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Radiation and inhibition of angiogenesis by canstatin synergize to induce HIF-1α–mediated tumor apoptotic switch
Claire Magnon, … , Michel Perricaudet, Martin Schlumberger
Claire Magnon, … , Michel Perricaudet, Martin Schlumberger
Published July 2, 2007
Citation Information: J Clin Invest. 2007;117(7):1844-1855. https://doi.org/10.1172/JCI30269.
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Research Article Oncology

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

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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-1α increases the activity of the canstatin-induced αvβ5 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-1α 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

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Figure 1

Therapeutic efficiency of AdNIS-131I therapy combined with AdCanHSA in vivo.

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Therapeutic efficiency of AdNIS-131I therapy combined with AdCanHSA in v...
(A) Growth of AdCO1-, AdNIS-, AdCanHSA-, and AdNIS-AdCanHSA–infected MDA-MB-231 xenografted tumors (2 intratumor injections of the appropriate adenoviruses, 72 hours apart) on nu/nu mice after injection of 300 μCi of 131I. Tumor volumes were measured once a week over 4 weeks. Results are mean ± SEM for 9 mice for each treatment group. Representative of 4 separate experiments. *P < 0.05. (B) ELISA quantification of CanHSA in the sera of the same mice represented above, at day 4 after injection of iodide. (C) In vivo kinetics of iodide uptake in AdCO1-, AdNIS-, AdCanHSA-, and AdCanHSA-AdNIS–infected MDA-MB-231 tumors (n = 3 per group). Infected tumors were removed 4, 8, and 24 hours following injection of 131I (300 μCi) i.p. 131I was measured using a gamma counter. Results are expressed as the mean number of μCi per milligram of tumor tissue ± SEM. (D) In vivo imaging of mice harboring AdNIS- or AdCanHSA-AdNIS–infected MDA-MB-231 xenografts (left flank) 4 hours after i.p. injection of 50 μCi of 123I and 24 hours before 131I injection. Images were acquired through scintigraphy over a 10-minute exposure and have an equivalent background. There was also physiological accumulation of iodide in the bladder, stomach, and thyroid gland. Mice were treated with l-thyroxine to avoid massive uptake by the thyroid. (E) In vivo assessment of iodide uptake by AdNIS- or AdCanHSA-AdNIS–infected MDA-MB-231 tumors 4 hours after 123I injection, as described for D. A fixed region of interest (ROI) was drawn and was imposed on each tumor and on each stomach (as standard uptake). Pixel intensity per ROI was measured with ImageJ software. Results are expressed as the ratio (tumor/stomach) between the maximal pixel intensity in the 2 ROIs.

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