Irradiation promotes Akt-targeting therapeutic gene delivery to the tumor vasculature

Sonveaux, Pierre; Frérart, Françoise; Bouzin, Caroline; Brouet, Agnès; DeWever, Julie; Jordan, Bénédicte F.; Gallez, Bernard; Feron, Olivier

doi:10.1016/j.ijrobp.2006.11.031

Cited by 20 publications

(10 citation statements)

References 16 publications

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“…Thyroid lobes were identified and delineated based on anatomical images and blood flow in area of interest was quantified from colored histogram pixels. 23 During measurements, mice were placed on a heating pad (37°C).…”

Section: Laser-doppler Blood Flow Measurementmentioning

confidence: 99%

Iodine Deficiency Induces a Thyroid Stimulating Hormone-Independent Early Phase of Microvascular Reshaping in the Thyroid

Gérard

Poncin

Caetano

et al. 2008

The American Journal of Pathology

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Expansion of the thyroid microvasculature is the earliest event during goiter formation, always occurring before thyrocyte proliferation; however, the precise mechanisms governing this physiological angiogenesis are not well understood. Using reverse transcriptase-polymerase chain reaction and immunohistochemistry to measure gene expression and laser Doppler to measure blood flow in an animal model of goitrogenesis, we show that thyroid angiogenesis occurred into two successive phases. The first phase lasted a week and involved vascular activation; this process was thyroid-stimulating hormone (TSH)-independent and was directly triggered by expression of vascular endothelial growth factor (VEGF) by thyrocytes as soon as the intracellular iodine content decreased. This early reaction was followed by an increase in thyroid blood flow and endothelial cell proliferation, both of which were mediated by VEGF and inhibited by VEGF-blocking antibodies. The second, angiogenic, phase was TSH-dependent and was activated as TSH levels increased. This phase involved substantial up-regulation of the major proangiogenic factors VEGF-A, fibroblast growth factor-2, angiopoietin 1, and NG2 as well as their receptors Flk-1/VEGFR2, Flt-1/ VEGFR1, and Tie-2. In conclusion, goiter-associated angiogenesis promotes thyroid adaptation to iodine deficiency. Specifically, as soon as the iodine supply is limited, thyrocytes produce proangiogenic signals that elicit early TSH-independent microvascular activation; if iodine deficiency persists, TSH plasma levels increase, triggering the second angiogenic phase that supports thyrocyte proliferation.

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Section: Laser-doppler Blood Flow Measurementmentioning

confidence: 99%

Iodine Deficiency Induces a Thyroid Stimulating Hormone-Independent Early Phase of Microvascular Reshaping in the Thyroid

Gérard

Poncin

Caetano

et al. 2008

The American Journal of Pathology

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“…29,30 In brief, B16 melanoma cells were injected at the vicinity of the saphenous arteriole in one of the rear legs. The arteriole and the downstream branches (diameters between 100 and 200 m) were progressively trapped in the growing tumor mass.…”

Section: Sirna Transfection and Immunoblottingmentioning

confidence: 99%

Caveolin-1 Is Critical for the Maturation of Tumor Blood Vessels through the Regulation of Both Endothelial Tube Formation and Mural Cell Recruitment

DeWever

Frérart

Bouzin

et al. 2007

The American Journal of Pathology

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“…Nevertheless, the precision of radiation treatment presents an opportunity to utilize tumor-specific promoters and inducible promoter systems. Furthermore, ionizing radiation has also been recently shown to enhance vascular tone through the induction of nitric oxide production by endothelial cells, leading to facilitated delivery and enhanced transgene expression (31). We hypothesize that approaches designed to express radiation-inducible gene therapy products will be synergistic, thereby improving tumor eradication while limiting toxicity to the normal tissue.…”

Section: Discussionmentioning

confidence: 99%

Radiation-inducible silencing of uPA and uPAR in vitro and in vivo in meningioma

Rao¹

2010

Int J Oncol

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Abstract. Stereospecific radiation treatment offers a distinct opportunity for temporal and spatial regulation of gene expression at tumor sites by means of inducible promoters. To this end, a plasmid, pCArG-U2, was constructed by incorporating nine CArG elements (in tandem) of EGR1 gene upstream to uPA and uPAR siRNA oligonucleotides in a pCi-neo vector. Radiation-induced siRNA expression was detected in a meningioma cell line (IOMM-Lee). Immunoblotting and RT-PCR analyses confirmed downregulation of uPA and uPAR. A similar effect was observed in transfected cells followed by H 2 O 2 treatment. Moreover, pre-treatment of transfected cells with N-acetyl L-cysteine blocked the silencing of uPA and uPAR, which further confirmed the oxidative damage-mediated downregulation. Cell proliferation assays and Western blot analysis for apoptotic molecules confirmed cell death in a radiation-inducible fashion. Migration and Matrigel invasion assays also revealed a marked decrease in migration and invasion. Immunocytochemistry showed a marked decrease in uPA and uPAR levels in transfected and irradiated cells. H&E staining revealed a decrease in the preestablished tumor volume among the animals treated with pCArG-U2 and radiation. Immunohistochemistry of the brain sections established with intracranial tumors also revealed a marked decrease in uPA and uPAR in a radiation-inducible fashion. Taken together, our data suggest pCArG-U2 as a suitable candidate for radiation-inducible gene therapy.

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Irradiation promotes Akt-targeting therapeutic gene delivery to the tumor vasculature

Cited by 20 publications

References 16 publications

Iodine Deficiency Induces a Thyroid Stimulating Hormone-Independent Early Phase of Microvascular Reshaping in the Thyroid

Iodine Deficiency Induces a Thyroid Stimulating Hormone-Independent Early Phase of Microvascular Reshaping in the Thyroid

Caveolin-1 Is Critical for the Maturation of Tumor Blood Vessels through the Regulation of Both Endothelial Tube Formation and Mural Cell Recruitment

Radiation-inducible silencing of uPA and uPAR in vitro and in vivo in meningioma

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