Glioblastomas (GBMs) are the most frequent malignant
brain tumors with very limited treatment options and nearly all GBM patients dying within 1 year.
Pleiotrophin (PTN,
HB-GAM,
HBNF, OSF-1) is a secreted
growth factor that shows mitogenic, chemotactic and transforming activity. While PTN expression is tightly regulated during embryogenesis and very limited in normal adult tissues, a marked PTN upregulation is seen in
tumors including
glioblastomas. Targeting of the PTN receptors, ALK and
RPTP-zeta, indicates a contribution of PTN-activated signaling pathways in
glioblastomas. However, the relevance of PTN expression itself is unknown especially since, besides PTN, at least one more
growth factor,
midkine (MK), signals through ALK and is expressed in
glioblastoma. Here we demonstrate the
biologic relevance of PTN in 2
glioblastoma cell lines in vitro and in vivo. We show that stable
ribozyme-targeting leads to a robust reduction of PTN
mRNA and
protein levels. This results in decreased cell proliferation, cell migration and soft
agar colony formation in vitro. Comparing clonal
ribozyme-transfected cells with different residual PTN levels, we establish a PTN gene-dose effect of
glioblastoma cell proliferation. In a subcutaneous
tumor xenograft mouse model, in vivo growth is markedly reduced upon PTN depletion, which is paralleled by decreased PTN serum levels. Furthermore, the immunohistochemical analysis of the
tumors shows reduced angiogenesis in PTN-depleted
tumors. We conclude that PTN is a rate-limiting
growth factor in
glioblastoma. Since PTN is overexpressed in
glioblastomas but rarely found in normal tissue, PTN may represent an attractive therapeutic target.