• Asian Pacific Journal of Cancer Prevention
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• 제15권22호
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• pp.9805-9812
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• 2014

Radixin, a member of the ERM (ezrin-radixin-moesin) family, plays important roles in cell motility, invasion and tumor progression. It is expressed in a variety of normal and neoplastic cells, including many types of epithelial and lymphoid examples. However, its function in glioblastomas remains elusive. Thus, in this study, radixin gene expression was first examined in the glioblastoma cells, then suppressed with a lentivirus-mediated short-hairpin RNA (shRNA) method.We found that there were high levels of radixin expression in glioblastoma U251cells. Radixin shRNA caused down-regulation of radixin gene expression and when radixin-silenced cells were implanted into nude mice, tumor growth was significantly inhibited as compared to blank control cells or nonsense shRNA cells. In addition, microvessel density in the tumors was significantly reduced. Thrombospondin-1 (TSP-1) and E-cadherin were up-regulated in radixin- suppressed glioblastoma U251 cells. In contrast, MMP9 was down-regulated. Taken together, our findings suggest that radixin is involved in GBM cell migration and invasion, and implicate TSP-1, E-cadherin and MMP9 as metastasis-inducing factors.

• Journal of Korean Neurosurgical Society
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• 제63권4호
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• pp.444-454
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• 2020

Objective : Glioblastoma multiforme (GBM) is the most aggressive for of brain tumor and treatment often fails due to the invasion of tumor cells into neighboring healthy brain tissues. Activation of the Janus kinase-signal transducer and activator of transcription (JAK/STAT) signaling pathway is essential for normal cellular function including angiogenesis, and has been proposed to have a pivotal role in glioma invasion. This study aimed to determine the dose-dependent effects of ruxolitinib, an inhibitor of JAK, on the interferon (IFN)-I/IFN-α/IFN-β receptor/STAT and IFN-γ/IFN-γ receptor/STAT1 axes of the IFN-receptor-dependent JAK/STAT signaling pathway in glioblastoma invasion and tumorigenesis in U87 glioblastoma tumor spheroids. Methods : We administered three different doses of ruxolitinib (50, 100, and 200 nM) to human U87 glioblastoma spheroids and analyzed the gene expression profiles of IFNs receptors from the JAK/STAT pathway. To evaluate activation of this pathway, we quantified the phosphorylation of JAK and STAT proteins using Western blotting. Results : Quantitative real-time polymerase chain reaction analysis demonstrated that ruxolitinib led to upregulated of the IFN-α and IFN-γ while no change on the hypoxia-inducible factor-1α and vascular endothelial growth factor expression levels. Additionally, we showed that ruxolitinib inhibited phosphorylation of JAK/STAT proteins. The inhibition of IFNs dependent JAK/STAT signaling by ruxolitinib leads to decreases of the U87 cells invasiveness and tumorigenesis. We demonstrate that ruxolitinib may inhibit glioma invasion and tumorigenesis through inhibition of the IFN-induced JAK/STAT signaling pathway. Conclusion : Collectively, our results revealed that ruxolitinib may have therapeutic potential in glioblastomas, possibly by JAK/STAT signaling triggered by IFN-α and IFN-γ.

• Laboraroty Animal Research
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• 제34권4호
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• pp.248-256
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• 2018

O-2-$^{18}F$-fluoroethyl-l-tyrosine ($[^{18}F]FET$) has been widely used for glioblastomas (GBM) in clinical practice, although evaluation of its applicability in non-clinical research is still lacking. The objective of this study was to examine the value of $[^{18}F]FET$ for treatment evaluation and prognosis prediction of anti-angiogenic drug in an orthotopic mouse model of GBM. Human U87MG cells were implanted into nude mice and then bevacizumab, a representative anti-angiogenic drug, was administered. We monitored the effect of anti-angiogenic agents using multiple imaging modalities, including bioluminescence imaging (BLI), magnetic resonance imaging (MRI), and positron emission tomography-computed tomography (PET/CT). Among these imaging methods analyzed, only $[^{18}F]FET$ uptake showed a statistically significant decrease in the treatment group compared to the control group (P=0.02 and P=0.03 at 5 and 20 mg/kg, respectively). This indicates that $[^{18}F]FET$ PET is a sensitive method to monitor the response of GBM bearing mice to anti-angiogenic drug. Moreover, $[^{18}F]FET$ uptake was confirmed to be a significant parameter for predicting the prognosis of anti-angiogenic drug (P=0.041 and P=0.007, on Days 7 and 12, respectively, on Pearson's correlation; P=0.048 and P=0.030, on Days 7 and 12, respectively, on Cox regression analysis). However, results of BLI or MRI were not significantly associated with survival time. In conclusion, this study suggests that $[^{18}F]FET$ PET imaging is a pertinent imaging modality for sensitive monitoring and accurate prediction of treatment response to anti-angiogenic agents in an orthotopic model of GBM.

• Asian Pacific Journal of Cancer Prevention
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• 제15권3호
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• pp.1333-1337
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• 2014

Background: Astrocytic tumors, the most common primary glial tumors of the central nervous system, are classified from low to high grade according to the degree of anaplasia and presence of necrosis. Despite advances in therapeutic management of high grade astrocytic tumors, prognosis remains poor. In the present study, the frequency and prognostic significance of c-erb-B2 in astrocytic tumors was investigated. Materials and Methods: Records of 72 patients with low- and high-grade astrocytic tumors were evaluated. The expression of C-erbB-2 was determined immunohistochemically and intensity was recorded as 0 to 3+. Tumors with weak staining (1+) or no staining (0) were considered Her-2 negative, while tumors with moderate (2+) and strong (3+) staining were considered Her-2 positive. Results: Of the 72 patients, 41 (56.9%) had glioblastoma (GBM), 10 (13.9%) had diffuse astrocytoma, 15 (20.8%) had anaplastic astrocytoma, 6 (8.3%) had pilocytic astrocytoma. C-erbB-2 overexpression was detected in the tumor specimens of 17 patients (23.6%). Six (8.3%) tumors, all GBMs, exhibited strong staining, 2 (2.7%) specimens, both GBMs, exhibited moderate staining, and 9 specimens, 5 of them GBMs (12.5%), exhibited weak staining. No staining was observed in diffuse astrocytoma and pilocytic astrocytoma specimens. Median overall survival of patients with C-erbB-2 negative and C-erbB-2 positive tumors were 30 months (95%CI: 22.5-37.4 months) and 16.9 months (95%CI: 4.3-29.5 months), respectively (p=0.244). Conclusions: Although there was no difference in survival, C-erbB-2 overexpression was observed only in the GBM subtype.

• Asian Pacific Journal of Cancer Prevention
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• 제16권3호
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• pp.971-977
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• 2015

Malignant glioblastoma multiforme (GBM) is the most malignant brain tumor and despite recent advances in diagnostics and treatment prognosis remains poor. In this retrospective study, we assessed the clinical and radiological parameters, as well as fluorescence in situ hybridization (FISH) of 1p19q deletion, in a series of cases. A total of 816 patients with GBM who received surgery and radiation between January 2010 and May 2014 were included in this study. Kaplan-Meier survival analysis and Cox regression analysis were used to find the factors independently influencing patient progression free survival (PFS) and overall survival (OS). Age at diagnosis, preoperative Karnofsky Performance Scale (KPS) score, KPS score change at 2 weeks after operation, neurological deficit symptoms, tumor resection extent, maximal tumor diameter, involvement of eloquent cortex or deep structure, involvement of brain lobe, Ki-67 and MMP9 expression level and adjuvant chemotherapy were statistically significant factors (p<0.05) for both PFS and OS in the univariate analysis. Cox proportional hazards modeling revealed that age ${\leq}50$ years, preoperative KPS score ${\geq}80$, KPS score change after operation ${\geq}0$, involvement of single frontal lobe, deep structure involvement, low Ki-67 and MMP9 expression and adjuvant chemotherapy were independent favorable factors (p<0.05) for patient clinical outcomes.

• Molecules and Cells
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• 제40권4호
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• pp.254-261
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• 2017

Glioblastomas (GBM) are very difficult to treat and their aggressiveness is one of the main reasons for this as well as for the frequent recurrences. MicroRNAs post-transcriptionally regulate their target genes through interaction between their seed sequence and 3'UTR of the target mRNAs. We previously reported that miR-296-3p is regulated by neurofibromatosis 2 (NF2) and enhances the invasiveness of GBM cells via SOCS2/STAT3. In this study, we investigated whether miR-296-5p, which originates from the same precursor miRNA as miR-296-3p, can increase the invasiveness of GBM cells. It was observed that miR-296-5p potentiated the invasion of various GBM cells including LN229, T98G, and U87MG. Through bioinformatics approaches, two genes were identified as miR-296-5p targets: caspase-8 (CASP8) and nerve growth factor receptor (NGFR). From results obtained from Ago2 immunoprecipitation and luciferase assays, we found that miR-296-5p downregulates CASP8 and NGFR through direct interaction between seed sequence of the miRNA and 3'UTR of the target mRNA. Knockdown of CASP8 or NGFR also increased the invasive ability of GBM cells, indicating that CASP8 and NGFR are involved in potentiation of invasiveness by miR-296-5p. Consistent with our findings, CASP8 was downregulated in brain metastatic lung cancer cells, which have a high level of miR-296-5p, compared to parental cells, suggesting that miR-296-5p may be generally associated with the acquisition of invasiveness. Collectively, our results implicate miR-296-5p as a potential cause of invasiveness in cancer and suggest it as a promising therapeutic target for GBM.

• Radiation Oncology Journal
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• 제14권3호
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• pp.181-189
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• 1996

목적 : 다형성 교모세포증 환자의 생존율에 영향을 미치는 예후인자와 치료성적을 분석하여 생존율을 향상시킬 수 있는 치료방법을 모색하고자 하였다. 대상 및 방법 : 1973년 1월부터 1993년 12월까지 연세의료원에서 치료를 시행받은 다형성 교모세포증 환자 121명을 대상으로 하여 이들의 생존율에 영향을 미치는 예후인자와 치료성적을 주된 증상의 발현 기간, 연령, 전신수행도 등의 임상특성과 수술적 절제 정도, 방사선치료여부 등의 치료와 관련된 요인으로 분류하여 분석하였다. 결과 : 전체 환자의 정중 생존 기간은 13개월이었고 2년 전체 생존율은 $20.8\%$였다. 단일변량분석에서 의미있는 예후인자로는 주된 증상의 발현 기간, 연령, 전신수행도, 방사선치료여부, 수술적 절제 정도 등이었으며 이들 예후인자에 따른 2년 전체 생존율은 각각 주된 증상의 발현기간이 3개월을 초과한 경우에는 $47.2\%$(p=0.0082), 연령이 50세 미만인 경우에는 $32.9\%$(p=0.0003), 전신수행도가 80이상인 경우에는 $36.9\%$(p=0.0422), 방사선치료를 시행한 경우에는 $22.9\%$(p=0.0030), 완전절제나 부분절제가 시행된 경우에는 $23.3\%$(p<0.000)이었고 다변량분석에서는 전신수행도를 제외한(p=0.8823) 주된 증상의 발현 기간, 연령, 방사선치료여부, 수술적 절제 정도 등이 의미있는 예후인자였다. 항암화학요법의 병용여부에 따른 2년 전체 생존을은 각각 $22.3\%$와 $19.4\%$이었다(p=0.6028). 주된 증상의 발현 기간이 3개월 이하인 경우와 연령이 50세 이상인 경우, 뇌정위적 생검만 시행된 경우를 위험인자로 보았을 때 위험인자가 없었던 환자군의 정중 생존 기간과 2년 전체 생존율은 각각 29개월과 $53.9\%$이었고 3개의 위험인자를 모두 가지고 있는 환자군의 정중 생존 기간과 2년 전체 생존율은 각각 4개월과 $0\%$이었다. 원발병소에서의 국소치료실패양상이 $86.4\%$(51/59)로 치료실패양상의 대부분을 차지하였다. 결론 : 주된 증상의 발현 기간, 연령, 방사선치료여부, 수술적 절제 정도 등이 생존율에 영향을 미치는 통계적으로 유의한 예후인자이었고 현재까지의 저조한 치료성적을 향상시키기 위해서는 국소제어율을 향상시키는 방안에 대한 연구가 진행되어야 할 것으로 생각된다.

• Investigative Magnetic Resonance Imaging
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• 제22권3호
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• pp.158-167
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• 2018

Purpose: To investigate the surgical, perfusion, and molecular characteristics of glioblastomas which influence long-term survival after treatment, and to explore the association between MR perfusion parameters and the presence of MGMT methylation and 1p/19q deletions. Materials and Methods: This retrospective study was approved by our institutional review board. A total 43 patients were included, all with pathologic diagnosis of glioblastoma with known MGMT methylation and 1p/19q deletion statuses. We divided these patients into long-term (${\geq}60\;months$, n = 7) and short-term (< 60 months, n = 36) survivors, then compared surgical extent, molecular status, and rCBV parameters between the two groups using Fisher's exact test or Mann-Whitney test. The rCBV parameters were analyzed according to the presence of MGMT methylation and 1p/19q deletions. We investigated the relationship between the mean rCBV and overall survival using linear correlation. Multivariable linear regression was performed in order to find the variables related to overall survival. Results: Long-term survivors (100% [7 of 7]) demonstrated a greater percentage of gross total or near total resection than short-term survivors (54.5% [18 of 33]). A higher prevalence of 1p/19q deletions was also noted among the long-term survivors (42.9% [3 of 7]) than the short-term survivors (0.0% [0 of 36]). The rCBV parameters did not differ between the long-term and short-term survivors. The rCBV values were marginally lower in patients with MGMT methylation and 1p/19q deletions. Despite no correlation found between overall survival and rCBV in the whole group, the short-term survivor group showed negative correlation ($R^2=0.181$, P = 0.025). Multivariable linear regression revealed that surgical extent and 1p/19q deletions, but not rCBV values, were associated with prolonged overall survival. Conclusion: While preoperative rCBV and 1p/19q deletion status are related to each other, only surgical extent and the presence of 1p/19q deletion in GBM patients may predict long-term survival.

• Korean Journal of Radiology
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• 제22권6호
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• pp.951-958
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• 2021

Objective: To evaluate the usefulness of virtual monochromatic images (VMIs) obtained using dual-layer dual-energy CT (DL-DECT) for evaluating brain tumors. Materials and Methods: This retrospective study included 32 patients with brain tumors who had undergone non-contrast head CT using DL-DECT. Among them, 15 had glioblastoma (GBM), 7 had malignant lymphoma, 5 had high-grade glioma other than GBM, 3 had low-grade glioma, and 2 had metastatic tumors. Conventional polychromatic images and VMIs (40-200 keV at 10 keV intervals) were generated. We compared CT attenuation, image noise, contrast, and contrast-to-noise ratio (CNR) between tumor and white matter (WM) or grey matter (GM) between VMIs showing the highest CNR (optimized VMI) and conventional CT images using the paired t test. Two radiologists subjectively assessed the contrast, margin, noise, artifact, and diagnostic confidence of optimized VMIs and conventional images on a 4-point scale. Results: The image noise of VMIs at all energy levels tested was significantly lower than that of conventional CT images (p < 0.05). The 40-keV VMIs yielded the best CNR. Furthermore, both contrast and CNR between the tumor and WM were significantly higher in the 40 keV images than in the conventional CT images (p < 0.001); however, the contrast and CNR between tumor and GM were not significantly different (p = 0.47 and p = 0.31, respectively). The subjective scores assigned to contrast, margin, and diagnostic confidence were significantly higher for 40 keV images than for conventional CT images (p < 0.01). Conclusion: In head CT for patients with brain tumors, compared with conventional CT images, 40 keV VMIs from DL-DECT yielded superior tumor contrast and diagnostic confidence, especially for brain tumors located in the WM.

• Asian Pacific Journal of Cancer Prevention
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• 제16권3호
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• pp.1001-1006
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• 2015

Background: With development and application of new and effective anti-cancer drugs, the median survival post-progression (SPP) is often prolonged, and the role of the median SPP on surrogacy performance should be considered. To evaluate the impact of the median SPP on the correlation between progression-free survival (PFS) and overall survival (OS), we performed simulations for treatment of four types of cancer, advanced gastric cancer (AGC), metastatic colorectal cancer (MCC), glioblastoma (GBM), and advanced non-small-cell lung cancer (ANSCLC). Materials and Methods: The effects of the median SPP on the statistical properties of OS and the correlation between PFS and OS were assessed. Further, comparisons were made between the surrogacy performance based on real data from meta-analyses and simulation results with similar scenarios. Results: The probability of a significant gain in OS and HR for OS was decreased by an increase of the SPP/OS ratio or by a decrease of observed treatment benefit for PFS. Similarly, for each of the four types of cancer, the correlation between PFS and OS was reduced as the median SPP increased from 2 to 12 months. Except for ANSCLC, for which the median SPP was equal to the true value, the simulated correlation between PFS and OS was consistent with the values derived from meta-analyses for the other three kinds of cancer. Further, for these three types of cancer, when the median SPP was controlled at a designated level (i.e., < 4 months for AGC, < 12 months for MCC, and <6 months for GBM), the correlation between PFS and OS was strong; and the power of OS reached 34.9% at the minimum. Conclusions: PFS is an acceptable surrogate endpoint for OS under the condition of controlling SPPs for AGC, MCC, and GBM at their limit levels; a similar conclusion cannot be made for ANSCLC.