title: 16-kDa fragment of pleiotrophin acts on endothelial and breast tumor cells and inhibits tumor development.
abstract: 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.
authors.affiliation: INSERM U745, Laboratoire de Génétique Moléculaire, Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris V, 4 avenue de l'Observatoire, 75006 Paris, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Ducès
authors.forename: Racha
authors.initials: R
authors.lastname: Karaky
authors.forename: Dominique
authors.initials: D
authors.lastname: Martel-Renoir
authors.forename: Lluis
authors.initials: L
authors.lastname: Mir
authors.forename: Yamina
authors.initials: Y
authors.lastname: Hamma-Kourbali
authors.forename: Ivan
authors.initials: I
authors.lastname: Biéche
authors.forename: Paule
authors.initials: P
authors.lastname: Opolon
authors.forename: Jean
authors.initials: J
authors.lastname: Delbé
authors.forename: José
authors.initials: J
authors.lastname: Courty
authors.forename: Michel
authors.initials: M
authors.lastname: Perricaudet
authors.forename: Frank
authors.initials: F
authors.lastname: Griscelli
mesh_terms: 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
chemical_list: D002352:Carrier Proteins; D016207:Cytokines; D050505:Mutant Proteins; D010446:Peptide Fragments; D011956:Receptors, Cell Surface; C066845:pleiotrophin