In vivo selective and distant killing of cancer cells using adenovirus-mediated decorin gene transfer.
Decorin is a well-known, ubiquitous proteoglycan that is a normal component of the ECM. Upon transgenic expression of decorin, tumor cells with diverse histogenetic background overexpress p21WAF1, a potent inhibitor of cyclin-dependent kinase activity, become arrested in G1, and fail to generate tumors in immunocompromised animals. Because decorin is a secreted protein, it has been recently suggested that decorin could act as an autocrine and paracrine regulator of tumor growth. Here, we demonstrate that adenovirus (Ad)-mediated transfer and expression of human decorin cDNA induced in vivo apoptosis of xenograft tumor cells in nude mice. This oncolytic activity was observed when the Ad vector encoding the decorin cDNA was injected intratumorally (i.t.) or i.v. Importantly, i.t. injection of the decorin Ad vector led to growth inhibition of the injected tumor associated with similar growth inhibition of a distant contralateral tumor, demonstrating a distant decorin antitumoral effect. Immunochemistry against human decorin and decorin quantitation in tumors confirmed that decorin migrated to the tumor distant site. Furthermore, decorin effect was specific to tumor cells, because neither apoptosis nor growth inhibition were observed in nontumoral human cells such as hepatocytes, endothelial cells, and fibroblasts, despite p21 overexpression.
Tralhão
J Guilherme
JG
INSERM E0016, Université René Descartes, Faculté Necker-Enfants Malades, Paris, France.
Schaefer
Liliana
L
Micegova
Miroslava
M
Evaristo
Cesar
C
Schönherr
Elke
E
Kayal
Samer
S
Veiga-Fernandes
Henrique
H
Danel
Claire
C
Iozzo
Renato V
RV
Kresse
Hans
H
Lemarchand
Patricia
P
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D017209:Apoptosis; D058575:Decorin; D016326:Extracellular Matrix Proteins; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D009374:Neoplasms, Experimental / Q000473:pathology / Q000628:therapy*; D011509:Proteoglycans / Q000235:genetics*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
C546878:DCN protein, human; C546879:Dcn protein, mouse; D058575:Decorin; D016326:Extracellular Matrix Proteins; D011509:Proteoglycans