Radiation and inhibition of angiogenesis by canstatin synergize to induce HIF-1alpha-mediated tumor apoptotic switch.

Abstract

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.

• Authors: Claire Magnon, Paule Opolon, Marcel Ricard, Elisabeth Connault, Patrice Ardouin, Ariane Galaup, Didier Métivier, Jean-Michel Bidart, Stéphane Germain, Michel Perricaudet, Martin Schlumberger
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 117 Issue 7 Pg. 1844-55 (Jul 2007) ISSN: 0021-9738 [Print] United States
• PMID: 17557121 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• COL4A2 protein, human
• Collagen Type IV
• Hypoxia-Inducible Factor 1, alpha Subunit
• Integrins
• Peptide Fragments
• Symporters
• sodium-iodide symporter

Topics

• Adenoviridae (genetics)
• Animals
• Apoptosis (radiation effects)
• Cell Line
• Collagen Type IV (genetics, metabolism)
• Disease Models, Animal
• Gene Expression Regulation, Neoplastic
• Genetic Therapy
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
• Integrins (metabolism)
• Mice
• Mice, Transgenic
• Mitochondria (metabolism)
• Neoplasms (blood supply, metabolism, pathology, therapy)
• Peptide Fragments (genetics, metabolism)
• Signal Transduction
• Symporters (genetics, metabolism)
• Xenograft Model Antitumor Assays