The Role of αvβ6 Integrin Binding Molecules in the Diagnosis and Treatment of Cancer

2020 ◽  
Vol 24 (21) ◽  
pp. 2393-2411
Author(s):  
Mauricio Urquiza ◽  
Valentina Guevara ◽  
Erika Diaz-Sana ◽  
Felipe Mora
Keyword(s):  
Tumor Imaging ◽  
Intraoperative Imaging ◽  
Foot And Mouth Disease ◽  
Tumor Detection ◽  
Binding Peptide ◽  
Normal Tissues ◽  
Mouth Disease Virus ◽  
Binding Peptides ◽  
Αvβ6 Integrin

Peptidic and non-peptidic αvβ6 integrin-binding molecules have been used in the clinic for detection and treatment of tumors expressing αvβ6 integrin, because this protein is expressed in malignant epithelial cells of the oral cavity, pancreas, breast, ovary, colon and stomach carcinomas but it is not expressed in healthy adult tissue except during wound healing and inflammation. This review focuses on the landscape of αvβ6 integrinbinding molecules and their use in cancer treatment and detection, and discusses recent designs for tumor detection, treatment, and immunotherapy. In the last ten years, several reviews about the αvβ6 integrin have been published but no one assessed the landscape of the αvβ6 integrin-binding molecules and their role in cancer detection and treatment. Firstly, this review describes the role of the αvβ6 integrin in normal tissues, how the expression of this protein is correlated with cancer severity and its role in cancer development. Taking into account the potential of αvβ6 integrin-binding molecules in detection and treatment of specific tumors, special attention is given to several high-affinity αvβ6 integrin-binding peptides used for tumor imaging; particularly, the αvβ6-binding peptide NAVPNLRGDLQVLAQKVART [A20FMDV2], derived from the foot and mouth disease virus. This peptide labeled with either 18F, 111In or with 68Ga has been used for PET imaging of αvβ6 integrin-positive tumors. Moreover, αvβ6 integrin-binding peptides have been used for photoacoustic and fluorescence imaging and could potentially be used in clinical application in cancer diagnosis and intraoperative imaging of αvβ6-integrin positive tumors. Additionally, non-peptidic αvβ6-binding molecules have been designed and used in the clinic for the detection and treatment of αvβ6-expressing tumors. Anti-αvβ6 integrin antibodies are another useful tool for selective identification and treatment of αvβ6 (+) tumors. The utility of these αvβ6 integrin-binding molecules as a tool for tumor detection and treatment is discussed, considering specificity, sensitivity and serum stability. Another use of the αvβ6 integrin-binding peptides is to modify the Ad5 cell tropism for inducing oncolytic activity of αvβ6-integrin positive tumor cells by expressing A20FMDV2 peptide within the fiber knob protein (Ad5NULL-A20). The newly designed oncolytic Ad5NULL-A20 virotherapy is promising for local and systemic targeting of αvβ6-overexpressing cancers. Finally, new evidence has emerged, indicating that chimeric antigen receptor (CAR) containing the αvβ6 integrin- binding peptide on top of CD28+CD3 endodomain displays a potent therapeutic activity in a diverse repertoire of solid tumor models.

scholarly journals Foot-and-Mouth Disease Virus Viroporin 2B Antagonizes RIG-I-Mediated Antiviral Effects by Inhibition of Its Protein Expression

2016 ◽  
Vol 90 (24) ◽  
pp. 11106-11121 ◽  
Author(s):  
Zixiang Zhu ◽  
Guoqing Wang ◽  
Fan Yang ◽  
Weijun Cao ◽  
Ruoqing Mao ◽  
...  
Keyword(s):  
Protein Expression ◽  
Foot And Mouth Disease ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Eukaryotic Translation ◽  
Mouth Disease Virus ◽  
2B Protein ◽  
Eukaryotic Translation Initiation ◽  
Cellular Apoptosis

ABSTRACTThe role of retinoic acid-inducible gene I (RIG-I) in foot-and-mouth disease virus (FMDV)-infected cells remains unknown. Here, we showed that RIG-I inhibits FMDV replication in host cells. FMDV infection increased the transcription of RIG-I, while it decreased RIG-I protein expression. A detailed analysis revealed that FMDV leader proteinase (Lpro), as well as 3C proteinase (3Cpro) and 2B protein, decreased RIG-I protein expression. Lproand 3Cproare viral proteinases that can cleave various host proteins and are responsible for several of the viral polyprotein cleavages. However, for the first time, we observed 2B-induced reduction of host protein. Further studies showed that 2B-mediated reduction of RIG-I is specific to FMDV, but not other picornaviruses, including encephalomyocarditis virus, enterovirus 71, and coxsackievirus A16. Moreover, we found the decreased protein level of RIG-I is independent of the cleavage of eukaryotic translation initiation factor 4 gamma, the induction of cellular apoptosis, or the association of proteasome, lysosome, and caspase pathways. A direct interaction was observed between RIG-I and 2B. The carboxyl-terminal amino acids 105 to 114 and amino acids 135 to 144 of 2B were essential for the reduction of RIG-I, while residues 105 to 114 were required for the interaction. These data suggest the antiviral role of RIG-I against FMDV and a novel antagonistic mechanism of FMDV that is mediated by 2B protein.IMPORTANCEThis study demonstrated that RIG-I could suppress FMDV replication during virus infection. FMDV infection increased the transcriptional expression of RIG-I, while it decreased RIG-I protein expression. FMDV 2B protein interacted with RIG-I and induced reduction of RIG-I. 2B-induced reduction of RIG-I was independent of the induction of the cleavage of eukaryotic translation initiation factor 4 gamma or cellular apoptosis. In addition, proteasome, lysosome, and caspase pathways were not involved in this process. This study provides new insight into the immune evasion mediated by FMDV and identifies 2B as an antagonistic factor for FMDV to evade the antiviral response.

scholarly journals Cellular DNAJA3, a Novel VP1-Interacting Protein, Inhibits Foot-and-Mouth Disease Virus Replication by Inducing Lysosomal Degradation of VP1 and Attenuating Its Antagonistic Role in the Beta Interferon Signaling Pathway

2019 ◽  
Vol 93 (13) ◽  
Author(s):  
Wei Zhang ◽  
Fan Yang ◽  
Zixiang Zhu ◽  
Yang Yang ◽  
Zhifang Wang ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Disease Virus ◽  
Nuclear Translocation ◽  
Foot And Mouth Disease ◽  
Lysosomal Degradation ◽  
Beta Interferon ◽  
Mouth Disease Virus ◽  
Antiviral Role ◽  
Fmdv Replication

ABSTRACTDnaJ heat shock protein family (Hsp40) member A3 (DNAJA3) plays an important role in viral infections. However, the role of DNAJA3 in replication of foot-and-mouth-disease virus (FMDV) remains unknown. In this study, DNAJA3, a novel binding partner of VP1, was identified using yeast two-hybrid screening. The DNAJA3-VP1 interaction was further confirmed by coimmunoprecipitation and colocalization in FMDV-infected cells. The J domain of DNAJA3 (amino acids 1 to 168) and the lysine at position 208 (K208) of VP1 were shown to be critical for the DNAJA3-VP1 interaction. Overexpression of DNAJA3 dramatically dampened FMDV replication, whereas loss of function of DNAJA3 elicited opposing effects against FMDV replication. Mechanistical study demonstrated that K208 of VP1 was critical for reducing virus titer caused by DNAJA3 using K208A mutant virus. DNAJA3 induced lysosomal degradation of VP1 by interacting with LC3 to enhance the activation of lysosomal pathway. Meanwhile, we discovered that VP1 suppressed the beta interferon (IFN-β) signaling pathway by inhibiting the phosphorylation, dimerization, and nuclear translocation of IRF3. This inhibitory effect was considerably boosted in DNAJA3-knockout cells. In contrast, overexpression of DNAJA3 markedly attenuated VP1-mediated suppression on the IFN-β signaling pathway. Poly(I⋅C)-induced phosphorylation of IRF3 was also decreased in DNAJA3-knockout cells compared to that in the DNAJA3-WT cells. In conclusion, our study described a novel role for DNAJA3 in the host’s antiviral response by inducing the lysosomal degradation of VP1 and attenuating the VP1-induced suppressive effect on the IFN-β signaling pathway.IMPORTANCEThis study pioneeringly determined the antiviral role of DNAJA3 in FMDV. DNAJA3 was found to interact with FMDV VP1 and trigger its degradation via the lysosomal pathway. In addition, this study is also the first to clarify the mechanism by which VP1 suppressed IFN-β signaling pathway by inhibiting the phosphorylation, dimerization, and nuclear translocation of IRF3. Moreover, DNAJA3 significantly abrogated VP1-induced inhibitive effect on the IFN-β signaling pathway. These data suggested that DNAJA3 plays an important antiviral role against FMDV by both degrading VP1 and restoring of IFN-β signaling pathway.

scholarly journals Modeling the role of carrier and mobile herds on foot-and-mouth disease virus endemicity in the Far North Region of Cameroon

Epidemics ◽  
2019 ◽  
Vol 29 ◽  
pp. 100355
Author(s):  
Patrick M Schnell ◽  
Yibo Shao ◽  
Laura W Pomeroy ◽  
Joseph H Tien ◽  
Mark Moritz ◽  
...  
Keyword(s):  
Disease Virus ◽  
Foot And Mouth Disease ◽  
Mouth Disease ◽  
Far North ◽  
Mouth Disease Virus ◽  
Foot And Mouth

scholarly journals The role of African buffalo in the epidemiology of foot-and-mouth disease in sympatric cattle and buffalo populations in Kenya

2018 ◽  
Author(s):  
George Omondi ◽  
Francis Gakuya ◽  
Jonathan Arzt ◽  
Abraham Sangula ◽  
Ethan Hartwig ◽  
...  
Keyword(s):  
Foot And Mouth Disease ◽  
Mouth Disease ◽  
Eastern Africa ◽  
African Buffalo ◽  
High Seroprevalence ◽  
Social Segregation ◽  
Mouth Disease Virus ◽  
Foot And Mouth ◽  
Advance Knowledge

Transmission of pathogens at wildlife-livestock interfaces poses a substantial challenge to the control of infectious diseases, including for foot-and-mouth disease virus (FMDV) in African buffalo and cattle. The extent to which buffalo play a role in the epidemiology of this virus in livestock populations remains unresolved in East Africa. Here, we show that FMDV occurs at high seroprevalence (~77%) in Kenyan buffalo. In addition, we recovered 80 FMDV VP1 sequences from buffalo, all of which were serotype SAT1 and SAT2, and seventeen FMDV VP1 sequences from cattle, which included serotypes A, O, SAT1 and SAT2. Notably, six individual buffalo were co-infected with both SAT1 and SAT2 serotypes. Our results suggest that transmission of FMDV between sympatric cattle and buffalo is rare. However, viruses from FMDV outbreaks in cattle elsewhere in Kenya were caused by viruses closely related to SAT1 and SAT2 viruses found in buffalo. We also show that the circulation of FMDV in buffalo is influenced by fine-scale geographic features, such as rivers, and that social segregation amongst sympatric herds may limit between-herd transmission. Our results significantly advance knowledge of the ecology and molecular epidemiology of FMDV at wildlife-livestock interfaces in Eastern Africa, and will help to inform the design of control and surveillance strategies for this disease in the region.

scholarly journals Potential role of wildlife in the USA in the event of a foot-and-mouth disease virus incursion

2019 ◽  
Vol 184 (24) ◽  
pp. 741-741 ◽  
Author(s):  
Vienna R Brown ◽  
Sarah N Bevins
Keyword(s):  
Disease Virus ◽  
Potential Role ◽  
Animal Feed ◽  
Foot And Mouth Disease ◽  
Mouth Disease ◽  
Animal Products ◽  
Mouth Disease Virus ◽  
Foot And Mouth ◽  
The Usa

Foot-and-mouth disease (FMD) is caused by foot-and-mouth disease virus (FMDV) which affects domestic and wild cloven-hoofed species. The FMD-free status of the USA and the tremendous economic impact of a virus incursion motivated the development of this evaluation of the potential role of wildlife in the event of a virus introduction. Additionally, this manuscript contains a summary of US vulnerabilities for viral incursion and persistence which focuses specifically on the possible role of wildlife. The legal movement of susceptible live animals, animal products, by-products and animal feed containing animal products pose a risk of virus introduction and spread. Additionally, the illegal movement of FMD-susceptible animals and their products and an act of bioterrorism present additional routes where FMDV could be introduced to the USA. Therefore, robust surveillance and rapid diagnostics in the face of a possible introduction are essential for detecting and controlling FMD as quickly as possible. Wildlife species and feral pigs present an added complexity in the case of FMDV introduction as they are typically not closely monitored or managed and there are significant logistical concerns pertaining to disease surveillance and control in these populations. Recommendations highlight the need to address existing knowledge gaps relative to the potential role of wildlife in FMDV introduction events.

scholarly journals Engineering a Single-Chain Fv Antibody to αvβ6 Integrin Using the Specificity-Determining Loop of a Foot-and-Mouth Disease Virus

2008 ◽  
Vol 382 (2) ◽  
pp. 385-401 ◽  
Author(s):  
Heide Kogelberg ◽  
Berend Tolner ◽  
Gareth J. Thomas ◽  
Danielle Di Cara ◽  
Shane Minogue ◽  
...  
Keyword(s):  
Disease Virus ◽  
Foot And Mouth Disease ◽  
Mouth Disease ◽  
Single Chain ◽  
Single Chain Fv ◽  
Mouth Disease Virus ◽  
Foot And Mouth ◽  
Fv Antibody ◽  
Αvβ6 Integrin ◽  
Single Chain Fv Antibody
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