Modulation of the tumor vasculature functionality by ionizing radiation accounts for tumor radiosensitization and promotes gene delivery

Sonveaux, Pierre; Dessy, Chantal; Brouet, Agnès; Jordan, Bénédicte F.; Grégoire, Vincent; Gallez, Bernard; Balligand, Jean‐Luc; Féron, Olivier

doi:10.1096/fj.02-0487fje

Cited by 83 publications

(62 citation statements)

References 31 publications

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“…However, it is not uncommon to find mature blood vessels with smooth muscle layers and neural junctions inside slowly growing tumors (1). It was previously confirmed that these arterioles remain sensitive to vasomodulation under tumor co-option but also are subject to major adaptations to the tumor microenvironment (26,27). Here, we found that BoNT-A inhibits the release of noradrenaline, a major endogenous vasomodulator that is responsible for the maintained sympathetic vascular tone through activation of vascular smooth muscle a-adrenoceptors.…”

Section: Discussionmentioning

confidence: 98%

Botulinum toxin potentiates cancer radiotherapy and chemotherapy.

Ansiaux

Baudelet

Cron

et al. 2006

Clinical Cancer Research

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Purpose: Structural and functional abnormalities in the tumor vascular network are considered factors of resistance of solid tumors to cytotoxic treatments.To increase the efficacy of anticancer treatments, efforts must be made to find new strategies for transiently opening the tumor vascular bed to alleviate tumor hypoxia (source of resistance to radiotherapy) and improve the delivery of chemotherapeutic agents. We hypothesized that Botulinum neurotoxin type A (BoNT-A) could interfere with neurotransmitter release at the perivascular sympathetic varicosities, leading to inhibition of the neurogenic contractions of tumor vessels and therefore improving tumor perfusion and oxygenation. Experimental Design: To test this hypothesis, BoNT-A was injected locally into mouse tumors (fibrosarcoma FSaII, hepatocarcinoma transplantable liver tumor), and electron paramagnetic resonance oximetry was used to monitor pO 2 in vivo repeatedly for 4 days. Additionally, contrast-enhanced magnetic resonance imaging was used to measure tumor perfusion in vivo. Finally, isolated arteries were mounted in wire myograph to monitor specifically the neurogenic tone developed by arterioles that were co-opted by the surrounding growing tumor cells. Results: Using these tumor models, we showed that local administration of BoNT-A (two sites; dose, 29 units/kg) substantially increases tumor oxygenation and perfusion, leading to a substantial improvement in the tumor response to radiotherapy (20 Gy of 250-kV radiation) and chemotherapy (cyclophosphamide, 50 mg/kg). This observed therapeutic gain results from an opening of the tumor vascular bed by BoNT-A because we showed that BoNT-A could inhibit neurogenic tone in the tumor vasculature. Conclusions: The opening of the vascular bed induced by BoNT-A offers a way to significantly increase the response of tumors to radiotherapy and chemotherapy.

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Section: Discussionmentioning

confidence: 98%

Botulinum toxin potentiates cancer radiotherapy and chemotherapy.

Ansiaux

Baudelet

Cron

et al. 2006

Clinical Cancer Research

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“…Determination of cell oxygen consumption was carried out using EPR as previously reported (49). Briefly, 2 × 10 7 viable cells/ml were sealed in glass capillary tubes in the presence of 0.2 mM of the O2 sensor 4-oxo-2,2,6,6-tetramethylpiperidine-d-15 N-1-oxyl (CDN isotopes) and with CHC where indicated.…”

Section: Methodsmentioning

confidence: 99%

Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice

Sonveaux¹,

Végran²,

Schroeder³

et al. 2008

J. Clin. Invest.

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Tumors contain oxygenated and hypoxic regions, so the tumor cell population is heterogeneous. Hypoxic tumor cells primarily use glucose for glycolytic energy production and release lactic acid, creating a lactate gradient that mirrors the oxygen gradient in the tumor. By contrast, oxygenated tumor cells have been thought to primarily use glucose for oxidative energy production. Although lactate is generally considered a waste product, we now show that it is a prominent substrate that fuels the oxidative metabolism of oxygenated tumor cells. There is therefore a symbiosis in which glycolytic and oxidative tumor cells mutually regulate their access to energy metabolites. We identified monocarboxylate transporter 1 (MCT1) as the prominent path for lactate uptake by a human cervix squamous carcinoma cell line that preferentially utilized lactate for oxidative metabolism. Inhibiting MCT1 with α-cyano-4-hydroxycinnamate (CHC) or siRNA in these cells induced a switch from lactate-fueled respiration to glycolysis. A similar switch from lactate-fueled respiration to glycolysis by oxygenated tumor cells in both a mouse model of lung carcinoma and xenotransplanted human colorectal adenocarcinoma cells was observed after administration of CHC. This retarded tumor growth, as the hypoxic/glycolytic tumor cells died from glucose starvation, and rendered the remaining cells sensitive to irradiation. As MCT1 was found to be expressed by an array of primary human tumors, we suggest that MCT1 inhibition has clinical antitumor potential.

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“…The molecular basis of the increase in pO 2 was recently investigated in a study combining EPR oximetry and molecular biology: it turns out to be nitric oxide mediated by changes in expression of eNOS and caveolin. 235 Open square: RX þ insulin þ pre-treatment with L-NAME. See Jordan et al 66 for details.…”

Section: Radiotherapymentioning

confidence: 99%

Assessment of tumor oxygenation by electron paramagnetic resonance: principles and applications

2004

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This review paper attempts to provide an overview of the principles and techniques that are often termed electron paramagnetic resonance (EPR) oximetry. The paper discusses the potential of such methods and illustrates they have been successfully applied to measure oxygen tension, an essential parameter of the tumor microenvironment. To help the reader understand the motivation for carrying out these measurements, the importance of tumor hypoxia is first discussed: the basic issues of why a tumor is hypoxic, why these hypoxic microenvironments promote processes driving malignant progression and why hypoxia dramatically influences the response of tumors to cytotoxic treatments will be explained. The different methods that have been used to estimate the oxygenation in tumors will be reviewed. To introduce the basics of EPR oximetry, the specificity of in vivo EPR will be discussed by comparing this technique with NMR and MRI. The different types of paramagnetic oxygen sensors will be presented, as well as the methods for recording the information (EPR spectroscopy, EPR imaging, dynamic nuclear polarization). Several applications of EPR for characterizing tumor oxygenation will be illustrated, with a special emphasis on pharmacological interventions that modulate the tumor microenvironment. Finally, the challenges for transposing the method into the clinic will also be discussed.

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Modulation of the tumor vasculature functionality by ionizing radiation accounts for tumor radiosensitization and promotes gene delivery

Cited by 83 publications

References 31 publications

Botulinum toxin potentiates cancer radiotherapy and chemotherapy.

Botulinum toxin potentiates cancer radiotherapy and chemotherapy.

Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice

Assessment of tumor oxygenation by electron paramagnetic resonance: principles and applications

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