The signaling mechanisms underlying malignant glioma invasiveness

2004 Fiscal Year Final Research Report Summary

• Project/Area Number: 15591544
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Cerebral neurosurgery
• Research Institution: Saitama Medical University
• Principal Investigator: MISHIMA Kazuhiko Saitama Medical School, Neurosurgery, Lecturer, 医学部, 講師 (00282640)
• Co-Investigator(Kenkyū-buntansha): NISHIKAWA Ryo Saitama Medical School, Neurosurgery, Associate professor, 医学部, 助教授 (90237678) ; MATSUTANI Masao Saitama Medical School, Neurosurgery, Professor, 医学部, 教授 (90010454)
• Project Period (FY): 2003 – 2004
• Keywords: Malignant glioma / MAPK / Invasion / EGFR

Research Abstract

The morbidity of malignant gliomas, grade III-IV, lies in the extensive migration and invasion of cells into brain parenchyma away from the main tumor mass that leads to recurrence after extirpation and adjuvant therapy. Therefore, it is important to determine the mechanisms that lead to cell migration in these high-grade tumors would provide a framework for the design of more effective therapeutic strategies.
Malignant gliomas have been shown to express increased levels of activated Ras through dysregulated signaling of receptor tyrosine kinases such as EGFR, mutant EGFR and PDGF-R. Dysregulated activation of Ras or its downstream effectors such as mitogen-activated protein kinase kinase (MEK) and MAPK has been shown to play a critical role in proliferation and tumorigenesis of glioma. However, a direct role for MAPK in regulating the invasive potential of malignant glioma cells remains to be established.
Here we report that glioma tissue samples show an elevated MAPK activation as compared with non-neoplastic brain samples. To investigate the role of activated MAPK on glioma invasion in situ, we used an in vivo brain tumor invasion model. We selected the established cell line LN-Z308 because it has low MAPK activity and it is not invasive when stereotactically injected into nude mouse brain.
We found that in vivo invasiveness was enhanced in constitutively activated MEK transfected LN-Z308, whereas control vector-transfected or wild type MEK transfected LN-Z308 cells produced demarcated tumors. These results suggest that constitutive activated MAPK plays a critical role in invasiveness of glioma cells. This pathway may represent therapeutic target for treatment of aggressive glioma.