Andreia Gameiro

University of Lisbon

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Fernando Ferreira

University of Lisbon

Jorge Correia

University of Lisbon

Catarina Nascimento

Hospital Beatriz Ângelo

Ana Catarina Urbano

University of Lisbon

João Ferreira

University of Lisbon

Filipe Almeida

Pontifícia Universidade Católica do Rio Grande do Sul

Fábia Escarigo

Polytechnic Institute of Castelo Branco

Maria Soares

Oxford University Hospitals NHS Trust

Paula Sapeta

Polytechnic Institute of Castelo Branco

V. Chu

Instituto de Engenharia de Sistemas e Computadores Microsistemas e Nanotecnologias

Cooperative Institutions

University of Lisbon

Centre for Research in Anthropology

Département Santé Animale

Instituto de Engenharia de Sistemas e Computadores Microsistemas e Nanotecnologias

Universidade Lusófona

Instituto Nacional de Investigação Agrária e Veterinária

Universidade Nova de Lisboa

Instituto Superior Técnico

Universidade do Porto

Polytechnic Institute of Castelo Branco

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Serum PD-1/PD-L1 Levels, Tumor Expression and PD-L1 Somatic Mutations in HER2-Positive and Triple Negative Normal-Like Feline Mammary Carcinoma Subtypes

Cancers (2020)

Catarina Nascimento Ana Catarina Urbano Andreia Gameiro João Ferreira Jorge Correia

Tumor microenvironment has gained great relevance due to its ability to regulate distinct checkpoints mediators, orchestrating tumor progression. Serum programmed cell death protein-1 (PD-1) and programmed death ligand-1 (PD-L1) levels were compared with healthy controls and with serum cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and tumor necrosis factor-alpha (TNF-α) levels in order to understand the role of PD-1/PD-L1 axis in cats with mammary carcinoma. PD-1 and PD-L1 expression was evaluated in tumor-infiltrating lymphocytes (TILs) and cancer cells, as the presence of somatic mutations. Results showed that serum PD-1 and PD-L1 levels were significantly higher in cats with HER2-positive (p = 0.017; p = 0.032) and triple negative (TN) normal-like mammary carcinomas (p = 0.004; p = 0.015), showing a strong positive correlation between serum CTLA-4 and TNF-α levels. In tumors, PD-L1 expression in cancer cells was significantly higher in HER2-positive samples than in TN normal-like tumors (p = 0.010), as the percentage of PD-L1-positive TILs (p = 0.037). PD-L1 gene sequencing identified two heterozygous mutations in exon 4 (A245T; V252M) and one in exon 5 (T267S). In summary, results support the use of spontaneous feline mammary carcinoma as a model for human breast cancer and suggest that the development of monoclonal antibodies may be a therapeutic strategy.

Tumor-infiltrating lymphocytes

Mammary tumor

10.3390/cancers12061386

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Citations (39)

Diagnostic Value of VEGF-A, VEGFR-1 and VEGFR-2 in Feline Mammary Carcinoma

Cancers (2021)

Catarina Nascimento Andreia Gameiro João Ferreira Jorge Correia Fernando Ferreira

Vascular endothelial growth factor (VEGF-A) plays an essential role in tumor-associated angiogenesis, exerting its biological activity by binding and activating membrane receptors, as vascular endothelial growth factor receptor 1 and 2 (VEGFR-1, VEGFR-2). In this study, serum VEGF-A, VEGFR-1, and VEGFR-2 levels were quantified in 50 cats with mammary carcinoma and 14 healthy controls. The expression of these molecules in tumor-infiltrating lymphocytes (TILs) and in cancer cells was evaluated and compared with its serum levels. Results obtained showed that serum VEGF-A levels were significantly higher in cats with HER2-positive and Triple Negative (TN) Normal-Like subtypes, when compared to control group (p = 0.001, p = 0.020). Additionally, serum VEGFR-1 levels were significantly elevated in cats presenting luminal A, HER2-positive and TN Normal-Like tumors (p = 0.011, p = 0.048, p = 0.006), as serum VEGFR-2 levels (p = 0.010, p = 0.046, p = 0.005). Moreover, a positive interaction was found between the expression of VEGF-A, VEGFR-1, and VEGFR-2 in TILs and their serum levels (p = 0.002, p = 0.003, p = 0.003). In summary, these findings point to the usefulness of VEGF-A and its serum receptors assessment in clinical evaluation of cats with HER2-positive and TN Normal-Like tumors, suggesting that targeted therapies against these molecules may be effective for the treatment of these animals, as described in human breast cancer.

Breast carcinoma

10.3390/cancers13010117

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Citations (20)

Serum HER2 levels are increased in cats with mammary carcinomas and predict tissue HER2 status

Oncotarget (2016)

Maria Soares Rita Ribeiro Shabir Najmudin Andreia Gameiro Rita Vaz‐Rodrigues

HER2 is overexpressed in about 30% of feline mammary carcinomas (FMC) and in 15-30% of breast cancers. Women with HER2-positive breast tumors are associated with shorter survival. This study aimed to optimize the detection and quantification of serum HER2 (sHER2) in cats and to evaluate its potential in diagnosing cats with mammary carcinomas (MC) overexpressing HER2. A prospective study was conducted in 60 queens showing MC and 20 healthy animals. Pre-operative serum samples were collected for sHER2 quantification using two immunoassays: ELISA and Dot blot assay. sHER2 levels were compared with tissue HER2 status assessed by immunohistochemistry. Queens with FMC showed significantly higher mean levels of sHER2 by both ELISA and Dot blot assay. A significant difference in the sHER2 levels was also found between cats with HER2-positive MC and those with low-expressing HER2 MC. A significant correlation between sHER2 levels and tumor HER2 status was also found, particularly when ELISA was used (r = 0.58, p < 0.0001). The value of 10 ng/ml was proposed as the optimal cutoff for both immunoassays by ROC analysis. Like in humans, sHER2 levels are increased in cats with MC HER2-positive, strongly suggesting that evaluation of sHER2 levels can be very useful in feline oncology. The results show that ELISA and Dot blot assay can replace the immunohistochemistry technique, due to their efficacy and lower costs for diagnostic purposes and for monitoring the response to anti-HER2 therapies in cats.

10.18632/oncotarget.7551

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Citations (33)

The Landscape of Tumor-Infiltrating Immune Cells in Feline Mammary Carcinoma: Pathological and Clinical Implications

Cells (2022)

Catarina Nascimento Andreia Gameiro Jorge Correia João Ferreira Fernando Ferreira

Feline mammary carcinoma (FMC) shares key molecular and clinicopathological features with human breast cancer. We have herein studied the inflammatory infiltrate of FMC in order to uncover potential therapeutic targets and prognostic markers. To this end, the expression of different markers (CD3, CD4, CD8, CD20, CD56, FoxP3, CD68 and CD163) was analyzed in total, stromal (s) and intratumoral (i) tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs), in 73 feline mammary carcinomas. The results revealed that higher percentages of sCD8+ TILs were associated with longer disease-free survival (p = 0.05) and overall survival (p = 0.021). Additionally, higher percentages of iCD4+ TILs correlated with positive lymph node status (p = 0.003), whereas CD163+ TAMs were associated with undifferentiated tumors (p = 0.013). In addition, sCD3+ (p = 0.033), sCD8+ (p = 0.044) and sCD68+ (p = 0.023) immune cells were enriched in triple negative normal-like carcinomas compared to other subtypes. Altogether, our results suggest that specific subsets of immune cells may play a major role in clinical outcome of cats with mammary carcinoma, resembling what has been reported in human breast cancer. These data further support the relevance of the feline model in breast cancer studies.

CD68

Tumor-infiltrating lymphocytes

Breast carcinoma

Tumor progression

10.3390/cells11162578

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Citations (14)

Integration of Single Cell Traps, Chemical Gradient Generator and Photosensors in a Microfluidic Platform for the Study of Alpha-Synuclein Toxicity in Yeast

Procedia Engineering (2014)

João Fernandes Sandra Tenreiro Catarina R. Pedrosa Andreia Gameiro V. Chu

Alpha-synuclein (aSyn) is a key player in Parkinson's disease. Genetically engineered yeast cells producing aSyn fused with GFP (aSyn-GFP) have been used to study this protein. In this work, we present a microfluidic platform with integrated photosensors that captures single yeast cells in arrays of hydrodynamic traps and exposes them to a chemical gradient of precise composition. This platform enables the study of the effects of aSyn expression level and aggregation in genetically modified yeast cells by chemical stimulation. The photosensors allow the detection of cells in the traps by measuring the variations in light transmission or of the fluorescence produced by aSyn-GFP for real-time signal acquisition.

10.1016/j.proeng.2014.11.273

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Citations (0)

Emerging Biomarkers and Targeted Therapies in Feline Mammary Carcinoma

Veterinary Sciences (2021)

Andreia Gameiro Ana Catarina Urbano Fernando Ferreira

Feline mammary carcinoma (FMC) is a common aggressive malignancy with a low survival rate that lacks viable therapeutic options beyond mastectomy. Recently, increasing efforts have been made to understand the molecular mechanisms underlying FMC development, using the knowledge gained from studies on human breast cancer to discover new diagnostic and prognostic biomarkers, thus reinforcing the utility of the cat as a cancer model. In this article, we review the current knowledge on FMC pathogenesis, biomarkers, and prognosis factors and offer new insights into novel therapeutic options for HER2-positive and triple-negative FMC subtypes.

Targeted Therapy

10.3390/vetsci8080164

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Citations (10)

O38 Giant oesophageal ulceration in a patient with systemic lupus erythematosus and antiphospholipid syndrome

European Journal of Internal Medicine (2003)

João Matos Costa F.J. Carrilho Andreia Gameiro Rocío Maldonado H. Garcia

10.1016/s0953-6205(03)91187-3

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Citations (0)

Industry 4.0 technologies applied to supply chain: a systematic literature review

International Journal of Logistics Systems and Management (2023)

Durand Bruno Andreia Gameiro Eduardo Guilherme Satolo

10.1504/ijlsm.2023.133531

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Citations (1)

Histone Deacetylase Inhibitors and Microtubule Inhibitors Induce Apoptosis in Feline Luminal Mammary Carcinoma Cells

Animals (2021)

Filipe Almeida Andreia Gameiro Jorge Correia Fernando Ferreira

Feline mammary carcinoma (FMC) is the third most common type of neoplasia in cats, sharing similar epidemiological features with human breast cancer. In humans, histone deacetylases (HDACs) play an important role in the regulation of gene expression, with HDAC inhibitors (HDACis) disrupting gene expression and leading to cell death. In parallel, microtubules inhibitors (MTIs) interfere with the polymerization of microtubules, leading to cell cycle arrest and apoptosis. Although HDACis and MTIs are used in human cancer patients, in cats, data is scarce. In this study, we evaluated the antitumor properties of six HDACis (CI-994, panobinostat, SAHA, SBHA, scriptaid, and trichostatin A) and four MTIs (colchicine, nocodazole, paclitaxel, and vinblastine) using three FMC cell lines (CAT-MT, FMCp, and FMCm), and compared with the human breast cancer cell line (SK-BR-3). HDACis and MTIs exhibited dose-dependent antitumor effects in FMC cell lines, and for all inhibitors, the IC50 values were determined, with one feline cell line showing reduced susceptibility (FMCm). Immunoblot analysis confirmed an increase in the acetylation status of core histone protein HDAC3 and flow cytometry showed that HDACis and MTIs lead to cellular apoptosis. Overall, our study uncovers HDACis and MTIs as promising anti-cancer agents to treat FMCs.

Trichostatin A

Vorinostat

Nocodazole

Histone deacetylase inhibitor

10.3390/ani11020502

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Citations (6)

HER2-Targeted Immunotherapy and Combined Protocols Showed Promising Antiproliferative Effects in Feline Mammary Carcinoma Cell-Based Models

Cancers (2021)

Andreia Gameiro Catarina Nascimento Jorge Correia Fernando Ferreira

Feline mammary carcinoma (FMC) is a highly prevalent tumor, showing aggressive clinicopathological features, with HER2-positive being the most frequent subtype. While, in human breast cancer, the use of anti-HER2 monoclonal antibodies (mAbs) is common, acting by blocking the extracellular domain (ECD) of the HER2 protein and by inducing cell apoptosis, scarce information is available on use these immunoagents in FMC. Thus, the antiproliferative effects of two mAbs (trastuzumab and pertuzumab), of an antibody–drug conjugate compound (T-DM1) and of combined treatments with a tyrosine kinase inhibitor (lapatinib) were evaluated on three FMC cell lines (CAT-MT, FMCm and FMCp). In parallel, the DNA sequence of the her2 ECD (subdomains II and IV) was analyzed in 40 clinical samples of FMC, in order to identify mutations, which can lead to antibody resistance or be used as prognostic biomarkers. Results obtained revealed a strong antiproliferative effect in all feline cell lines, and a synergistic response was observed when combined therapies were performed. Additionally, the mutations found were not described as inducing resistance to therapy in breast cancer patients. Altogether, our results suggested that anti-HER2 mAbs could become useful in the treatment of FMC, particularly, if combined with lapatinib, since drug-resistance seems to be rare.

Lapatinib

Pertuzumab

10.3390/cancers13092007

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Citations (15)