Immunohistochemical detection of phosphorylated JAK-2 and STAT-5 proteins and correlation with erythropoietin receptor (EpoR) expression status in human brain tumors.

Phosphorylated (activated) forms of Janus Kinase 2 (pJAK-2) and STAT-5 transcription factor (pSTAT-5), which are preferentially expressed after binding of erythropoietin (Epo) to its receptor EpoR, are known to be implicated in the molecular mechanisms controlling brain development. The purpose of this study was to investigate the expression of these proteins (pJAK-2, pSTAT-5, and EpoR) in human brain tumors compared with normal brain. Using specific antibodies and immunohistochemistry on formalin-fixed, paraffin-embedded semi-serial tissue sections a total of 87 human brain tumors and samples from normal brain tissue were studied. pJAK-2/pSTAT-5 nuclear co-expression was detected in 39% of astrocytomas, 43% of oligodendrogliomas, 50% of ependymomas, and in all (100%) of the medulloblastomas examined. In contrast, most of the meningiomas showed weak or no immunoreactivity for pJAK-2/pSTAT-5 proteins. A significant percentage of tumors exhibited pSTAT-5 immunoreactivity, being pJAK-2 immunonegative. EpoR/pJAK-2/pSTAT-5 co-expression was detected in a small percentage of astrocytomas (18%) and ependymomas (33%). Oligodendrogliomas and medulloblastomas were EpoR immunonegative. Tumor vessels exhibited EpoR, pJAK-2, and pSTAT-5 immunoreactivity. In normal brain tissue, EpoR immunoreactivity was detected in neurons and vessels whereas pSTAT-5 and pJAK-2 immunoreactivity was limited to some neurons and a few glial cells, respectively. These results indicate the existence of ligand (other than Epo)-dependent or independent JAK-2 activation that leads to constitutive activation of STAT-5 in most human brain tumors. Given the oncogenic potential of the JAK/STAT pathway, detection of different pJAK-2 and pSTAT-5 expression profiles between groups of tumors may reflect differences in the biological behavior of the various human brain tumors.