Radiation and inhibition of angiogenesis by canstatin synergize to induce HIF-1α–mediated tumor apoptotic switch
Claire Magnon, Paule Opolon, Marcel Ricard, Elisabeth Connault, Patrice Ardouin, Ariane Galaup, Didier Métivier, Jean-Michel Bidart, Stéphane Germain, Michel Perricaudet, Martin Schlumberger
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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Research Article Oncology

Radiation and inhibition of angiogenesis by canstatin synergize to induce HIF-1α–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-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 2

Combined effects of AdNIS-131I therapy with AdCanHSA in transgenic TRP-1 mouse model.

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Combined effects of AdNIS-131I therapy with AdCanHSA in transgenic TRP-1...
(A) Immunohistological analysis of AdNIS-infected RPE tumor with an anti-NIS polyclonal antibody (original magnification, ×50). (B) Higher-magnification of boxed area in A (original magnification, ×200). Positive cells were located in the RPE tumor and in the retina (arrows). (C) Representative nontumor eye section with location of retina, choroid, sclera, and lens (arrows). (D–H) Histology of the RPE tumor 45 days after birth. Representative transgenic eye section treated with 2 systemic injections of Adx and a single intraorbital injection of Ady, and a single 131I injection of 300 μCi. AdCO1 and AdCO1 (D); AdCO1 and AdNIS (E); AdCanHSA and AdCO1 (F); or AdCanHSA and AdNIS (G and H) (original magnification, ×25). Note that AdCO1-treated tumor cells grew consistently and occupied half of the eyeball when mice were 45 days old (D). In contrast, only a few tumor cells persisted in AdCanHSA-AdNIS–treated eyeball (H). t, tumor. (I–M) Higher-magnification images of areas in black boxes in D–H, respectively (original magnification, ×100). (S) Measurement of tumor areas in the posterior eyeball of each TRP-1 transgenic mouse treated with the appropriate adenoviruses. Results are the mean ± SEM (n = 10). (N–R) Assessment of intratumor vascularization using lectin immunostaining after each treatment described above (original magnification, ×100). AdCO1 and AdCO1 (N); AdCO1 and AdNIS (O); AdCanHSA and AdCO1 (P); AdCanHSA and AdNIS (Q and R) (same as in black boxes in D–H). Original magnification, ×200. (T) Mean number of intratumor vessels for each group ± SEM. *P < 0.05.