Radiation and inhibition of angiogenesis by canstatin synergize to induce HIF-1alpha-mediated tumor apoptotic switch.
Tumor radioresponsiveness depends on endothelial cell death, which leads in turn to tumor hypoxia. Radiation-induced hypoxia was recently shown to trigger tumor radioresistance by activating angiogenesis through hypoxia-inducible factor 1-regulated (HIF-1-regulated) cytokines. We show here that combining targeted radioiodide therapy with angiogenic inhibitors, such as canstatin, enhances direct tumor cell apoptosis, thereby overcoming radio-induced HIF-1-dependent tumor survival pathways in vitro and in vivo. We found that following dual therapy, HIF-1alpha increases the activity of the canstatin-induced alpha(v)beta(5) signaling tumor apoptotic pathway and concomitantly abrogates mitotic checkpoint and tetraploidy triggered by radiation. Apoptosis in conjunction with mitotic catastrophe leads to lethal tumor damage. We discovered that HIF-1 displays a radiosensitizing activity that is highly dependent on treatment modalities by regulating key apoptotic molecular pathways. Our findings therefore support a crucial role for angiogenesis inhibitors in shifting the fate of radiation-induced HIF-1alpha activity from hypoxia-induced tumor radioresistance to hypoxia-induced tumor apoptosis. This study provides a basis for developing new biology-based clinically relevant strategies to improve the efficacy of radiation oncology, using HIF-1 as an ally for cancer therapy.
Magnon
Claire
C
CNRS-UMR 8121, Laboratoire de vectorologie et transfert de gènes, Département de Médecine Nucléaire, Villejuif, France. claire.magnon@mssm.edu
Opolon
Paule
P
Ricard
Marcel
M
Connault
Elisabeth
E
Ardouin
Patrice
P
Galaup
Ariane
A
Métivier
Didier
D
Bidart
Jean-Michel
JM
Germain
Stéphane
S
Perricaudet
Michel
M
Schlumberger
Martin
M
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000528:radiation effects*; D002460:Cell Line; D024141:Collagen Type IV / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D015316:Genetic Therapy; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D016023:Integrins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D009369:Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology* / Q000628:therapy; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D027981:Symporters / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000099209:Sodium-Iodide Symporters
D024141:Collagen Type IV; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016023:Integrins; D010446:Peptide Fragments; D027981:Symporters; D000099209:Sodium-Iodide Symporters; C502625:COL4A2 protein, human