First mouse model for HPV ‐related penile cancer

Authors and Afilliations:
Beatriz Medeiros-Fonseca^a, Verónica F. Mestre^a, Diogo Estêvão^b,c,d, Diego F. Sanchez^e, Sofía Cañete-Portillo^e, María José Fernández-Nestosa^e, Fátima Casaca^f, Sandra Silva^f, Haissa Brito^g, Ana Félix^h,i, Rui Medeiros^b,c,d,j,k, Bruno Colaço^a,l, Paula A. Oliveira^a,m, Margarida MSM Bastosⁿ, Peter S. Nelson^o,p, Funda Vakar-Lopez^o, Isabel Gaivão^q, Luciane Brito^g, Carlos Lopes^f,r,s, Antonio L. Cubilla^e, Rui M. Gil da Costa^a,b,g,m,n*

^a CITAB, Universidade de Trás-os-Montes e Alto Douro, UTAD, Vila Real, Portugal;

^b Grupo de Oncologia Molecular e Patologia Viral, CI-IPOP, IPO-Porto, Porto, Portugal;

^c Faculdade de Medicina, Universidade do Porto, Porto, Portugal;

^d Serviço de Virologia, IPO- Porto, Porto, Portugal;

^e Instituto de Patología e Investigación and Universidad Nacional de Asunción, Asunción, Paraguay;

^f Botelho Moniz Análises Clínicas (BMAC), Porto, Portugal;

^g Biobanco de Tumores e DNA do Maranhão, PPGSAD, Universidade Federal do Maranhão (UFMA), São Luís, Maranhão, Brasil;

^h Nova Medical School, Universidade Nova de Lisboa, Lisboa, Portugal;

ⁱ Serviço de Anatomia Patológica, IPO-Lisboa, Lisboa, Portugal;

^j Liga Portuguesa Contra o Cancro — Núcleo Regional do Norte, Porto, Portugal;

^k CEBIMED, Faculdade de Ciências da Saúde, Universidade Fernando Pessoa, Porto, Portugal;

^l Departamento de Zootecnia, Universidade de Trás-os-Montes e Alto Douro, UTAD, Vila Real; 

^m Departamento de Ciências Veterinárias, Universidade de Trás-os-Montes e Alto Douro, UTAD, Vila Real, Portugal; Portugal;

ⁿ LEPABE, Faculdade de Engenharia, Universidade do Porto, Porto, Portugal;

^o Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA;

^p University of Washington, Seattle, WA, USA;

^q CECAV and Department of Genetics and Biotechnology, University of Trás-os-Montes and Alto Douro (UTAD), Vila Real, Portugal

^r Grupo de Patologia Experimental, Ci-IPOP, IPO-Porto, Porto, Portugal;

^s Departamento de Patologia e Imunologia Molecular, ICBAS, Universidade do Porto, Portugal.

Abstract: 

Penile cancer is an under‐studied disease that occurs more commonly in developing countries and 30–50% of cases show high‐risk human papillomavirus (HPV) infection. Therapeutic advances are slow, largely due to the absence of animal models for translational research. Here, we report the first mouse model for HPV‐related penile cancer. Ten‐week‐old mice expressing all the HPV16 early genes under control of the cytokeratin 14 (Krt14 ) gene promoter and matched wild‐type controls were exposed topically to dimethylbenz(o)anthracene (DMBA) or vehicle for 16 weeks. At 30 weeks of age mice were sacrificed for histological analysis. Expression of Ki67, cytokeratin 14 and of the HPV16 oncogenes E6 and E7 was confirmed using immunohistochemistry and quantitative PCR, respectively. HPV16‐transgenic mice developed intraepithelial lesions including condylomas and penile intraepithelial neoplasia (PeIN). Lesions expressed cytokeratin 14 and the HPV16 oncogenes E6 and E7 and showed deregulated cell proliferation, demonstrated by Ki67‐positive supra‐basal cells. HPV16‐transgenic mice exposed to DMBA showed increased penile intraepithelial neoplasia (PeIN) incidence and squamous cell carcinoma. Malignant lesions showed varied histological features closely resembling those of HPV‐associated human penile cancers. Wild‐type mice showed no malignant or pre‐malignant lesions even when exposed to DMBA. These observations provide the first experimental evidence to support the etiological role of HPV16 in penile carcinogenesis. Importantly, this is the first mouse model to recapitulate key steps of HPV‐related penile carcinogenesis and to reproduce morphological and molecular features of human penile cancer, providing a unique in vivo tool for studying its biology and advancing basic and translational research.

Journal: Journal of Pathology

Link: https://onlinelibrary.wiley.com/doi/abs/10.1002/path.5475