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Sublethal dose of irradiation enhances invasion of malignant glioma cells through p53-MMP 2 pathway in U87MG mouse brain tumor model.

Pei J, Park IH, Ryu HH, Li SY, Li CH, Lim SH, Wen M, Jang WY, Jung S - Radiat Oncol (2015)

Bottom Line: TIMP-2 expression did not increase in U87MG cells.MMP-2 activity decreased in p53 knock-downed U87MG cells but increased in the control group.Tumor cells invaded by radiation overexpressed MMP-2 and p53 and revealed high gelatinolytic activity compared with those of non-radiated tumor cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurosurgery, Chonnam National University Hwasun Hospital and Mediacal School, 322 Seoyang-ro, Hwasun-eup, Hwasun-gun, Jeonnam, 519-763, Republic of Korea.

ABSTRACT

Background: Glioblastoma is a highly lethal neoplasm that frequently recurs locally after radiotherapy, and most of these recurrences originate from near the irradiated target field. In the present study, we identified the effects of radiation on glioma invasion and p53, TIMP-2, and MMP-2 expression through in vitro and in vivo experiments.

Methods: The U87MG (wt p53) and U251 (mt p53) human malignant glioma cell lines were prepared, and the U2OS (wt 53) and Saos2 (del p53) osteosarcoma cell lines were used as p53 positive and negative controls. The four cell lines and p53 knock-downed U87MG cells received radiation (2-6 Gy) and were analyzed for expression of p53 and TIMP-2 by Western blot, and MMP-2 activity was detected by zymography. In addition, the effects of irradiation on directional invasion of malignant glioma were evaluated by implanting nude mice with bioluminescent u87-Fluc in vivo followed by MMP-2, p53, and TIMP-2 immunohisto-chemistry and in situ zymography.

Results: MMP-2 activity and p53 expression increased in proportional to the radiation dose in cell lines with wt p53, but not in the cell lines with del or mt p53. TIMP-2 expression did not increase in U87MG cells. MMP-2 activity decreased in p53 knock-downed U87MG cells but increased in the control group. Furthermore, radiation enhanced MMP-2 activity and increased tumor margin invasiveness in vivo. Tumor cells invaded by radiation overexpressed MMP-2 and p53 and revealed high gelatinolytic activity compared with those of non-radiated tumor cells.

Conclusion: Radiation-induced upregulation of p53 modulated MMP-2 activity, and the imbalance between MMP-2 and TIMP-2 may have an important role in glioblastoma invasion by degrading the extracellular matrix. Bioluminescent "U87-Fluc"was useful for observing tumor formation without sacrifice after implanting tumor cells in the mouse brain. These findings suggest that the radiotherapy involved field for malignant glioma needs to be reconsidered, and that future trials should investigate concurrent pharmacologic therapies that inhibit invasion associated with radiotherapy.

No MeSH data available.


Related in: MedlinePlus

Tumor growth rate analyses using Optical Bioluminescence Imaging. U87-Fluc bearing nude mice brain were continuously observed through tumor bioluminescence by the IVIS 100 imaging system. For pilot study we designated control group (non-radiated group) and two groups (radiated group). Among radiated group, one group was exposed to fractionated dose radiation (2Gy x 5) and another group was exposed to single dose radiation (6 Gy)
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Fig4: Tumor growth rate analyses using Optical Bioluminescence Imaging. U87-Fluc bearing nude mice brain were continuously observed through tumor bioluminescence by the IVIS 100 imaging system. For pilot study we designated control group (non-radiated group) and two groups (radiated group). Among radiated group, one group was exposed to fractionated dose radiation (2Gy x 5) and another group was exposed to single dose radiation (6 Gy)

Mentions: U87-Fluc-bearing nude mice brains were observed continuously by tumor bioluminescence using the IVIS 100 imaging system to determine the effects of radiation on tumor growth. Additional file 1: Figure S1 illustrates the process used to assess the radiation effects on brain tumors in vivo. The mouse brains were exposed to radiation after tumor formation had been observed by tumor bioluminescence. As shown in Fig. 4, notable retardation of tumor growth was observed in the single 6 Gy exposed group, compared with that in the control groups. However, the brain tumors continued to grow, and the final growth rate was similar to that of the control group from about day 20. No difference was found in the radiation-fractionated group, compared to the control group, indicating that the single dose (6 Gy) treatment or low dose fractionated irradiation was insufficient for complete control of tumor growth.Fig. 4


Sublethal dose of irradiation enhances invasion of malignant glioma cells through p53-MMP 2 pathway in U87MG mouse brain tumor model.

Pei J, Park IH, Ryu HH, Li SY, Li CH, Lim SH, Wen M, Jang WY, Jung S - Radiat Oncol (2015)

Tumor growth rate analyses using Optical Bioluminescence Imaging. U87-Fluc bearing nude mice brain were continuously observed through tumor bioluminescence by the IVIS 100 imaging system. For pilot study we designated control group (non-radiated group) and two groups (radiated group). Among radiated group, one group was exposed to fractionated dose radiation (2Gy x 5) and another group was exposed to single dose radiation (6 Gy)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4554349&req=5

Fig4: Tumor growth rate analyses using Optical Bioluminescence Imaging. U87-Fluc bearing nude mice brain were continuously observed through tumor bioluminescence by the IVIS 100 imaging system. For pilot study we designated control group (non-radiated group) and two groups (radiated group). Among radiated group, one group was exposed to fractionated dose radiation (2Gy x 5) and another group was exposed to single dose radiation (6 Gy)
Mentions: U87-Fluc-bearing nude mice brains were observed continuously by tumor bioluminescence using the IVIS 100 imaging system to determine the effects of radiation on tumor growth. Additional file 1: Figure S1 illustrates the process used to assess the radiation effects on brain tumors in vivo. The mouse brains were exposed to radiation after tumor formation had been observed by tumor bioluminescence. As shown in Fig. 4, notable retardation of tumor growth was observed in the single 6 Gy exposed group, compared with that in the control groups. However, the brain tumors continued to grow, and the final growth rate was similar to that of the control group from about day 20. No difference was found in the radiation-fractionated group, compared to the control group, indicating that the single dose (6 Gy) treatment or low dose fractionated irradiation was insufficient for complete control of tumor growth.Fig. 4

Bottom Line: TIMP-2 expression did not increase in U87MG cells.MMP-2 activity decreased in p53 knock-downed U87MG cells but increased in the control group.Tumor cells invaded by radiation overexpressed MMP-2 and p53 and revealed high gelatinolytic activity compared with those of non-radiated tumor cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurosurgery, Chonnam National University Hwasun Hospital and Mediacal School, 322 Seoyang-ro, Hwasun-eup, Hwasun-gun, Jeonnam, 519-763, Republic of Korea.

ABSTRACT

Background: Glioblastoma is a highly lethal neoplasm that frequently recurs locally after radiotherapy, and most of these recurrences originate from near the irradiated target field. In the present study, we identified the effects of radiation on glioma invasion and p53, TIMP-2, and MMP-2 expression through in vitro and in vivo experiments.

Methods: The U87MG (wt p53) and U251 (mt p53) human malignant glioma cell lines were prepared, and the U2OS (wt 53) and Saos2 (del p53) osteosarcoma cell lines were used as p53 positive and negative controls. The four cell lines and p53 knock-downed U87MG cells received radiation (2-6 Gy) and were analyzed for expression of p53 and TIMP-2 by Western blot, and MMP-2 activity was detected by zymography. In addition, the effects of irradiation on directional invasion of malignant glioma were evaluated by implanting nude mice with bioluminescent u87-Fluc in vivo followed by MMP-2, p53, and TIMP-2 immunohisto-chemistry and in situ zymography.

Results: MMP-2 activity and p53 expression increased in proportional to the radiation dose in cell lines with wt p53, but not in the cell lines with del or mt p53. TIMP-2 expression did not increase in U87MG cells. MMP-2 activity decreased in p53 knock-downed U87MG cells but increased in the control group. Furthermore, radiation enhanced MMP-2 activity and increased tumor margin invasiveness in vivo. Tumor cells invaded by radiation overexpressed MMP-2 and p53 and revealed high gelatinolytic activity compared with those of non-radiated tumor cells.

Conclusion: Radiation-induced upregulation of p53 modulated MMP-2 activity, and the imbalance between MMP-2 and TIMP-2 may have an important role in glioblastoma invasion by degrading the extracellular matrix. Bioluminescent "U87-Fluc"was useful for observing tumor formation without sacrifice after implanting tumor cells in the mouse brain. These findings suggest that the radiotherapy involved field for malignant glioma needs to be reconsidered, and that future trials should investigate concurrent pharmacologic therapies that inhibit invasion associated with radiotherapy.

No MeSH data available.


Related in: MedlinePlus