas and brain metastases.Material and methodsAs many controversies have been aroused concerning the experience and future application of BRT, this article reviews the existing heterogeneities in terms of implants choice, optimal dose rate, targeting volume, timing of BRT, patients selection, substantial efficacy, BRT in comparison with stereotactic convergence therapy techniques and BRT in combination with other treatment modalities (data were identified by Pubmed searches).Results and conclusionThough it is inconvincible to argue for the routine use of BRT, BRT may provide a choice for patients with large recurrent or inoperable deep-seated tumors, especially with the Glia-site technique. Radiotherapies including BRT may hold more promise if biologic mechanisms of radiation could be better understand and biologic modifications could be added in clinical trials.

The Predictive but Not Prognostic Value of MGMT Promoter Methylation Status in Elderly Glioblastoma Patients: A Meta-Analysis

Background The clinical implication of O6-methylguanine-DNA methyltransferase (MGMT) promoter status is ill-defined in elderly glioblastoma patients. Here we report a meta-analysis to seek valid evidence for its clinical relevance in this subpopulation. Methods Literature were searched and reviewed in a systematic manner using the PubMed, EMBASE and Cochrane databases. Studies investigating the association between MGMT promoter status and survival data of elderly patients (≥65 years) were eligible for inclusion. Results Totally 16 studies were identified, with 13 studies included in the final analyses. The aggregate proportion of MGMT promoter methylation in elderly patients was 47% (95% confidence interval [CI]: 42–52%), which was similar to the value for younger patients. The analyses showed differential effects of MGMT status on overall survival (OS) of elderly patients according to assigned treatments: methylated vs. unmethylated: (1) temozolomide (TMZ)-containing therapies: hazard ratio [HR] 0.49, 95% CI 0.41–0.58; (2) TMZ-free therapies: HR 0.97, 95% CI 0.77–1.21. More importantly, a useful predictive value was observed by an interaction analysis: TMZ-containing therapies vs. RT alone: (1) methylated tumors: HR 0.48, 95% CI 0.36–0.65; (2) unmethylated tumors: HR 1.14; 95% CI 0.90–1.44. Conclusion The meta-analysis reports an age-independent presence of MGMT promoter methylation. More importantly, the study encouraged routine testing of MGMT promoter status especially in elderly glioblastoma patients by indicating a direct linkage between biomarker test and individual treatment decision. Future studies are needed to justify the mandatory testing in younger patients.