CAR- or αv integrin-binding ablated adenovirus vectors, but not fiber-modified vectors containing RGD peptide, do not change the systemic gene transfer properties in mice

Mizuguchi, Hiroyuki; Koizumi, Noriko; Hosono, Tetsuji; Ishii‐Watabe, Akiko; Uchida, Eiji; Utoguchi, Naoki; Watanabe, Yoshihisa; Hayakawa, Tetsuo

doi:10.1038/sj.gt.3301701

Cited by 98 publications

(75 citation statements)

References 34 publications

(61 reference statements)

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“…33 However, it has been reported that adenovirus infection is possible without ␣V integrinvirus interaction. [45][46][47] Here, adenovirus was found to be an effective vector to transfer genes into melanoma cells. Based on staining for ␤-galactosidase activity, all cell lines including the ␣V-negative WM-115 cells could be successfully infected with RAdlacZ control virus.…”

Section: Decrease In Cell Surface Expression Of ␣V Integrin Promotes mentioning

confidence: 99%

αV integrin promotes in vitro and in vivo survival of cells in metastatic melanoma

Koistinen

Ahonen

Kähäri

et al. 2004

Intl Journal of Cancer

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The expression of integrin ␣V subunit on 4 melanomaderived cell lines (A2058, SK-mel-5, WM-115 and WM-266-4) was analyzed. WM-115 cells, which originate from a primary tumor, were negative, whereas all 3 metastasis-derived lines had high levels of ␣V. To study ␣V integrins in the survival of melanoma cells, we developed a novel strategy that is exempt from extracellular inhibitors of ligand binding, which can activate integrin signaling and have integrin-independent effects on apoptosis. A recombinant adenovirus was used to transfer cDNA coding for a single-chain intracellular anti-␣V integrin antibody into the melanoma cells. Anti-␣V integrin adenovirus effectively inhibited the cell surface expression of ␣V integrins. In cell culture experiments, the depletion of ␣V integrins detached cells from extracellular matrix and induced apoptosis. Moreover, it prevented WM-266-4 cells from forming tumors in severe combined immunodeficiency mice but it could not prevent the growth of tumors that were formed by ␣V-negative WM-115 cells. Our results indicate that in primary melanomas there are cells that survive without ␣V integrins, whereas during the progression of disease cells can develop a dependency on these receptors. Furthermore, the data oppose the possibility that in melanoma cells apoptosis could occur due to direct activation of caspases by ligand-free ␣V integrins on the cell surface. © 2004 Wiley-Liss, Inc. Key words: integrin; melanoma; intracellular single-chain antibody; adenovirusThe ␣V integrin can form a heterodimeric adhesion receptor with 5 different integrin ␤ subunits, namely, ␤1, ␤3, ␤5, ␤6 and ␤8. These receptors bind to various extracellular matrix proteins such as fibronectin, vitronectin and osteopontin. In adult individuals, relatively few cell types express significant amounts of ␣V, and genetic data from mouse experiments indicate that most organs develop properly even in the absence of all ␣V integrins. 1 In human melanoma, the expression of ␣V together with its partner ␤3 has been connected to tumor growth, disease progression and poor prognosis. 2-8 Additionally, ␣V integrins may play a role in the progression of ovarian carcinoma, cervical tumors, breast cancer and squamous cell carcinoma, 9 -13 and it has also been connected to the formation of bone metastasis in prostate cancer. 14 Based on the analysis of knockout mice, it is obvious that in vivo, most normal cell types can survive without ␣V integrins. 1 In cancer cells, the inhibition of ␣V function has been associated with apoptosis, and appropriate ligand binding may be essential for the function of ␣V integrins during cancer progression. For example, the secretion of osteopontin, a ligand for ␣V␤3, by melanocytes has been reported to promote antiapoptotic signaling. 15 Furthermore, after disruption of cell-matrix contacts, unbound ␣V integrins may promote apoptosis in human melanoma and human intestinal carcinoma cells. 16,17 It has also been reported that in T24-E carcinoma cells, death is stimulated by attachment to the extrac...

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Section: Decrease In Cell Surface Expression Of ␣V Integrin Promotes mentioning

confidence: 99%

αV integrin promotes in vitro and in vivo survival of cells in metastatic melanoma

Koistinen

Ahonen

Kähäri

et al. 2004

Intl Journal of Cancer

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“…delivery. [4][5][6] Several studies have documented the role of blood coagulation factors in mediating liver gene transfer in vivo and the mechanism underlying Ad5 hepatocyte transduction. [7][8][9][10][11][12] We demonstrated that coagulation factor X (FX) binds to the hexon protein of Ad5 at high affinity (B2 nM) and that this interaction mediates hepatocyte transduction following i.v.…”

mentioning

confidence: 99%

“…delivery. 4,5,19 FX-binding-ablated Ad5 vectors have shown substantially reduced hepatocyte transduction in mice and rats following i.v. delivery.…”

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confidence: 99%

Coagulation factor X mediates adenovirus type 5 liver gene transfer in non-human primates (Microcebus murinus)

et al. 2011

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Coagulation factor X (FX)-binding ablated adenovirus type 5 (Ad5) vectors have been genetically engineered to ablate the interaction with FX, resulting in substantially reduced hepatocyte transduction following intravenous administration in rodents. Here, we quantify viral genomes and gene transfer mediated by Ad5 and FX-binding-ablated Ad5 vectors in non-human primates. Ad5 vectors accumulated in and mediated gene transfer predominantly to the liver, whereas FX-binding-ablated vectors primarily targeted the spleen but showed negligible liver gene transfer. In addition, we show that Ad5 binding to hepatocytes may be due to the presence of heparan sulfate proteoglycans (HSPGs) on the cell membrane. Therefore, the Ad5-FX-HSPG pathway mediating liver gene transfer in rodents is also the mechanism underlying Ad5 hepatocyte transduction in Microcebus murinus.

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“…Strategies to inhibit hepatocyte and/or liver Kupffer cell uptake by ablating CAR-or integrin-binding motifs in the Ad capsid have been largely unsuccessful, however, indicating that native Ad tropism determinants contribute little to vector hepatotropism in vivo. [40][41][42][43][44] These data notwithstanding, work by several groups has implicated the fiber protein as a major structural determinant of liver tropism in vivo (reviewed by Nicklin et al 45 ). For example, shortening of the native fiber shaft domain of the Ad5 fiber 46 or replacement of the Ad5 shaft with the short Ad3 shaft domain 47 was shown to attenuate liver uptake in vivo following intravenous delivery.…”

Section: Transductional Targeting Of Admentioning

confidence: 99%

Transductional targeting of adenovirus vectors for gene therapy

2006

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CAR- or αv integrin-binding ablated adenovirus vectors, but not fiber-modified vectors containing RGD peptide, do not change the systemic gene transfer properties in mice

Abstract: Targeted gene delivery to the tissue of interest by recombinant adenovirus (Ad)

Cited by 98 publications

References 34 publications

αV integrin promotes in vitro and in vivo survival of cells in metastatic melanoma

αV integrin promotes in vitro and in vivo survival of cells in metastatic melanoma

Coagulation factor X mediates adenovirus type 5 liver gene transfer in non-human primates (Microcebus murinus)

Transductional targeting of adenovirus vectors for gene therapy

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