The growth and
metastasis of solid
tumors rely on the activities of
polypeptide growth factors. However, numerous
growth factors are expressed in
tumors, and it is difficult to decipher which are essential for
tumor progression. We found the secreted
growth factor pleiotrophin (PTN) expressed at high levels in a number of human tumor cell lines as well as in
tumor samples. To assess the role of PTN in
tumor growth, we inactivated the PTN gene with PTN-targeted
hammerhead ribozyme constructs. Cotransfection of PTN and of the
ribozymes inhibited PTN-induced colony formation of PTN-responsive cells whereas a point mutant, catalytically inactive
ribozyme was ineffective. Colony formation induced by transfections with a closely related
growth factor (
midkine) was not affected by the
ribozymes. In human
melanoma cells that express high levels of PTN
mRNA, stable transfection with PTN-targeted
ribozymes quenched production of PTN, inhibited colony formation of the cells, and prevented their
tumor growth in mice. This demonstrates that expression of a
growth factor can be a rate-limiting step for malignant progression and suggests that
ribozymes could be used therapeutically to target
tumor growth factors.