scholarly journals Adenovirus Receptor Expression in Cancer and Its Multifaceted Role in Oncolytic Adenovirus Therapy

2020 ◽  
Vol 21 (18) ◽  
pp. 6828
Author(s):  
Lobke C.M. Hensen ◽  
Rob C. Hoeben ◽  
Selas T.F. Bots
Keyword(s):  
Tumor Cells ◽  
Human Adenovirus ◽  
Adenovirus Type ◽  
Oncolytic Adenovirus ◽  
Receptor Expression ◽  
Future Directions ◽  
Viral Spread ◽  
Before And After ◽  
Tumor Types ◽  
Adenovirus Receptor

Oncolytic adenovirus therapy is believed to be a promising way to treat cancer patients. To be able to target tumor cells with an oncolytic adenovirus, expression of the adenovirus receptor on the tumor cell is essential. Different adenovirus types bind to different receptors on the cell, of which the expression can vary between tumor types. Pre-existing neutralizing immunity to human adenovirus species C type 5 (HAdV-C5) has hampered its therapeutic efficacy in clinical trials, hence several adenoviral vectors from different species are currently being developed as a means to evade pre-existing immunity. Therefore, knowledge on the expression of appropriate adenovirus receptors on tumor cells is important. This could aid in determining which tumor types would benefit most from treatment with a certain oncolytic adenovirus type. This review provides an overview of the known receptors for human adenoviruses and how their expression on tumor cells might be differentially regulated compared to healthy tissue, before and after standardized anticancer treatments. Mechanisms behind the up- or downregulation of adenovirus receptor expression are discussed, which could be used to find new targets for combination therapy to enhance the efficacy of oncolytic adenovirus therapy. Additionally, the utility of the adenovirus receptors in oncolytic virotherapy is examined, including their role in viral spread, which might even surpass their function as primary entry receptors. Finally, future directions are offered regarding the selection of adenovirus types to be used in oncolytic adenovirus therapy in the fight against cancer.

The endosomal epsilon-coatomer protein is involved in human adenovirus type 5 internalisation

2002 ◽  
Vol 50 (4) ◽  
pp. 481-489 ◽  
Author(s):  
Cs. Jeney ◽  
Boglárka Banizs ◽  
Orsolya Dobay ◽  
Keyword(s):  
Chinese Hamster ◽  
Human Adenovirus ◽  
Adenovirus Type ◽  
Inhibitory Effect ◽  
Bafilomycin A1 ◽  
Cho Cell ◽  
Coxsackie Adenovirus Receptor ◽  
Downstream Effector ◽  
Adenovirus Receptor ◽  
Adenovirus Type 5

The effects of bafilomycin A1 and of the reduced level of endosomal epsilon-COP (coatomer protein) on the infectivity of human adenovirus type 5 were investigated in Coxsackie adenovirus receptor- (CAR-) transfected Chinese hamster ovary (CHO) cells. The endosomal proton pump inhibitor bafilomycin A1 was able to cause only partial inhibition. Using ldlF cells (an epsilon-COP thermosensitive mutant CHO cell line) the reduction of epsilon-COP level also had partial inhibitory effect. Based on these results and comparing them to existing models of the adenovirus entry, we propose a refined model in which there are two pathways of adenoviral entry: the first one involves the epsilon-COP as the downstream effector of the acidification and can be blocked by bafilomycin A1 and the second one is a pH-independent pathway.

scholarly journals Chimpanzee adenovirus CV-68 adapted as a gene delivery vector interacts with the coxsackievirus and adenovirus receptor

2002 ◽  
Vol 83 (1) ◽  
pp. 151-155 ◽  
Author(s):  
Christopher J. Cohen ◽  
Zhi Quan Xiang ◽  
Guang-Ping Gao ◽  
Hildegund C. J. Ertl ◽  
James M. Wilson ◽  
...  
Keyword(s):  
Gene Delivery ◽  
Cho Cells ◽  
Human Adenovirus ◽  
Adenovirus Type ◽  
Soluble Form ◽  
Delivery Vector ◽  
Coxsackievirus And Adenovirus Receptor ◽  
Adenovirus Receptor ◽  
Adenovirus Type 5 ◽  
Dependent Mechanism

A replication-defective form of chimpanzee adenovirus type 68 (C68) has been developed to circumvent problems posed by widespread preexisting immunity to common human adenovirus vectors. To investigate the determinants of C68 tropism, its interaction with the coxsackievirus and adenovirus receptor (CAR) was studied. Although CHO cells were resistant to transduction by C68 as well as by adenovirus type 5 (Ad5), CHO cells expressing either human or murine CAR were transduced readily. C68 transduction, like Ad5 transduction, was blocked when cells were exposed to anti-CAR antibody or when virus was exposed to a soluble form of the CAR extracellular domain. These results indicate that gene delivery by C68 occurs by a CAR-dependent mechanism.

scholarly journals Replication-Defective Vector Based on a Chimpanzee Adenovirus

2001 ◽  
Vol 75 (23) ◽  
pp. 11603-11613 ◽  
Author(s):  
Steven F. Farina ◽  
Guang-ping Gao ◽  
Z. Q. Xiang ◽  
John J. Rux ◽  
Roger M. Burnett ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Human Adenovirus ◽  
Adenovirus Type ◽  
Open Reading Frames ◽  
Hypervariable Regions ◽  
293 Cells ◽  
Coxsackievirus And Adenovirus Receptor ◽  
Cross Neutralization ◽  
Adenovirus Receptor ◽  
Adenovirus Type 5

ABSTRACT An adenovirus previously isolated from a mesenteric lymph node from a chimpanzee was fully sequenced and found to be similar in overall structure to human adenoviruses. The genome of this virus, called C68, is 36,521 bp in length and is most similar to subgroup E of human adenovirus, with 90% identity in most adenovirus type 4 open reading frames that have been sequenced. Substantial differences in the hexon hypervariable regions were noted between C68 and other known adenoviruses, including adenovirus type 4. Neutralizing antibodies to C68 were highly prevalent in sera from a population of chimpanzees, while sera from humans and rhesus monkeys failed to neutralize C68. Furthermore, infection with C68 was not neutralized from sera of mice immunized with human adenovirus serotypes 2, 4, 5, 7, and 12. A replication-defective version of C68 was created by replacing the E1a and E1b genes with a minigene cassette; this vector was efficiently transcomplemented by the E1 region of human adenovirus type 5. C68 vector transduced a number of human and murine cell lines. This nonhuman adenoviral vector is sufficiently similar to human serotypes to allow growth in 293 cells and transduction of cells expressing the coxsackievirus and adenovirus receptor. As it is dissimilar in regions such as the hexon hypervariable domains, C68 vector avoids significant cross-neutralization by sera directed against human serotypes.

Characteristics of Human Adenovirus Type 12 Induced Hamster Tumor Cells in Tissue Culture.

1964 ◽  
Vol 116 (3) ◽  
pp. 563-568 ◽  
Author(s):  
K. I. ◽  
G. Van Hoosier ◽  
L. Samper ◽  
G. Taylor ◽  
J. J. Trentin
Keyword(s):  
Tissue Culture ◽  
Tumor Cells ◽  
Human Adenovirus ◽  
Adenovirus Type ◽  
Human Adenovirus Type 12

scholarly journals Studies on the Interaction of Tumor-Derived HD5 Alpha Defensins with Adenoviruses and Implications for Oncolytic Adenovirus Therapy

2017 ◽  
Vol 91 (6) ◽  
Author(s):  
Charles Vragniau ◽  
Jens-Martin Hübner ◽  
Peter Beidler ◽  
Sucheol Gil ◽  
Kamola Saydaminova ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Human Adenovirus ◽  
Oncolytic Adenovirus ◽  
Endosomal Escape ◽  
Capsid Proteins ◽  
Lateral Spread ◽  
Host Responses ◽  
Progeny Virus ◽  
Viral Spread ◽  
Epithelial Junctions

ABSTRACT Defensins are small antimicrobial peptides capable of neutralizing human adenovirus (HAdV) in vitro by binding capsid proteins and blocking endosomal escape of virus. In humans, the alpha defensin HD5 is produced by specialized epithelial cells of the gastrointestinal and genito-urinary tracts. Here, we demonstrate, using patient biopsy specimens, that HD5 is also expressed as an active, secreted peptide by epithelial ovarian and lung cancer cells in situ. This finding prompted us to study the role of HD5 in infection and spread of replication-competent, oncolytic HAdV type 3 (HAdV3). HAdV3 produces large amounts of penton-dodecahedra (PtDd), virus-like particles, during replication. We have previously shown that PtDd are involved in opening epithelial junctions, thus facilitating lateral spread of de novo-produced virions. Here, we describe a second function of PtDd, namely, the blocking of HD5. A central tool to prove that viral PtDd neutralize HD5 and support spread of progeny virus was an HAdV3 mutant virus in which formation of PtDd was disabled (mut-Ad3GFP, where GFP is green fluorescent protein). We demonstrated that viral spread of mut-Ad3GFP was blocked by synthetic HD5 whereas that of the wild-type (wt) form (wt-Ad3GFP) was only minimally impacted. In human colon cancer Caco-2 cells, induction of cellular HD5 expression by fibroblast growth factor 9 (FGF9) significantly inhibited viral spread and progeny virus production of mut-Ad3GFP but not of wt-Ad3GFP. Finally, the ectopic expression of HD5 in tumor cells diminished the in vivo oncolytic activity of mut-Ad3GFP but not of wt-Ad3GFP. These data suggest a new mechanism of HAdV3 to overcome innate antiviral host responses. Our study has implications for oncolytic adenovirus therapy. IMPORTANCE Previously, it has been reported that human defensin HD5 inactivates specific human adenoviruses by binding to capsid proteins and blocking endosomal escape of virus. The central new findings described in our manuscript are the following: (i) the discovery of a new mechanism used by human adenovirus serotype 3 to overcome innate antiviral host responses that is based on the capacity of HAdV3 to produce subviral penton-dodecahedral particles that act as decoys for HD5, thus preventing the inactivation of virus progeny produced upon replication; (ii) the demonstration that ectopic HD5 expression in cancer cells decreases the oncolytic efficacy of a serotype 5-based adenovirus vector; and (iii) the demonstration that epithelial ovarian and lung cancers express HD5. The study improves our understanding of how adenoviruses establish infection in epithelial tissues and has implications for cancer therapy with oncolytic adenoviruses.

scholarly journals Adenovirus Type 11 Uses CD46 as a Cellular Receptor

2003 ◽  
Vol 77 (17) ◽  
pp. 9183-9191 ◽  
Author(s):  
Anna Segerman ◽  
John P. Atkinson ◽  
Marko Marttila ◽  
Veronica Dennerquist ◽  
Göran Wadell ◽  
...  
Keyword(s):  
Cho Cells ◽  
Chinese Hamster ◽  
Human Adenovirus ◽  
Adenovirus Type ◽  
Host Cells ◽  
Cellular Receptor ◽  
Transfected Cells ◽  
Coxsackie Adenovirus Receptor ◽  
Adenovirus Receptor

ABSTRACT The 51 human adenovirus serotypes are divided into six species (A to F). Many adenoviruses use the coxsackie-adenovirus receptor (CAR) for attachment to host cells in vitro. Species B adenoviruses do not compete with CAR-binding serotypes for binding to host cells, and it has been suggested that species B adenoviruses use a receptor other than CAR. Species B adenoviruses mainly cause disease in the respiratory tract, the eyes, and in the urinary tract. Here we demonstrate that adenovirus type 11 (Ad11; of species B) binds to Chinese hamster ovary (CHO) cells transfected with CD46 (membrane cofactor protein)-cDNA at least 10 times more strongly than to CHO cells transfected with cDNAs encoding CAR or CD55 (decay accelerating factor). Nonpermissive CHO cells were rendered permissive to Ad11 infection upon transfection with CD46-cDNA. Soluble Ad11 fiber knob but not Ad7 or Ad5 knob inhibited binding of Ad11 virions to CD46-transfected cells, and anti-CD46 antibodies inhibited both binding of and infection by Ad11. From these results we conclude that CD46 is a cellular receptor for Ad11.

Sensitivity of Human Oral Tumor Cells to Human Adenovirus

1979 ◽  
Vol 58 (8) ◽  
pp. 1815-1823 ◽  
Author(s):  
Gary F. Guest ◽  
Wendell D. Winters
Keyword(s):  
Squamous Cell Carcinoma ◽  
Oral Squamous Cell Carcinoma ◽  
Tumor Cells ◽  
Human Adenovirus ◽  
Adenovirus Type ◽  
Normal Lung ◽  
Early Passage ◽  
Oral Tumor ◽  
Oral Tumors

Human cells in early passage cultures of benign oral tumors, normal oral tissues, normal lung tissues and, especially, in long-term established oral carcinoma cultures were highly susceptible to infection by human adenovirus types 5, 21, and 31. In contrast, replication of each adenovirus type was markedly limited in inoculated cells of newly-established oral squamous cell carcinoma cultures.

scholarly journals Induction of p53-Independent Apoptosis by the Adenovirus E4orf4 Protein Requires Binding to the Bα Subunit of Protein Phosphatase 2A

2000 ◽  
Vol 74 (17) ◽  
pp. 7869-7877 ◽  
Author(s):  
Richard C. Marcellus ◽  
Helen Chan ◽  
Denis Paquette ◽  
Sarah Thirlwell ◽  
Dominique Boivin ◽  
...  
Keyword(s):  
Cell Death ◽  
Protein Phosphatase ◽  
Protein Phosphatase 2A ◽  
Point Mutations ◽  
Human Adenovirus ◽  
Adenovirus Type ◽  
Cell Killing ◽  
Productive Infection ◽  
Viral Spread ◽  
Phosphatase 2A

ABSTRACT Previous studies have indicated that the E4orf4 protein of human adenovirus type 2 (Ad2) induces p53-independent apoptosis. We believe that this process may play a role in cell death and viral spread at the final stages of productive infection. E4orf4 may also be of therapeutic value in treating some diseases, including cancer, through its ability to induce apoptosis when expressed individually. The only previously identified biochemical function of E4orf4 is its ability to associate with the Bα subunit of protein phosphatase 2A (PP2A). We have used a genetic approach to determine the role of such interactions in E4orf4-induced cell death. E4orf4 deletion mutants were of only limited value, as all were highly defective. We found that E4orf4 proteins from most if not all adenovirus serotypes induced cell death, and thus point mutations were introduced that converted the majority of highly conserved residues to alanines. Such mutants were used to correlate Bα-subunit binding, association with PP2A activity, and cell killing following the transfection of appropriate cDNAs into p53-null H1299 or C33A cells. The results indicated that binding of the Bα subunit is essential for induction of cell death, as every mutant that failed to bind efficiently was totally defective for cell killing. This class of mutations (class I) largely involved residues between amino acids 51 and 89. Almost all E4orf4 mutant proteins that associated with PP2A killed cancer cells at high levels; however, several mutants that associated with significant levels of PP2A were defective for killing (class II). Thus, binding of E4orf4 to PP2A is essential for induction of p53-independent apoptosis, but E4orf4 may possess one or more additional functions required for cell killing.

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