Stem Cell Marker Nestin and c-Jun NH2-Terminal Kinases in Tumor and Peritumor Areas of Glioblastoma Multiforme: Possible Prognostic Implications

Abstract

Purpose: It has been hypothesized that brain tumors are derived from stem cell or transiently dividing precursor transformation. Furthermore, c-Jun NH 2 -terminal kinases (JNKs) have been involved in gliomagenesis. This study analyzes stem cell marker nestin and JNK expression in glioblastoma multiforme (GBM) and peritumor tissue and assesses their possible prognostic implications. Experimental Design: Nestin and both total JNK (tJNK) and phosphorylated JNK (pJNK) expression was investigated by immunohistochemistry in 20 GBMs. Samples were derived from tumors (first area), from tissues at a distance <1 cm (second area), and between 1 and 3.5 cm (third area) from the macroscopic tumor border. The relationships between patients' age, Karnofsky performance status, gender, protein expression, and survival were analyzed. Results: Nestin cytoplasmic immunoreactivity was observed in the majority of cells in tumor but infrequently in peritumor areas. tJNK, observed in the nucleus and cytoplasm, was widely expressed in the three areas; pJNK, mostly located in the nuclei, was found in a variable percentage of cells in the tumor and peritumor tissue. Nestin and JNK expression in peritumor areas was independent of the presence of neoplastic cells. Univariate analysis indicated that survival was longer (19 versus 12 months; P = 0.01) for patients whose pJNK/nestin and (pJNK/ tJNK)/nestin ratios in the second area were z2.619 and z0.026, respectively. The same variables showed an independent prognostic value in multivariate analysis. Conclusions: Nestin and JNK expression indicates that peritumor tissue, independently of the presence of neoplastic cells, may present signs of transformation. Moreover, pJNK/nestin and (pJNK/tJNK)/nestin ratios in that tissue seem to have some prognostic implications in GBM patients.

Assessment of angiogenesis by CD105 and nestin expression in peritumor tissue of glioblastoma

“…This is in complete agreement with our previous findings showing that JNK and nestin expression in the second area correlates with patients' survival (13).…”

“…Nevertheless, all the above reports do not define the areas of peritumor tissue used for analysis, nor their distance from the tumor edge. In this regard, we recently showed in peritumor tissue, up to 3.5 cm from the tumor margin, the presence of phosphorylated (p) extracellular signal-regulated kinases (ERKs) and c-Jun NH 2 terminal kinases (JNKs) (12,13) regulating cell proliferation, differentiation, motility and apoptosis (14). The neural stem cell marker nestin was also expressed in the same tissue.…”

“…Both kinases and nestin were present not only in activated astrocytes but also in apparently normal glial cells. In addition, the pJNK/nestin and (pJNK/total JNK)/nestin ratios at a distance <1 cm from the tumor border have been shown to carry a prognostic significance in GBM patients (13).…”

“…Markers of endothelial activation, such as pERK1/2, pJNKs and nestin, are expressed in the vessel walls of both GBM and peritumor areas (12,13,15,16) and their expression may be induced by growth factors and chemokines secreted by tumor cells, which diffuse in the peritumor areas and are presumably involved in the rapid turnover of the endothelial cells.…”

c-Jun N-terminal kinase has a pivotal role in the maintenance of self-renewal and tumorigenicity in glioma stem-like cells

“…Though it remains unknown, we assume that malignant glioma cells may be clonally selected during brain tumor progression and escaped JNK-mediated apoptotic pathways. Indeed, the ratio of JNK to Nestin, a stem cell marker, in glioma tissues is linked to patient prognosis, 46 suggesting a role for JNK in glioma stemness. Also, our study clearly implicates the JNK pathway in selfrenewal and tumorigenicity of glioma cells.…”