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Glioblastoma multiforme (GBM), the most malignant astrocytic tumor, is characterized by marked heterogeneity of its cytological composition, high local invasiveness, and very low metastatic tendency. Despite aggressive multimodal treatment strategies combining cytoreductive surgery followed by radio- and chemo-therapy, the median survival of patients is 12 months. Following surgical removal, more than 90% of GBMs recur about 2 cm from the edge of the resection and the resection of 98% or more of the tumor volume is an independent variable associated with a longer survival time. Nestin, a specific marker of neuroepithelial stem cells, is expressed in stem/progenitor cells during CNS development. JNK plays an essential role in cellular transformation and tumor growth and JNK activation is required by oncogenes for these processes. Both nestin and phosphorylated JNK (pJNK) are infrequently detected in normal brain tissue. To define the biological characteristics of tissue surrounding GBM, we investigated the presence of nestin and total (t) and pJNK in tumor and peritumor tissue of GBM. Immunohistochemical analysis was performed to determine expression of nestin, and tJNK and pJNK on tissue sections derived from the GBM (tumor; 1st area), from the tissue at a distance <1 cm (2nd area), and from up to 3.5 cm (3rd area) away from the margin of GBM. Results demonstrate that the percentage of nestin positive cells was higher in GBM (1st area) than in the 2nd and 3rd areas (p<0.001), but no difference was seen between the 2nd and 3rd areas. Nestin was cytoplasmic and was often evident in the vascular endothelium. It was also seen in cytoplasmic extensions of glial cells in the peritumor areas. Nuclear and cytoplasmic expression of tJNK was observed in tumor and surrounding areas, with higher expression seen in peritumor tissue compared to GBM (p<0.05). Activated JNK (pJNK), predominantly localized in the nuclei, was also found in the three areas with no statistically significant difference in the immunoreactivity (p>0.05) and was present in neoplastic cells, activated astrocytes, and apparently normal cells. When the patients were dichotomized by the median value of pJNK/nestin ratio, the survival time was longer for patients whose ratio was >0.90 in the 1st area and >2.63 in the 2nd area (Kaplan-Meier analysis; p<0.05). A trend towards significance was seen for patients in the 3rd area whose pJNK/nestin ratio was >3.98. Results of this study demonstrate the presence of pJNK and nestin in GBM and surrounding tumor area. Moreover, pJNK expression in peritumor tissue, even in the absence of neoplastic cells, may represent an environmental stress or the dissemination of cytokines from the tumor mass to the surrounding microenvironment. Nevertheless, the concomitant nestin expression may suggest a tendency towards neoplastic transformation and may influence patient’s survival.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA