PMID- 16218777
OWN - NLM
STAT- MEDLINE
DCOM- 20060103
LR  - 20121115
IS  - 1043-0342 (Print)
IS  - 1043-0342 (Linking)
VI  - 16
IP  - 10
DP  - 2005 Oct
TI  - Amino-terminal fragment of urokinase inhibits tumor cell invasion in vitro and in 
      vivo: respective contribution of the urokinase plasminogen activator 
      receptor-dependent or -independent pathway.
PG  - 1157-67
AB  - The urokinase plasminogen activator (uPA) is implicated in both cancer cell 
      invasion and angiogenesis. It can interact with a specific receptor (uPAR) via 
      the epidermal growth factor (EGF)-like domain in the urokinase amino-terminal 
      fragment (ATF) in a species-specific manner. Our previous studies showed that 
      adenovirusmediated delivery of murine ATF (AdmATF) suppressed human tumor growth 
      in mouse models, by inhibiting murine angiogenesis. However, we cannot exclude 
      its putative inhibitory action on human cancer cell invasion through a 
      uPAR-independent pathway. To further investigate the mechanisms of ATF, we 
      constructed another adenovirus, AdhmATF, expressing humanized murine ATF (hmATF). 
      hmATF binds to human uPAR but not to murine uPAR. We compared the antagonist 
      effect of both AdmATF and AdhmATF on human and murine cancer cells. In vitro, the 
      supernatant from AdhmATF-infected cells repressed 79% of membrane-associated uPA 
      activity on human MDA-MB-231 cells, whereas that from AdmATF-infected cells 
      repressed 35% of membrane-associated uPA activity. On murine LLC cells, the 
      supernatant from AdhmATF-infected cells inhibited 29% of cell surface uPA 
      activity, whereas that from AdmATF-infected cells inhibited 74% of cell surface 
      uPA activity. Similar results were obtained in a cell invasion assay. In vivo, 
      intratumoral injection of the adenoviruses into LLC tumors on day 24 
      postinjection induced lower but significant tumor growth suppression by AdhmATF 
      (tumor volume was 1185 +/- 128 mm3), whereas suppression by AdmATF was greater 
      (407 +/- 147 mm3). In the MDA-MB-231 tumor model, on day 52 postinjection, tumor 
      size was 187 +/- 47 mm3 in the AdhmATF-treated group and 468 +/- 65 mm3 in the 
      AdmATF-treated group. The LLC and MDA-MB- 231 cell lines transfected by mATF or 
      hmATF genes showed growth inhibition In vivo equivalent to the results obtained 
      by adenovirus treatment. These results demonstrate the strong anticancer activity 
      of ATF even when its uPAR-binding affinity has been suppressed, and indicate that 
      ATF exerts an antitumor effect via dual mechanisms: essentially through targeting 
      the uPA-uPAR system via the EGF-like domain and partially through targeting a 
      uPAR-independent interaction via the kringle domain.
FAU - Li, Hong
AU  - Li H
AD  - CNRS UMR8121, Institut Gustave Roussy, 94805 Villejuif, France. lihong@igr.fr
FAU - Soria, Claudine
AU  - Soria C
FAU - Griscelli, Frank
AU  - Griscelli F
FAU - Opolon, Paule
AU  - Opolon P
FAU - Soria, Jeannette
AU  - Soria J
FAU - Yeh, Patrice
AU  - Yeh P
FAU - Legrand, Chantal
AU  - Legrand C
FAU - Vannier, Jean Pierre
AU  - Vannier JP
FAU - Belin, Dominique
AU  - Belin D
FAU - Perricaudet, Michel
AU  - Perricaudet M
FAU - Lu, He
AU  - Lu H
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Hum Gene Ther
JT  - Human gene therapy
JID - 9008950
RN  - 0 (PLAUR protein, human)
RN  - 0 (Peptide Fragments)
RN  - 0 (Plaur protein, mouse)
RN  - 0 (Receptors, Cell Surface)
RN  - 0 (Receptors, Urokinase Plasminogen Activator)
RN  - EC 3.4.21.73 (Urokinase-Type Plasminogen Activator)
SB  - IM
MH  - *Adenoviridae
MH  - Animals
MH  - Cell Line, Tumor
MH  - Female
MH  - *Genetic Therapy/methods
MH  - *Genetic Vectors
MH  - Humans
MH  - Mice
MH  - Mice, Mutant Strains
MH  - Neoplasm Invasiveness
MH  - Neoplasm Transplantation
MH  - Neoplasms, Experimental/metabolism/pathology/*therapy
MH  - Peptide Fragments/administration & dosage/genetics
MH  - Receptors, Cell Surface/*metabolism
MH  - Receptors, Urokinase Plasminogen Activator
MH  - *Urokinase-Type Plasminogen Activator/administration & dosage/chemistry/genetics
EDAT- 2005/10/13 09:00
MHDA- 2006/01/04 09:00
CRDT- 2005/10/13 09:00
PHST- 2005/10/13 09:00 [pubmed]
PHST- 2006/01/04 09:00 [medline]
PHST- 2005/10/13 09:00 [entrez]
AID - 10.1089/hum.2005.16.1157 [doi]
PST - ppublish
SO  - Hum Gene Ther. 2005 Oct;16(10):1157-67. doi: 10.1089/hum.2005.16.1157.