Pleiotrophin signaling through PTNR in glioblastoma multiforme

Glioblastoma multiforme is the most common and most lethal primary human brain cancer. Receptor tyrosine kinases play an established role in glioblastoma growth, at least in part by activation of the phosphatidyl inositol 3-kinase signaling pathway. The Wellstein laboratory has recently identified the anaplastic lymphoma kinase (ALK) as a pleiotrophin receptor (PTNR). Pleiotrophin is a heparin-binding polypeptide growth factor expressed in the developing central nervous system and in human brain cancers. Here the role of pleiotrophin signaling through PTNR in glioblastoma is investigated. PTNR is expressed in human glioblastoma tumor sections but not in normal brain. In addition, PTNR mRNA was detected in three of seven human glioblastoma and glioma cell lines. A panel of U87MG clones was generated through ribozyme targeting of PTNR that express decreased levels of PTNR mRNA. These cells display attenuated responsiveness to pleiotrophin-induced Akt phosphorylation correlating with their expression of PTNR mRNA. While the in vitro growth of these cells is unaltered regardless of PTNR mRNA levels, they display a remarkable variation in sensitivity to apoptosis induced by cis-diamminedichloroplatinum II, a well-characterized chemotherapeutic agent. Most dramatically, the in vivo growth of these cells as tumor xenografts in nude mice is limited by the levels of residual PTNR mRNA. This difference in growth appears to be due to varying levels of apoptosis in the xenograft tumors. These findings directly implicate the pleiotrophin-PTNR signaling axis in the growth of glioblastoma multiforme by promoting cell survival in response to pro-apoptotic stimuli.