A Novel Model for Papillomavirus-Mediated Anal Disease and Cancer Using the Mouse Papillomavirus

Blaine-Sauer, Simon; Shin, Myeong-Kyun; Ward-Shaw, Ella; Lambert, Paul F.

doi:10.1128/mbio.01611-21

Cited by 17 publications

(40 citation statements)

References 74 publications

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“…Approximately 85-95% of anal SCC development in humans is due to HPV infection, while the remaining 5-15% of cases occur from an unknown etiology. [4] Although mice can be infected in the anal tract with the mouse papillomavirus MmuPV1 [14,22], the KC mice in this study did not develop anal SCC as a result of MmuPV1 or HPV infection. Immunocompetent mice, such as the KC mice, have been shown to rapidly clear MmuPV1 in the anal tract.…”

Section: Discussionmentioning

confidence: 58%

“…Representative anal SCC tumors in KC mice were evaluated for MmuPV1 viral transcripts using RNAScope and for MmuPV1 DNA using PCR. [14] No MmuPV1 signal was detected by RNAScope (Fig 3A), and no MmuPV1 DNA was detected within the anal tumors of the KC mice (Fig 3B). Together, these data show that the anal SCC in this study was not driven by papillomavirus infection.…”

Section: Anal Carcinogenesis In Kc Mice Was Not Due To Papillomavirus Infectionmentioning

confidence: 97%

“…MmuPV1 detection was performed using the RNAscope 2.5 HD Assay-Brown kit (Advanced Cell Diagnostics, Newark, CA; 322300) and probe to MmuPV1 E4 (473281) as previously described. [14] NSG mouse anal tissues that were infected with MmuPV1 or mock infected [14] were included as positive and negative controls, respectively.…”

Section: Rnascope In Situ Hybridizationmentioning

confidence: 99%

“…[15] DNA recovery from FFPE tissues and MmuPV1 detection by PCR DNA was isolated from two formalin fixed paraffin embedded slides per sample as previously described. [14] PCR was performed using primers specific to the MmuPV1 genome in the L1 region (F: 5'-GGAAGGAGAGAGCAAGTGTATG-3', R: 5'-GGGTTTGGTGTGTTGGTTTG-3') and analyzed via agarose gel.…”

Section: Estrogen Receptor Alpha Immunofluorescencementioning

confidence: 99%

“…Mouse papillomavirus (MmuPV1) has been associated with the development of anal disease and cancer in mice [14,22]. The animal facility where the mice are housed is routinely screened for MmuPV1 and it has not been detected in our colony, and immunocompetent C57Bl6 mice are known to rapidly clear MmuPV1 before tumor development occurs [22].…”

Section: Anal Carcinogenesis In Kc Mice Was Not Due To Papillomavirus Infectionmentioning

confidence: 99%

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Sex-dependent development of Kras-induced anal squamous cell carcinoma in mice

Walcheck

Turco

Blaine-Sauer

et al. 2021

Preprint

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Anal squamous cell carcinoma (SCC) will be diagnosed in an estimated 9,080 adults in the United States this year, and rates have been rising over the last several decades. Most people that develop anal SCC have associated human papillomavirus (HPV) infection (∼85-95%), with approximately 5-15% of anal SCC cases occurring in HPV-negative patients from unknown etiology. This study identified and characterized a Kras-driven, female sex hormone-dependent development of anal squamous cell carcinoma (SCC) in the LSL-KrasG12D ; Pdx1-Cre (KC) mouse model that is not dependent on papillomavirus infection. One hundred percent of female KC mice develop anal SCC, while no male KC mice develop tumors. Both male and female KC anal tissue express Pdx1 and Cre-recombinase mRNA, and the activated mutant KrasG12D gene. Although the driver gene mutation KrasG12D is present in anus of both sexes, only female KC mice develop Kras-mutant induced anal SCC. To understand the sex-dependent differences, KC male mice were castrated and KC female mice were ovariectomized. Castrated KC males displayed an unchanged phenotype with no anal tumor formation. In contrast, ovariectomized KC females demonstrated a marked reduction in anal SCC development, with only 15% developing anal SCC. Finally, exogenous administration of estrogen rescued the tumor development in ovariectomized KC female mice and induced tumor development in castrated KC males. These results confirm that the anal SCC is estrogen mediated. The delineation of the role of female sex hormones in mediating mutant Kras to drive anal SCC pathogenesis highlights a subtype of anal SCC that is independent of papillomavirus infection. These findings may have clinical applicability for the papillomavirus-negative subset of anal SCC patients that typically respond poorly to standard of care chemoradiation.

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Section: Discussionmentioning

confidence: 58%

Section: Anal Carcinogenesis In Kc Mice Was Not Due To Papillomavirus Infectionmentioning

confidence: 97%

Section: Rnascope In Situ Hybridizationmentioning

confidence: 99%

Section: Estrogen Receptor Alpha Immunofluorescencementioning

confidence: 99%

Section: Anal Carcinogenesis In Kc Mice Was Not Due To Papillomavirus Infectionmentioning

confidence: 99%

See 3 more Smart Citations

Sex-dependent development of Kras-induced anal squamous cell carcinoma in mice

Walcheck

Turco

Blaine-Sauer

et al. 2021

Preprint

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The Larynx is Protected from Secondary and Vertical Papillomavirus Infection in Immunocompetent Mice

King,

Rademacher,

Ward‐Shaw

et al. 2023

The Laryngoscope

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ObjectiveMouse papillomavirus MmuPV1 causes both primary and secondary infections of the larynx in immunocompromised mice. Understanding lateral and vertical transmission of papillomavirus to the larynx would benefit patients with recurrent respiratory papillomatosis (RRP). To test the hypothesis that the larynx is uniquely vulnerable to papillomavirus infection, and to further develop a mouse model of RRP, we assessed whether immunocompetent mice were vulnerable to secondary or vertical laryngeal infection with MmuPV1.MethodsLarynges were collected from 405 immunocompetent adult mice that were infected with MmuPV1 in the oropharynx, oral cavity, or anus, and 31 mouse pups born to immunocompetent females infected in the cervicovaginal tract. Larynges were analyzed via polymerase chain reaction (PCR) of lavage fluid or whole tissues for viral DNA, histopathology, and/or in situ hybridization for MmuPV1 transcripts.ResultsDespite some positive laryngeal lavage PCR screens, all laryngeal tissue PCR and histopathology results were negative for MmuPV1 DNA, transcripts, and disease. There was no evidence for lateral spread of MmuPV1 to the larynges of immunocompetent mice that were infected in the oral cavity, oropharynx, or anus. Pups born to infected mothers were negative for laryngeal MmuPV1 infection from birth through weaning age.ConclusionSecondary and vertical laryngeal MmuPV1 infections were not found in immunocompetent mice. Further work is necessary to explore immunologic control of laryngeal papillomavirus infection in a mouse model and to improve preclinical models of RRP.Level of EvidenceN/a Laryngoscope, 2023

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Small DNA tumor viruses and human cancer: Preclinical models of virus infection and disease

Spurgeon

2022

Tumour Virus Research

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A Novel Model for Papillomavirus-Mediated Anal Disease and Cancer Using the Mouse Papillomavirus

Cited by 17 publications

References 74 publications

Sex-dependent development of Kras-induced anal squamous cell carcinoma in mice

Sex-dependent development of Kras-induced anal squamous cell carcinoma in mice

The Larynx is Protected from Secondary and Vertical Papillomavirus Infection in Immunocompetent Mice

Small DNA tumor viruses and human cancer: Preclinical models of virus infection and disease

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