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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Experimental Models for Studying HPV-Positive and HPV-Negative Penile Cancer: New Tools for An Old Disease

Cancers (2021)

Beatriz Medeiros‐Fonseca Antonio L. Cubilla Haissa O. Brito Tânia Martins Rui Medeiros

Penile cancer is an uncommon malignancy that occurs most frequently in developing countries. Two pathways for penile carcinogenesis are currently recognized: one driven by human papillomavirus (HPV) infection and another HPV-independent route, associated with chronic inflammation. Progress on the clinical management of this disease has been slow, partly due to the lack of preclinical models for translational research. However, exciting recent developments are changing this landscape, with new in vitro and in vivo models becoming available. These include mouse models for HPV+ and HPV− penile cancer and multiple cell lines representing HPV− lesions. The present review addresses these new advances, summarizing available models, comparing their characteristics and potential uses and discussing areas that require further improvement. Recent breakthroughs achieved using these models are also discussed, particularly those developments pertaining to HPV-driven cancer. Two key aspects that still require improvement are the establishment of cell lines that can represent HPV+ penile carcinomas and the development of mouse models to study metastatic disease. Overall, the growing array of in vitro and in vivo models for penile cancer provides new and useful tools for researchers in the field and is expected to accelerate pre-clinical research on this disease.

Translational Research

10.3390/cancers13030460

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Citations (10)

Ozone therapy prevents the onset of dysplasia in HPV16-transgenic mice—A pre-clinical efficacy and safety analysis

Biomedicine & Pharmacotherapy (2018)

Cecília Peirone Verónica F. Mestre Beatriz Medeiros‐Fonseca Bruno Colaço Maria João Pires

10.1016/j.biopha.2018.05.018

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Laurus nobilis(laurel) aqueous leaf extract's toxicological and anti-tumor activities in HPV16-transgenic mice

Food & Function (2018)

Beatriz Medeiros‐Fonseca Verónica F. Mestre Bruno Colaço Maria João Pires Tânia Martins

Cancers induced by HPV remain a significant public health threat, fueling the study of new therapies.

Laurus nobilis

Aqueous extract

10.1039/c8fo00783g

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Citations (22)

Aloysia citrodora extract as a chemopreventive agent against HPV16-induced lesions: findings from K14-HPV16 mice

Exploration of Medicine (2024)

Beatriz Medeiros‐Fonseca Ana I. Faustino‐Rocha Jéssica Silva Mónica G. Silva Maria João Pires

Aim: Aloysia citrodora has a long history of traditional use in treating various ailments. This study evaluated the in vivo chemopreventive efficacy and systemic toxicity of an extract of A. citrodora in a transgenic mouse model of HPV16 (human papillomavirus type 16)-induced cancer. Methods: The experiment involved six groups (n = 5): group 1 (G1, wild-type (WT), water), group 2 (G2, HPV, water), group 3 (G3, WT, 0.013 g/mL), group 4 (G4, HPV, 0.006 g/mL), group 5 (G5, HPV, 0.008 g/mL), and group 6 (G6, HPV, 0.013 g/mL). Throughout the assay, humane endpoints, body weight, food, and water consumption were recorded weekly. The internal organs and skin of the mice were collected for analysis after they were sacrificed. Toxicological parameters that were studied included hematological and biochemical blood markers, splenic and hepatic histology, and hepatic oxidative stress. Results: A. citrodora extract seems to reduce the incidence of dysplastic and in situ carcinoma skin lesions induced by HPV16 in this model, suggesting that dietary supplementation with concentrations of 0.008 g/mL and 0.013 g/mL may have beneficial chemopreventive effects. Conclusions: The extract did not induce any concentration-dependent toxicological effects on any of the parameters included in the study, indicating a favorable toxicological profile under these experimental conditions.

10.37349/emed.2024.00228

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Canine and feline papillomaviruses: an update

Frontiers in Veterinary Science (2023)

Beatriz Medeiros‐Fonseca Ana I. Faustino‐Rocha Rui Medeiros Paula A. Oliveira Rui M. Gil da Costa

Papillomaviruses are small viruses able to cause disease not only in mammalians, but also in birds and reptiles. In recent years, a rising number of papillomaviruses have been identified in dogs and cats, totaling 24 canine papillomavirus (CPV) and six feline papillomavirus (FcaPV). The canine and feline papillomaviruses (CPVs and FcaPVs, respectively) are responsible for multiple lesions in these domestic species but the potential pathological relevance of some recently identified types remains to be determined. CPVs are associated with oral papillomatosis, cutaneous papillomas and viral pigmented plaques, and have been rarely associated with the development of oral and cutaneous squamous cell carcinomas in their canine hosts. FcaPVs are associated with oral papillomas, viral plaques, and Bowenoid in situ carcinomas. The present review provides readers with the more recent advances on dog and cat papillomavirus research, bringing an update on this field to both veterinary practitioners and the virology community at large.

Bovine papillomavirus

Papillomaviridae

Papillomatosis

Koilocyte

10.3389/fvets.2023.1174673

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Citations (5)

Assessing the in-vivo effects of Aloysia citrodora extract: data from K14-HPV16 transgenic mice

Journal of Comparative Pathology (2024)

Beatriz Medeiros‐Fonseca Helena Vala Cármen Nóbrega Ana I. Faustino‐Rocha Rui Medeiros

10.1016/j.jcpa.2024.03.077

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HPV16 is sufficient to induce squamous cell carcinoma specifically in the tongue base in transgenic mice

The Journal of Pathology (2020)

Verónica F. Mestre Beatriz Medeiros‐Fonseca Diogo Estêvão Fátima Casaca Sandra Silva

Abstract Head and neck squamous cell carcinomas (HNSCCs) associated with human papillomavirus (HPV) occur specifically in the tonsils and the tongue base, but the reasons for this specificity remain unknown. We studied the distribution of oral and pharyngeal lesions in HPV16‐transgenic mice where the expression of all the HPV16 early genes is targeted to keratinising squamous epithelia by the cytokeratin 14 ( Krt14 ) gene promoter. At 30 weeks of age, 100% of mice developed low‐ and high‐grade intraepithelial dysplasia at multiple sites. Twenty per cent of animals developed invasive cancers that remarkably were restricted to the tongue base, in association with the circumvallate papilla. The lesions maintained expression of CK14 (KRT14) and the HPV16 E6 and E7 oncogenes, and displayed deregulated cell proliferation and up‐regulation of p16 INK4A . Malignant lesions were poorly differentiated and destroyed the tongue musculature. We hypothesised that the tongue base area might contain a transformation zone similar to those observed in the cervix and anus, explaining why HPV‐positive cancers target that area specifically. Immunohistochemistry for two transformation zone markers, CK7 (KRT7) and p63 (TP63), revealed a squamocolumnar junction in the terminal duct of von Ebner's gland, composed of CK7 + luminal cells and p63 + basal cells. Dysplastic and invasive lesions retained diffuse p63 expression but only scattered positivity for CK7. Site‐specific HPV‐induced carcinogenesis in the tongue base may be explained by the presence of a transformation zone in the circumvallate papilla. This mouse model reproduces key morphological and molecular features of HPV‐positive HNSCC, providing a unique in vivo tool for basic and translational research. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Lingual papilla

Malignant Transformation

Major duodenal papilla

10.1002/path.5387

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Citations (30)

Effect of lemon juice enriched with melatonin (Citrus lemon L.) in the treatment of K14HPV16 mice

Acta Horticulturae (2024)

F. Badiche el Hilali Beatriz Medeiros‐Fonseca Paula A. Oliveira Daniel Valero

Lemon juice

Citrus limon

Fruit juice

Rough lemon

10.17660/actahortic.2024.1387.3

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Sixty years of research on bracken fern (Pteridium spp.) toxins: Environmental exposure, health risks and recommendations for bracken fern control

Environmental Research (2024)

Rui M. Gil da Costa Andrew Povey Beatriz Medeiros‐Fonseca Carmel Ramwell Connie O’Driscoll

Bracken fern (Pteridium spp.) is a highly problematic plant worldwide due to its toxicity in combination with invasive properties on former farmland, in deforested areas and on disturbed natural habitats. The carcinogenic potential of bracken ferns has caused scientific and public concern for six decades. Its genotoxic effects are linked to illudane-type glycosides (ITGs), their aglycons and derivatives. Ptaquiloside is considered the dominating ITG, but with significant contributions from other ITGs. The present review aims to compile evidence regarding environmental pollution by bracken fern ITGs, in the context of their human and animal health implications. The ITG content in bracken fern exhibits substantial spatial, temporal, and chemotaxonomic variation. Consumption of bracken fern as food is linked to human gastric cancer but also causes urinary bladder cancers in bovines browsing on bracken. Genotoxic metabolites are found in milk and meat from bracken fed animals. ITG exposure may also take place via contaminated water with recent data pointing to concentrations at microgram/L-level following rain events. Airborne ITG-exposure from spores and dust has also been documented. ITGs may synergize with major biological and environmental carcinogens like papillomaviruses and Helicobacter pylori to induce cancer, revealing novel instances of chemical and biological co-carcinogenesis. Thus, the emerging landscape from six decades of bracken research points towards a global environmental problem with increasingly complex health implications.

Bracken

Pteridium aquilinum

Environmental Pollution

10.1016/j.envres.2024.119274

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Citations (4)

The Effect of Lemon Juice (Citrus limon L.) Treated with Melatonin on the Health Status and Treatment of K14HPV16 Mice

Antioxidants (2024)

Fátima Badiche-El Hilali Beatriz Medeiros‐Fonseca Jéssica Silva Ana C. Silvestre‐Ferreira Maria João Pires

Lemon is a fruit rich in antioxidant properties and has several health benefits, namely the reduction of skin edema and anticarcinogenic properties, which are due to its high content of bioactive compounds. Melatonin can improve and preserve the properties of lemon for longer and also has health benefits. The aim of this study was to evaluate the effects of oral administration of lemon juice after melatonin treatment on murinometric parameters of wild-type (WT) mice and transgenic mice carrying human papillomavirus (HPV). Two trials were performed for oral administration of the lemon extract compound: in drinking water and in diet. First of all, lemons were treated by immersion with melatonin at 10 mM. Then, lemons were squeezed, and the juice obtained was freeze-dried and stored to be subsequently added to drinking water or diet, according to the assay. Thus, mice were divided into eight groups in the drink assay (each with n = 5): group 1 (G1, WT, control), group 2 (G2, WT, 1 mL lemon), group 3 (G3, WT, 1.5 mL lemon), group 4 (G4, WT, 2 mL lemon), group 5 (G5, HPV16, control), group 6 (G6, HPV16, 1 mL lemon) group 7 (G6, HPV16, 1.5 mL lemon) and group 8 (G6, HPV16, 2 mL lemon). The diet assay was divided into four groups: group 1 (G1, WT, control), group 2 (G2, WT, 4 mL lemon), group 3 (G3, HPV16, control) and group 4 (G4, HPV16, 4 mL lemon). In the drink assay, the highest concentration of melatonin (308 ng/100 mL) was for groups 4 and 8, while in the food assay, there was only one concentration of melatonin (9.96 ng/g) for groups 2 and 4. Both trials lasted 30 days. During this time, body weight, food and water were recorded. Afterward, they were sacrificed, and samples were collected for different analyses. At the concentrations used, the lemon juice with melatonin had no adverse effects on the animals’ health and showed a positive outcome in modifying weight gain and enhancing antioxidant activity in mice. Moreover, a reduction in the incidence of histological lesions was observed in treated animals. Further research is needed to better understand the effects of lemon extract on health and treatment outcomes in this animal model.

Lemon juice

Citrus limon

Negative control

10.3390/antiox13050588

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