Anomalies of growth factor signaling have been reported in malignant human gliomas. The extracellular signal-regulated kinases (ERKs) play a crucial role in transducing growth factor signals to the nucleus and are involved in a wide range of biological responses, including cell proliferation, differentiation and motility. ERK1/2 is expressed and activated in glioblastoma multiforme (GBM). However, no information is available in literature concerning the presence and activity of ERK1/2 in the peritumor tissue. In the present study, we evaluated by immunohistochemistry total and phosphorylated (t and p) ERK1/2 expression in 31 cases of primary GBM and in tissue surrounding the enhanced lesion at different distances up to 3.5 cm from the tumor margin. Total ERK1/2 was, as expected, uniformly expressed not only in GBM but in the areas around the tumor also, which showed higher levels of immunolabeling. ERK1/2 activation was observed in GBM as well as in peritumor tissue, with no statistical difference in the level of the enzymatic activities. In particular, in the peritumor tissue pERK1/2 was present independently of neoplastic cells not only in reactive astrocytes, but in apparently normal glial cells also. These results indicate that ERK1/2 pathway may participate in GBM growth and progression. In addition, they strongly suggest that ERK1/2 stimulation may be linked not only to tissue reactivity to tumor invasion, but also to cell motility or represent per se a sign of transformation. Finally, our findings highlight the meaning of the extension of neoplasm fingers beyond the outer margin of GBM. Patients with neoplastic cells at <10% or without neoplastic cells in peritumor areas showed a higher survival time compared with those with neoplastic elements at ≥10%. In addition, a percentage ≥10 of neoplastic elements in peritumor tissue was associated with an approximately 4-fold increased death risk.

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