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Bacillus anthracis Protective Antigen Shows High Specificity for a UV Induced Mouse Model of Cutaneous Squamous Cell Carcinoma

Squamous cell carcinoma (SCC) accounts for the majority of non-melanoma skin cancer related deaths, particularly in immunosuppressed persons. Identification of biomarkers that could be used to identify or treat SCC would be of significant benefit. The anthrax toxin receptors, Tumor Endothelial Marke...

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Autores principales: Crawford, Theo, Fletcher, Nicholas, Veitch, Margaret, Gonzalez Cruz, Jazmina L., Pett, Nicola, Brereton, Ian, Wells, James W., Mobli, Mehdi, Tesiram, Yasvir
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6379334/
https://www.ncbi.nlm.nih.gov/pubmed/30809524
http://dx.doi.org/10.3389/fmed.2019.00022
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author Crawford, Theo
Fletcher, Nicholas
Veitch, Margaret
Gonzalez Cruz, Jazmina L.
Pett, Nicola
Brereton, Ian
Wells, James W.
Mobli, Mehdi
Tesiram, Yasvir
author_facet Crawford, Theo
Fletcher, Nicholas
Veitch, Margaret
Gonzalez Cruz, Jazmina L.
Pett, Nicola
Brereton, Ian
Wells, James W.
Mobli, Mehdi
Tesiram, Yasvir
author_sort Crawford, Theo
collection PubMed
description Squamous cell carcinoma (SCC) accounts for the majority of non-melanoma skin cancer related deaths, particularly in immunosuppressed persons. Identification of biomarkers that could be used to identify or treat SCC would be of significant benefit. The anthrax toxin receptors, Tumor Endothelial Marker 8 (TEM8) and Capillary Morphogenesis Gene 2 (CMG2), are endothelial receptors involved in extracellular matrix homeostasis and angiogenesis that are selectively upregulated on numerous tumors. One method of targeting these receptors is Protective Antigen (PA), a protein produced by B. anthracis that mediates binding and translocation of anthrax toxins into cells. PA targeted toxins have been demonstrated to selectively inhibit tumor growth and angiogenesis, but tumor selectivity of PA is currently unknown. In this work fluorescently labeled PA was shown to maintain receptor dependent binding and internalization in vitro. Utilizing a human papillomavirus transgenic mouse model that develops cutaneous SCC in response to ultraviolet irradiation we identified tumor uptake of PA in vivo. The intravenously administered PA resulted in tumor specific localization, with exclusive tumor detection 24 h post injection. Ex vivo analysis identified significantly higher fluorescence in the tumor compared to adjacent healthy tissue and major clearance organs, demonstrating low non-specific uptake and rapid clearance. While both TEM8 and CMG2 were observed to be overexpressed in SCC tumor sections compared to control skin, the intravenously administered PA was primarily co-localized with TEM8. These results suggest that PA could be systemically administered for rapid identification of cutaneous SCC, with potential for further therapeutic development.
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spelling pubmed-63793342019-02-26 Bacillus anthracis Protective Antigen Shows High Specificity for a UV Induced Mouse Model of Cutaneous Squamous Cell Carcinoma Crawford, Theo Fletcher, Nicholas Veitch, Margaret Gonzalez Cruz, Jazmina L. Pett, Nicola Brereton, Ian Wells, James W. Mobli, Mehdi Tesiram, Yasvir Front Med (Lausanne) Medicine Squamous cell carcinoma (SCC) accounts for the majority of non-melanoma skin cancer related deaths, particularly in immunosuppressed persons. Identification of biomarkers that could be used to identify or treat SCC would be of significant benefit. The anthrax toxin receptors, Tumor Endothelial Marker 8 (TEM8) and Capillary Morphogenesis Gene 2 (CMG2), are endothelial receptors involved in extracellular matrix homeostasis and angiogenesis that are selectively upregulated on numerous tumors. One method of targeting these receptors is Protective Antigen (PA), a protein produced by B. anthracis that mediates binding and translocation of anthrax toxins into cells. PA targeted toxins have been demonstrated to selectively inhibit tumor growth and angiogenesis, but tumor selectivity of PA is currently unknown. In this work fluorescently labeled PA was shown to maintain receptor dependent binding and internalization in vitro. Utilizing a human papillomavirus transgenic mouse model that develops cutaneous SCC in response to ultraviolet irradiation we identified tumor uptake of PA in vivo. The intravenously administered PA resulted in tumor specific localization, with exclusive tumor detection 24 h post injection. Ex vivo analysis identified significantly higher fluorescence in the tumor compared to adjacent healthy tissue and major clearance organs, demonstrating low non-specific uptake and rapid clearance. While both TEM8 and CMG2 were observed to be overexpressed in SCC tumor sections compared to control skin, the intravenously administered PA was primarily co-localized with TEM8. These results suggest that PA could be systemically administered for rapid identification of cutaneous SCC, with potential for further therapeutic development. Frontiers Media S.A. 2019-02-12 /pmc/articles/PMC6379334/ /pubmed/30809524 http://dx.doi.org/10.3389/fmed.2019.00022 Text en Copyright © 2019 Crawford, Fletcher, Veitch, Gonzalez Cruz, Pett, Brereton, Wells, Mobli and Tesiram. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Medicine
Crawford, Theo
Fletcher, Nicholas
Veitch, Margaret
Gonzalez Cruz, Jazmina L.
Pett, Nicola
Brereton, Ian
Wells, James W.
Mobli, Mehdi
Tesiram, Yasvir
Bacillus anthracis Protective Antigen Shows High Specificity for a UV Induced Mouse Model of Cutaneous Squamous Cell Carcinoma
title Bacillus anthracis Protective Antigen Shows High Specificity for a UV Induced Mouse Model of Cutaneous Squamous Cell Carcinoma
title_full Bacillus anthracis Protective Antigen Shows High Specificity for a UV Induced Mouse Model of Cutaneous Squamous Cell Carcinoma
title_fullStr Bacillus anthracis Protective Antigen Shows High Specificity for a UV Induced Mouse Model of Cutaneous Squamous Cell Carcinoma
title_full_unstemmed Bacillus anthracis Protective Antigen Shows High Specificity for a UV Induced Mouse Model of Cutaneous Squamous Cell Carcinoma
title_short Bacillus anthracis Protective Antigen Shows High Specificity for a UV Induced Mouse Model of Cutaneous Squamous Cell Carcinoma
title_sort bacillus anthracis protective antigen shows high specificity for a uv induced mouse model of cutaneous squamous cell carcinoma
topic Medicine
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6379334/
https://www.ncbi.nlm.nih.gov/pubmed/30809524
http://dx.doi.org/10.3389/fmed.2019.00022
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