16-kDa fragment of pleiotrophin acts on endothelial and breast tumor cells and inhibits tumor development.
Pleiotrophin (PTN) is a 136-amino acid secreted heparin-binding protein that is considered as a rate-limiting growth and an angiogenic factor in the onset, invasion, and metastatic process of many tumors. Its mitogenic and tumorigenic activities are mediated by the COOH-terminal residues 111 to 136 of PTN, allowing it to bind to cell surface tyrosine kinase-linked receptors. We investigated a new strategy consisting in evaluating the antitumor effect of a truncated PTN, lacking the COOH-terminal 111 to 136 portion of the molecule (PTNDelta111-136), which may act as a dominant-negative effector for its mitogenic, angiogenic, and tumorigenic activities by heterodimerizing with the wild-type protein. In vitro studies showed that PTNDelta111-136 selectively inhibited a PTN-dependent MDA-MB-231 breast tumor and endothelial cell proliferation and that, in MDA-MB-231 cells expressing PTNDelta111-136, the vascular endothelial growth factor-A and hypoxia-inducible factor-1alpha mRNA levels were significantly decreased by 59% and 71%, respectively, compared with levels in wild-type cells. In vivo, intramuscular electrotransfer of a plasmid encoding a secretable form of PTNDelta111-136 was shown to inhibit MDA-MB-231 tumor growth by 81%. This antitumor effect was associated with the detection of the PTNDelta111-136 molecule in the muscle and tumor extracts, the suppression of neovascularization within the tumors, and a decline in the Ki-67 proliferative index. Because PTN is rarely found in normal tissue, our data show that targeted PTN may represent an attractive and new therapeutic approach to the fight against cancer.
Ducès
Aurélie
A
INSERM U745, Laboratoire de Génétique Moléculaire, Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris V, 4 avenue de l'Observatoire, 75006 Paris, France.
Karaky
Racha
R
Martel-Renoir
Dominique
D
Mir
Lluis
L
Hamma-Kourbali
Yamina
Y
Biéche
Ivan
I
Opolon
Paule
P
Delbé
Jean
J
Courty
José
J
Perricaudet
Michel
M
Griscelli
Frank
F
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000098:blood supply / Q000473:pathology*; D002352:Carrier Proteins / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D051379:Mice; D008819:Mice, Nude; D008970:Molecular Weight; D050505:Mutant Proteins / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000473:pathology; D010446:Peptide Fragments / Q000494:pharmacology*; D011956:Receptors, Cell Surface / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D002352:Carrier Proteins; D016207:Cytokines; D050505:Mutant Proteins; D010446:Peptide Fragments; D011956:Receptors, Cell Surface; C066845:pleiotrophin