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.

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We analyzed the expression and amplification of cyclin D1 and CDK4 genes in ovarian carcinomas. Northern blot analysis revealed overexpression of cyclin D1 in 12 of 65 (18%) ovarian carcinomas while CDK4 was overexpressed in 7 of 48 cases (14%). None of the tumors showed amplification of any of the 2 genes. Overexpression of cyclin D1 and CDK4 transcripts was correlated, suggesting a role of both genes in altered growth control of ovarian cancer cells. Elevated levels of cyclin D1 were significantly associated with a wellmoderately differentiated grade (G1-G2) (p F 0.005). No significant association was found between cyclin D1 expression and estrogen receptor, progesterone and epidermal growth factor receptor content. Cyclin D1 expression does not appear to be associated with clinical outcome in human ovarian cancer, although a longer follow-up period and screening of other molecules involved in the same pathway would be necessary to assess this hypothesis. Int. J. Cancer 74:390-395, 1997.r 1997 Wiley-Liss, Inc.The prognostic characterization of patients with ovarian cancer, which is based on clinico-pathological criteria, is largely inadequate. Fifty percent of the patients, after optimal surgical debulking and a pathologically complete response to primary chemotherapy, will develop a recurrence of the tumor and will die within 2 years. Thus, the development of additional prognostic factors, closely related to tumor cell biology, is essential for identification of patients with a particularly poor prognosis.Attention has recently been focused on genetic alterations of several proto-oncogenes and tumor suppressor genes that mediate signal transduction pathways involved in cell proliferation and differentiation as well as cell cycle control. Cyclins are a family of cell cycle control proteins that regulate cell cycle progression by associating with and activating cyclin-dependent kinases (CDKs). Since the major regulatory events leading to mammalian cell proliferation and differentiation occur in the G 0 to G 1 phases and/or in the G 1 to S phase transition during the cell cycle, the deregulated expression of G 1 or G 1 /S phase cyclins or their related CDKs may cause loss of cell cycle control and thereby contribute to neoplastic transformation. Cyclin D1 is known to regulate cell cycle progression at the G 1 -S checkpoint, and its overexpression shortens the G 1 -S transition. To function as a positive regulator of G 1 progression, cyclin D1 needs to bind to its catalytic subunit, CDK4. When activated by cyclin D1, CDK4 phosphorylates the retinoblastoma tumor suppressor protein (pRb), resulting in release of pRbmediated G 1 arrest. Indeed, the unphosphorylated form of pRb is thought to restrain cell cycle progression by binding and inactivating members of the E2F family of transcription factors, the inhibitory effect being abolished by phosphorylation. The cyclin D1/CDK4 complex can be inhibited by various proteins including some members of the p16 family of cell cycle inhibitors. Amplification and/or overexpre...

Anomalies of growth factor signaling have been reported in malignant human gliomas. The extracellular signalregulated 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.

The assessment of nm23 content may provide useful information for prognostic characterization of ovarian cancer patients.