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β-HPV Infection Correlates with Early Stages of Carcinogenesis in Skin Tumors and Patient-Derived Xenografts from a Kidney Transplant Recipient Cohort

Many malignancies that occur in high excess in kidney transplant recipients (KTRs) are due to viruses that thrive in the setting of immunosuppression. Keratinocyte carcinoma (KC), the most frequently occurring cancer type in KTR, has been associated with skin infection by human papillomavirus (HPV)...

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Autores principales: Borgogna, Cinzia, Olivero, Carlotta, Lanfredini, Simone, Calati, Federica, De Andrea, Marco, Zavattaro, Elisa, Savoia, Paola, Trisolini, Elena, Boldorini, Renzo, Patel, Girish K., Gariglio, Marisa
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5807414/
https://www.ncbi.nlm.nih.gov/pubmed/29459852
http://dx.doi.org/10.3389/fmicb.2018.00117
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author Borgogna, Cinzia
Olivero, Carlotta
Lanfredini, Simone
Calati, Federica
De Andrea, Marco
Zavattaro, Elisa
Savoia, Paola
Trisolini, Elena
Boldorini, Renzo
Patel, Girish K.
Gariglio, Marisa
author_facet Borgogna, Cinzia
Olivero, Carlotta
Lanfredini, Simone
Calati, Federica
De Andrea, Marco
Zavattaro, Elisa
Savoia, Paola
Trisolini, Elena
Boldorini, Renzo
Patel, Girish K.
Gariglio, Marisa
author_sort Borgogna, Cinzia
collection PubMed
description Many malignancies that occur in high excess in kidney transplant recipients (KTRs) are due to viruses that thrive in the setting of immunosuppression. Keratinocyte carcinoma (KC), the most frequently occurring cancer type in KTR, has been associated with skin infection by human papillomavirus (HPV) from the beta genus. In this report, we extend our previous investigation aimed at identifying the presence of active β-HPV infection in skin tumors from KTRs through detection of viral protein expression. Using a combination of antibodies raised against the E4 and L1 proteins of the β-genotypes, we were able to visualize infection in five tumors [one keratoacanthoma (KA), three actinic keratoses (AKs), and one seborrheic keratoses (SKs)] that were all removed from two patients who had been both transplanted twice, had developed multiple KCs, and presented with a long history of immunosuppression (>30 years). These infected tissues displayed intraepidermal hyperplasia and increased expression of the ΔNp63 protein, which extended into the upper epithelial layers. In addition, using a xenograft model system in nude mice displaying a humanized stromal bed in the site of grafting, we successfully engrafted three AKs, two of which were derived from the aforementioned KTRs and displayed β-HPV infection in the original tumor. Of note, one AK-derived xenograft, along with its ensuing lymph node metastasis, was diagnosed as squamous cell carcinoma (SCC). In the latter, both β-HPV infection and ΔNp63 expression were no longer detectable. Although the overall success rate of engrafting was very low, the results of this study show for the first time that β-HPV(+) and ΔNp63(+) intraepidermal hyperplasia can indeed progress to an aggressive SCC able to metastasize. Consistent with a series of reports attributing a causative role of β-HPV at early stages of skin carcinogenesis through ΔNp63 induction and increased keratinocytes stemness, here we provide in vivo evidence that these events are also occurring in the affected skin of KTRs. Due to these β-HPV-driven molecular pathways, the nascent tumor cell is able to acquire a high enough number of carcinogenic insults that its proliferation and survival will eventually become independent of viral gene expression.
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spelling pubmed-58074142018-02-19 β-HPV Infection Correlates with Early Stages of Carcinogenesis in Skin Tumors and Patient-Derived Xenografts from a Kidney Transplant Recipient Cohort Borgogna, Cinzia Olivero, Carlotta Lanfredini, Simone Calati, Federica De Andrea, Marco Zavattaro, Elisa Savoia, Paola Trisolini, Elena Boldorini, Renzo Patel, Girish K. Gariglio, Marisa Front Microbiol Microbiology Many malignancies that occur in high excess in kidney transplant recipients (KTRs) are due to viruses that thrive in the setting of immunosuppression. Keratinocyte carcinoma (KC), the most frequently occurring cancer type in KTR, has been associated with skin infection by human papillomavirus (HPV) from the beta genus. In this report, we extend our previous investigation aimed at identifying the presence of active β-HPV infection in skin tumors from KTRs through detection of viral protein expression. Using a combination of antibodies raised against the E4 and L1 proteins of the β-genotypes, we were able to visualize infection in five tumors [one keratoacanthoma (KA), three actinic keratoses (AKs), and one seborrheic keratoses (SKs)] that were all removed from two patients who had been both transplanted twice, had developed multiple KCs, and presented with a long history of immunosuppression (>30 years). These infected tissues displayed intraepidermal hyperplasia and increased expression of the ΔNp63 protein, which extended into the upper epithelial layers. In addition, using a xenograft model system in nude mice displaying a humanized stromal bed in the site of grafting, we successfully engrafted three AKs, two of which were derived from the aforementioned KTRs and displayed β-HPV infection in the original tumor. Of note, one AK-derived xenograft, along with its ensuing lymph node metastasis, was diagnosed as squamous cell carcinoma (SCC). In the latter, both β-HPV infection and ΔNp63 expression were no longer detectable. Although the overall success rate of engrafting was very low, the results of this study show for the first time that β-HPV(+) and ΔNp63(+) intraepidermal hyperplasia can indeed progress to an aggressive SCC able to metastasize. Consistent with a series of reports attributing a causative role of β-HPV at early stages of skin carcinogenesis through ΔNp63 induction and increased keratinocytes stemness, here we provide in vivo evidence that these events are also occurring in the affected skin of KTRs. Due to these β-HPV-driven molecular pathways, the nascent tumor cell is able to acquire a high enough number of carcinogenic insults that its proliferation and survival will eventually become independent of viral gene expression. Frontiers Media S.A. 2018-02-05 /pmc/articles/PMC5807414/ /pubmed/29459852 http://dx.doi.org/10.3389/fmicb.2018.00117 Text en Copyright © 2018 Borgogna, Olivero, Lanfredini, Calati, De Andrea, Zavattaro, Savoia, Trisolini, Boldorini, Patel and Gariglio. 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 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 Microbiology
Borgogna, Cinzia
Olivero, Carlotta
Lanfredini, Simone
Calati, Federica
De Andrea, Marco
Zavattaro, Elisa
Savoia, Paola
Trisolini, Elena
Boldorini, Renzo
Patel, Girish K.
Gariglio, Marisa
β-HPV Infection Correlates with Early Stages of Carcinogenesis in Skin Tumors and Patient-Derived Xenografts from a Kidney Transplant Recipient Cohort
title β-HPV Infection Correlates with Early Stages of Carcinogenesis in Skin Tumors and Patient-Derived Xenografts from a Kidney Transplant Recipient Cohort
title_full β-HPV Infection Correlates with Early Stages of Carcinogenesis in Skin Tumors and Patient-Derived Xenografts from a Kidney Transplant Recipient Cohort
title_fullStr β-HPV Infection Correlates with Early Stages of Carcinogenesis in Skin Tumors and Patient-Derived Xenografts from a Kidney Transplant Recipient Cohort
title_full_unstemmed β-HPV Infection Correlates with Early Stages of Carcinogenesis in Skin Tumors and Patient-Derived Xenografts from a Kidney Transplant Recipient Cohort
title_short β-HPV Infection Correlates with Early Stages of Carcinogenesis in Skin Tumors and Patient-Derived Xenografts from a Kidney Transplant Recipient Cohort
title_sort β-hpv infection correlates with early stages of carcinogenesis in skin tumors and patient-derived xenografts from a kidney transplant recipient cohort
topic Microbiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5807414/
https://www.ncbi.nlm.nih.gov/pubmed/29459852
http://dx.doi.org/10.3389/fmicb.2018.00117
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