Abstract. Solid tumors are abnormal tissues containing tumor and non-tumor cells, also known as tumor stromal cells. However, the malignant potential of tumor stromal cells remains largely unknown. The aim of the present study was to investigate the malignant potential of host bone marrow-derived stroma cells in transplanted subcutaneous tumors of the glioma stem/progenitor cells (GSPCs) labeled using the dual-color fluorescent tracer technique. The previously established human glioma stem/progenitor cell line SU3 was transfected with red fluorescence protein (SU3-RFP) and transplanted subcutaneously into green fluorescent protein (GFP) transgenic nude mice and chimeric mice in which GFP was only expressed by bone marrow-derived cells (BMDCs). The xenograft tumors were subcultured in vitro and two immortalized GFP-expressing stromal cell lines were cloned from the transplanted tumors. The two cloned cell lines showed an accelerated growth rate, loss of cell contact inhibition, high cloning efficiency, and high DNA content and telocentric (murine) chromosomes with heteroploid characteristics. The tumorigenesis rate (10/10, 1x10 6 ) of these host stromal cells was further evidence of malignant transformation. Immunofluorescence assay of the two host cell lines showed that they expressed fibroblast markers such as FAP, S100A4 and α-SMA, as well as mesenchymal cell markers such as CD44 and CD105. In conclusion, bone marrow-derived stromal fibroblasts recruited to tumors have the potential for malignant transformation induced by the tumor microenvironment, which provides new evidence for the role of the stroma in malignant transformation.
The aim of this study is to investigate the inhibitory effects of 2T-P400, a derivative of temozolomide (TMZ), on glioma growth. SHG-44 and U373 human glioblastoma cell lines and SHG-44 cell subcutaneous and intracranial xenograft mouse models were used as the model system for these studies. Cell growth was analyzed using MTT assay. For intracranial glioma xenograft model, mouse brains were obtained and made as paraffin section for immunohistochemical staining. Tumor volume was calculated with this formula: tumor volume = length × width2/ 2. The results showed that 2T-P400 or TMZ significantly inhibits cell growth in a concentration dependent manner with the IC50 values of 12.90 ± 1.05 or 9.73 ± 2.12 μg/ml on SHG-44 cell line and 13.12 ± 0.86 or 10.13 ± 1.02 μg/ml on U373 cell line respectively. In SHG-44 cell subcutaneous xenograft model, the tumor volume of 2T-P400 or TMZ treated group was 1,062.12 ± 204.76 or 803.59 ± 110.32 mm3 respectively, which was significantly smaller than that in physiological saline (with volume of 1,968.85 ± 348.37 mm3) treated group. In intracranial xenograft model, the tumor volume of 2T-P400 or TMZ group was 6.12 ± 1.69 or 5.58 ± 1.45 mm3 respectively, significantly smaller than that in physiological saline group of 33.08 ± 6.88 mm3. Moreover, polyethylene glycol 400 (PEG400) exhibited no significant tumor growth inhibition. Our results indicated that 2T-P400 posses the same growth inhibitory effect as TMZ on glioblastoma cell lines and the subcutaneously and intracranially transplanted gliomas in xenograft mouse models. It may be a suitable alternate of TMZ for the treatment of glioma via intravenous administration route.
Abstract. The present study aimed to investigate the alteration of the DNA damage signaling pathway profile in radiation-treated glioblastoma stem-like cells (GSLCs), and also aimed to explore potential targets for overcoming glioblastoma radioresistance. Serum-free medium was used to isolate and culture GSLCs. Cell growth was detected using a cell counting kit-8 assay and cell sorting analysis was performed by flow cytometry. X-ray irradiation was produced by a Siemens-Primus linear accelerator. Reverse transcription-quantitative polymerase chain reaction (qPCR) was performed to investigate target genes. SPSS 15.0 was used for all statistical analyses. Human glioblastoma U251 and U87 cells were cultured in serum-free medium supplemented with epidermal growth factor and fibroblast growth factor 2, which constitutes tumor sphere medium, and demonstrated sphere formation, with significantly increased the proportion of CD133 + and Nestin + cells, which are referred to as GSLCs. The present data revealed that treatment with 10 Gy X-ray radiation alters the expression profile of DNA damage-associated genes in GSLCs. The expression levels of 12 genes demonstrated a ≥2-fold increase in the irradiated U87 GSLCs compared with the untreated U87 GSLCs. Three genes, consisting of XPA, RAD50 and PPP1R15A, were selected from the 12 genes by gene functional searching and qPCR confirmatory studies, as these genes were considered to be potential targets for overcoming radioresistance. The expression of XPA, RAD50 and PPP1R15A is significantly increased in U87 and U251 radiation resistant GSLCs, indicating three potential targets for overcoming the radioresistance of GSLCs.
Various organs of the body have distinct microenvironments with diverse biological characteristics that can influence the growth of tumors within them. However, the mechanisms underlying the interactions between tumor and host cells are currently not well understood. In the present study, a dual-color fluorescence-tracing glioma orthotopic implantation model was developed, in which C6 rat glioma cells labeled with the red fluorescent dye CM-Dil, and SU3 human glioma cells stably expressing red fluorescence protein, were inoculated into the right caudate nucleus of transgenic female C57BL/6 nude mice expressing enhanced green fluorescent protein. The dual-color tracing with whole-body in vivo fluorescence imaging of xenografts was performed using a live imaging system. Frozen sections of the transplanted tumor were prepared for histological analyses, in order to detect the presence of invading tumor cells, blood vessels and cellular fusion. Dual-color images were able to distinguish between red tumor cells and green host cells. The results of the present study suggested that a dual-color fluorescence-tracing glioma orthotopic implantation model may be convenient for detecting tumor location, angiogenesis, cellular fusion, and the tumor microenvironment.
Objective: The effects of interventional embolization and craniotomy clipping on the treatment of intracranial aneurysms were investigated in this study, as well as their influence on the hemodynamics of postoperative patients. Methods: 102 patients with intracranial aneurysms were selected as the research objects, and they were rolled into an experimental (group A) and a control group (group B) according to the random number table method, with 51 cases in each group. The group A was treated with intravascular interventional embolization, and the group B received craniotomy clipping. Besides, a biodegradable magnesium titanium alloy biological stent was independently developed in this study, which was applied to endovascular interventional embolization in the group A. The hemodynamic model was established by using three-dimensional (3D) computer hemodynamic numerical simulation technology. Besides, the effects of all the patients before and after treatment were evaluated, in terms of blood pressure (BP), average wall shear stress (WSS) (AWSS), AWSS gradient (AWSSG), oscillatory shear index (OSI), aneurysm formation index (AFI), gradient oscillation number (GON), and intraoperative complication rate. Results: After 3 days of treatment, the BP, AWSS, and AWSSG of patients from the two groups were higher than those before treatment. The index values of the group A were greater markedly than the values of the group B (P < 0.05); the BP of the group A and the group B at the 0th day, 1st day, 3rd day, 5th day, and 7th day after treatment was 21±5.1 Versus 20.1±4.7, 22±4.8 Versus 21.1± 5.17, 26±6.2 Versus 22.31±5.21, 27±5.77 Versus 24.02±5.11, and 30±6.09 Versus 24.99±5.03, respectively; AWSSG values were 120±10.11 Versus 120.1±10.98, 130.1±10.36 Versus 123.3±11.06, 162.5±9.92 Versus 131.31±10.97, 171±8.13 Versus 155.02±8.36, and 200.1±7.22 Versus 180.01±8.98 in turn. GON and OSI were both decreased, and the values of various indexes in the group A were sharply lower than those of the group B (P < 0.05); the values of GON at the 0th day, 1st day, 3rd day, 5th day, and 7th day after treatment in the group A and the group B were 0.077±0.01 Versus 0.08±0.011, 0.07±0.012 Versus 0.073 ± 0.01, 0.051 ± 0.02 Versus 0.071 ± 0.011, 0.045 ± 0.01 Versus 0.069 ± 0.011, and 0.042 ± 0.012 Versus 0.063±0.013, respectively; OSI values were 4.8±0.51 Versus 4.9±0.52, 3.6±0.52 Versus 3.62±0.51, 2.82±0.51 Versus 3.1 ± 0.57, 1.9 ± 0.512 Versus 2.91 ± 0.51, and 0.5 ± 0.51 Versus 1.8 ± 0.501 in turn. By comparing the intraoperative complications and postoperative mortality risk score (MRS) of patients in the two groups, it was found that the incidence of intraoperative complications and postoperative MRS scores in the group A were lower steeply than those of the group B, suggesting that endovascular interventional embolization had a better effect on the treatment of intracranial aneurysms. Conclusion: Endovascular interventional embolization based on biodegradable magnesium alloy coated scaffold could better improve the distribution of shear stress on the vascular wall, stabilize vascular blood flow, and achieve better therapeutic effect for patients.
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