Characterization of the bystander effect of somatostatin receptor sst2 after in vivo gene transfer into human pancreatic cancer cells.
Pancreatic cancer is one of the most aggressive and devastating human malignancies. The present study was conducted to determine whether in vivo sst2 gene transfer into human pancreatic tumors would impair tumor progression, and to characterize sst2 antitumoral bystander mechanisms. sst2 administration, using the synthetic vector PEI, strongly inhibited tumor progression of human pancreatic adenocarcinoma, in vivo. sst2 gene transfer induced intratumoral production of its ligand somatostatin. Disruption of this autocrine loop by RNA interference completely reversed sst2 antitumoral activity. Mice depleted of natural killer (NK) cells did not hamper sst2 tumor growth inhibition. However, microvessel density and vascular endothelial growth factor (VEGF) expression were markedly reduced in sst2-transfected tumors, whereas sst3 somatostatin receptor was upregulated. Depleting somatostatin by RNA interference completely abolished the sst2 inhibitory effect on VEGF expression and tumor angiogenesis, and sst2-induced sst3 expression in peripheral tumor vessels. We conclude that in vivo sst2 gene transfer elicited intratumoral somatostatin production and strongly impaired human pancreatic tumor growth. NK cells were not involved in this antitumoral bystander effect. VEGF and tumor vascularization were identified as novel targets for sst2-mediated antitumoral bystander effect. sst3 somatostatin receptor was upregulated in sst2-transfected tumors. Therefore, in vivo gene delivery of sst2 receptor to target the angiogenic process in pancreatic ductal adenocarcinoma might be a new therapeutic approach for treatment of pancreatic cancer in patients with unresectable disease.
Carrere
Nicolas
N
INSERM U531, Institut Louis Bugnard, IFR31, CHU Rangueil, 31432 Toulouse, France.
Vernejoul
Fabienne
F
Souque
Anny
A
Asnacios
Amani
A
Vaysse
Nicole
N
Pradayrol
Lucien
L
Susini
Christiane
C
Buscail
Louis
L
Cordelier
Pierre
P
D000818:Animals; D019898:Autocrine Communication / Q000235:genetics; D024201:Bystander Effect / Q000235:genetics; D002277:Carcinoma / Q000098:blood supply / Q000378:metabolism / Q000628:therapy; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation / Q000379:methods; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000628:therapy; D017481:Receptors, Somatostatin / Q000235:genetics / Q000378:metabolism*
D017481:Receptors, Somatostatin