Heparan Sulfate Glycosaminoglycans Are Receptors Sufficient To Mediate the Initial Binding of Adenovirus Types 2 and 5

Dechecchi, Maria Cristina; Melotti, Paola; Bonizzato, Alberto; Santacatterina, Maria; Chilosi, Marco; Cabrini, Giulio

doi:10.1128/jvi.75.18.8772-8780.2001

Cited by 248 publications

(201 citation statements)

References 45 publications

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“…Many cell types, including endothelial cells, express heparan sulfates, which have been shown to be able to act as secondary adenoviral attachment receptors and can thus influence adenoviral tropism. 43 Furthermore, the a v b 3 /a v b 5 integrins that are required for internalization of the hybrid virus are highly overexpressed in tumor endothelial cells and a cationic nanoparticle coupled to an integrin a v b 3 -targeting ligand was recently used to deliver genes selectively to angiogenic blood vessels. 2 The selectivity of Ad5/35 targeting can also be markedly improved by locoregional administration as demonstrated here by using hepatic artery delivery.…”

Section: Endothelial Targeting By a Hybrid Virusmentioning

confidence: 99%

Efficient infection of tumor endothelial cells by a capsid-modified adenovirus

et al. 2005

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Targeted antiangiogenic gene therapy is an attractive approach to treat metastatic cancer. However, the relative paucity of the receptors of the commonly used adenovirus serotype 5 in endothelial cells as compared with liver cells undermines the use of this vector for targeting the endothelial cells in tumors. To overcome this problem, we analyzed the ability of a hybrid Ad5/35 virus, where the serotype 5 fiber has been replaced with the fiber from serotype 35, to target tumor vasculature. Infection of human umbilical vein endothelial cells (HUVECs) with Ad5/35 at MOI 120 infected 100% of cells. In contrast, infection with Ad5 at the same MOI infected only 10% HUVECs. Ad5/35 was even more effective in transducing human aortic endothelial cells (HAECs), as infection with Ad5/35 at MOI 3.6 was sufficient to transduce 95% of cells. Gene expression analyses demonstrated that infection of HUVECs and HAECs with Ad5/35 resulted in between 1 and 3 orders of magnitude higher gene expression than infection with Ad5. Furthermore, various liver-derived cells were less infectable with Ad5/35 than Ad5, indicating a favorable toxicity profile for this virus. In a rat colon carcinoma tumor model, Ad5 was located mainly in the liver parenchyma after hepatic artery administration. In contrast, Ad5/35 was found only in the angiogenesis-rich border region of the tumor. Double immunostaining revealed that Ad5/35 colocalized with CD31 and Flk-1 positive endothelial cells. These results indicate that Ad5/ 35 may be useful in anticancer strategies targeting tumor endothelial cells.

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Section: Endothelial Targeting By a Hybrid Virusmentioning

confidence: 99%

Efficient infection of tumor endothelial cells by a capsid-modified adenovirus

et al. 2005

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“…More recently, it was shown that heparan sulfate glycosaminoglycans can be receptors that mediate binding of adenovirus types 2 and 5. 6 In many bladder cancer cells, adenoviral gene transfer is impaired. Li et al reported that several human bladder cancer cell lines lacked expression of CAR, although the genomic sequences for the gene were intact.…”

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confidence: 99%

Histone deacetylase inhibitors upregulate expression of the coxsackie adenovirus receptor (CAR) preferentially in bladder cancer cells

et al. 2004

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Studies on bladder cancer cell lines have shown that low adenoviral (Ad) infectivity is associated with low-level coxsackie adenovirus receptor (CAR) expression. Recently, we and others demonstrated a tumor stage-and grade-dependent downregulation of CAR expression in a large series of clinical bladder cancer specimens. Here, we demonstrate adenoviral gene transfer can be markedly enhanced in bladder cancer cells by upregulation of CAR through the use of certain differentiating agents, including the histone deacetylase inhibitors (HDACI) trichostatin A and sodium phenylbutyrate. CAR upregulation to supraphysiologic levels was demonstrated by quantitative rt-PCR, Western blotting, flow cytometry and adenoviral gene transfer. Normal urothelial cells and CAR-positive papilloma cells (RT4) failed to demonstrate upregulation under the same conditions. Upregulation was cell cycle dependent, associated with increased adenoviral gene transfer and persisted for at least 7 days after a single treatment. Such upregulation, however, appears to be tumor cell specific, as other CAR-negative cell lines failed to demonstrate enhanced adenoviral gene transfer with the same treatments. These results provide a rational basis for combining HDACI therapy with gene therapy as a method of augmenting activity in bladder cancer, but this strategy may not be universally applicable to other cell types.

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“…18,19 Other receptors have been described for Ad5, although the nature of their interaction(s) with the Ad5 virion is unclear and their roles appear limited. These receptors include heparin sulfate glycosaminoglycans, 20,21 class I major histocompatability complex 22 and vascular cell adhesion molecule-1. 23 Following receptor binding, receptor-mediated endocytosis of the virion is effected by interaction of penton base Arg-Gly-Asp (RGD) motifs with cellular integrins, including avb3 and avb5, 24 avb1, 25 a 3 b1 and a 5 b1.…”

Section: Adenovirus Structurementioning

confidence: 99%