Beatriz Medeiros‐Fonseca

Instituto Português de Oncologia Francisco Gentil

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Paula A. Oliveira

University of Trás-os-Montes and Alto Douro

Rui M. Gil da Costa

Universidade Federal do Maranhão

Rui Medeiros

Portuguese League Against Epilepsy

Margarida M. S. M. Bastos

Universidade do Porto

Maria João Pires

University of Trás-os-Montes and Alto Douro

Verónica F. Mestre

University of Trás-os-Montes and Alto Douro

Ana I. Faustino‐Rocha

University of Évora

Haissa O. Brito

Universidade Federal do Maranhão

Bruno Colaço

University of Trás-os-Montes and Alto Douro

Helena Vala

Polytechnic Institute of Viseu

Cooperative Institutions

University of Trás-os-Montes and Alto Douro

Universidade do Porto

Instituto Português de Oncologia Francisco Gentil

IPO Porto

Association for the Development of Douro Viticulture

Polytechnic Institute of Bragança

University of Lisbon

Universidade Federal do Maranhão

University of Aveiro

Rede de Química e Tecnologia

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Corrigendum: Pteridium spp. and Bovine Papillomavirus: Partners in Cancer

Frontiers in Veterinary Science (2022)

Beatriz Medeiros‐Fonseca Ana Lúcia Abreu‐Silva Rui Medeiros Paula A. Oliveira Rui M. Gil da Costa

[This corrects the article DOI: 10.3389/fvets.2021.758720.].

Bovine papillomavirus

10.3389/fvets.2022.860838

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Citations (1)

Pathological Features of Benign and Malignant Epithelial Abnormalities of the Penis in Transgenic Mice. An Experimental Model to Study HPV-Related Penile Carcinogenesis. Evaluation of 87 Cases

Sofía Cañete‐Portillo Beatriz Medeiros‐Fonseca Verónica F. Mestre Diogo Estêvão Diego F. Sánchez

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HPV16 induces penile intraepithelial neoplasia and squamous cell carcinoma in transgenic mice: first mouse model for HPV‐related penile cancer

The Journal of Pathology (2020)

Beatriz Medeiros‐Fonseca Verónica F. Mestre Diogo Estêvão Diego F. Sánchez Sofía Cañete‐Portillo

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(a)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 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. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

10.1002/path.5475

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Human Papillomavirus 16-Transgenic Mice as a Model to Study Cancer-Associated Cachexia

International Journal of Molecular Sciences (2020)

Sara Peixoto da Silva Joana Santos Verónica F. Mestre Beatriz Medeiros‐Fonseca Paula A. Oliveira

Cancer cachexia is a multifactorial syndrome characterized by general inflammation, weight loss and muscle wasting, partly mediated by ubiquitin ligases such as atrogin-1, encoded by Fbxo32. Cancers induced by high-risk human papillomavirus (HPV) include anogenital cancers and some head-and-neck cancers and are often associated with cachexia. The aim of this study was to assess the presence of cancer cachexia in HPV16-transgenic mice with or without exposure to the chemical carcinogen 7,12-dimethylbenz(a)anthracene (DMBA). Male mice expressing the HPV16 early region under the control of the cytokeratin 14 gene promoter (K14-HPV16; HPV+) and matched wild-type mice (HPV−) received DMBA (or vehicle) topically over 17 weeks of the experiment. Food intake and body weight were assessed weekly. The gastrocnemius weights and Fbxo32 expression levels were quantified at sacrifice time. HPV-16-associated lesions in different anatomic regions were classified histologically. Although unexposed HPV+ mice showed higher food intake than wild-type matched group (p < 0.01), they presented lower body weights (p < 0.05). This body weight trend was more pronounced when comparing DMBA-exposed groups (p < 0.01). The same pattern was observed in the gastrocnemius weights (between the unexposed groups: p < 0.05; between the exposed groups: p < 0.001). Importantly, DMBA reduced body and gastrocnemius weights (p < 0.01) when comparing the HPV+ groups. Moreover, the Fbxo32 gene was overexpressed in DMBA-exposed HPV+ compared to control mice (p < 0.05). These results show that K14-HPV16 mice closely reproduce the anatomic and molecular changes associated with cancer cachexia and may be a good model for preclinical studies concerning the pathogenesis of this syndrome.

Wasting Syndrome

10.3390/ijms21145020

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HPV infection as a risk factor for atherosclerosis: A connecting hypothesis

Medical Hypotheses (2020)

Daniel Ruan Alves Reis Beatriz Medeiros‐Fonseca Jadna Maryane Pereira Costa Clariano Pires de Oliveira Neto Rui M. Gil da Costa

Atheroma

Pathogenesis

Extracellular Vesicles

10.1016/j.mehy.2020.109979

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Exploring the therapeutic potential of Quercus ilex acorn extract in papillomavirus-induced lesions

Veterinary World (2024)

Beatriz Medeiros‐Fonseca Ana I. Faustino‐Rocha Maria João Pires Maria João Neuparth Helena Vala

Papillomaviruses (PVs) infections have been documented in numerous animal species across different regions worldwide. They often exert significant impacts on animal health and livestock production. Scientists have studied natural products for over half a century due to their diverse chemical composition, acknowledging their value in fighting cancer. Acorns (Quercus ilex) are believed to have several unexplored pharmacological properties. This study aimed to evaluate the in vivo safety and cancer chemopreventive activity of an infusion extract of Q. ilex in a transgenic mouse model of human PV (HPV)-16, which developed squamous cell carcinomas through a multistep process driven by HPV16 oncogenes. Q. ilex extract was prepared by heating in water at 90°C and then characterized by mass spectrometry. Phenolic compounds from this extract were administered in drinking water to female mice in three different concentrations (0.03, 0.06, and 0.09 g/mL) over a period of 28 consecutive days. Six groups (n = 6) were formed for this study: group 1 (G1, wildtype [WT], water), group 2 (G2, HPV, water), group 3 (G3, WT, 0.09 g/mL), group 4 (G4, HPV, 0.03 g/mL), group 5 (G5, HPV, 0.06 g/mL), and group 6 (G6, HPV, 0.09 g/mL). Throughout the experiment, humane endpoints, body weight, food intake, and water consumption were recorded weekly. Following the experimental period, all mice were sacrificed, and blood, internal organs, and skin samples were collected. Blood was used to measure glucose and microhematocrit and later biochemical parameters, such as creatinine, urea, albumin, alanine aminotransferase, and total proteins. Histological analysis was performed on skin and organ samples. The administration of Q. ilex extract resulted in a statistically significant increase in relative organ weight among HPV transgenic animals, indicating adaptive biological response to the tested concentrations. Moreover, a reduction in characteristic skin lesions was observed in animals treated with the 0.06 and 0.09 g/mL extract. These results provide a favorable chemopreventive profile for Q. ilex extract at concentrations of 0.06 and 0.09 g/mL. This study highlights the potential of Q. ilex extract as a safe and effective therapeutic strategy against HPV16-associated lesions in transgenic mouse models. The limitation of our study was the durability of transgenic animals. As a more sensitive species, we must always be careful with the durability of the test. We intend to study concentrations of 0.06 and 0.09 g/mL for longer to further investigate their possible effects.

Acorn

Bovine papillomavirus

10.14202/vetworld.2024.2644-2658

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Differential Incidence of Tongue Base Cancer in Male and Female HPV16-Transgenic Mice: Role of Female Sex Hormone Receptors

Pathogens (2021)

Clariano Pires de Oliveira Neto Beatriz Medeiros‐Fonseca Diogo Estêvão Verónica F. Mestre Natália R. Costa

A growing proportion of oropharyngeal squamous cell carcinomas (OPSCC) are associated with infection by high-risk human papillomavirus (HPV). For reasons that remain largely unknown, HPV+OPSCC is significantly more common in men than in women. This study aims to determine the incidence of OPSCC in male and female HPV16-transgenic mice and to explore the role of female sex hormone receptors in the sexual predisposition for HPV+ OPSCC. The tongues of 30-weeks-old HPV16-transgenic male (n = 80) and female (n = 90) and matched wild-type male (n = 10) and female (n = 10) FVB/n mice were screened histologically for intraepithelial and invasive lesions in 2017 at the Centre for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), Portugal. Expression of estrogen receptors alpha (ERα) and beta (ERβ), progesterone receptors (PR) and matrix metalloproteinase 2 (MMP2) was studied immunohistochemically. Collagen remodeling was studied using picrosirius red. Female mice showed robust ERα and ERβ expression in intraepithelial and invasive lesions, which was accompanied by strong MMP2 expression and marked collagen remodeling. Male mice showed minimal ERα, ERβ and MMP2 expression and unaltered collagen patterns. These results confirm the association of HPV16 with tongue base cancer in both sexes. The higher cancer incidence in female versus male mice contrasts with data from OPSCC patients and is associated with enhanced ER expression via MMP2 upregulation.

MMP2

Progesterone receptor

10.3390/pathogens10101224

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Citations (3)