Portuguese Oncology Institute Porto

Vila Real de Santo António, Portugal

Portuguese Oncology Institute Porto

Vila Real de Santo António, Portugal
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Patel H.R.H.,University of London | Henrique R.,Portuguese Oncology Institute Porto | Henrique R.,University of Porto | Jeronimo C.,University of Porto
Expert Review of Anticancer Therapy | Year: 2014

Prostate cancer (PCa) is the most common neoplasia among men in developed countries and a leading cause of cancer-related morbidity and mortality. PCa is a very heterogeneous disease, both clinically and biologically. Currently, it is difficult to stratify patients into risk groups that entail different disease management. Therefore, a personalized view of this disease is mandatory, through the development of new and more accurate biomarkers that may help clinicians to stratify patients according to threat that PCa poses for each patient. Hence, this review focuses on recent developments of molecular and immunohistochemical biomarkers for PCa risk stratification that might enable a personalized approach to PCa patients. However, despite the increasing amount of available data, there is also an urgent need to translate the most promising biomarkers for clinical use through large multicenter validation trials. Ultimately, these will contribute for an improved clinical management of PCa patients. © Informa UK, Ltd.

Graca I.,Polytechnic Institute of Porto | Palmeira C.,Portuguese Oncology Institute Porto | Henrique R.,University of Porto | Jeronimo C.,University of Porto
Current Pharmaceutical Design | Year: 2014

Background: Current therapeutic strategies for advanced prostate cancer (PCa) are largely ineffective. Because aberrant DNA methylation associated with inappropriate gene-silencing is a common feature of PCa, DNA methylation inhibitors might constitute an alternative therapy. In this study we aimed to evaluate the anti-cancer properties of RG108, a novel non-nucleoside inhibitor of DNA methyltransferases (DNMT), in PCa cell lines. Methods: The anti-tumoral impact of RG108 in LNCaP, 22Rv1, DU145 and PC-3 cell lines was assessed through standard cell viability, apoptosis and cell cycle assays. Likewise, DNMT activity, DNMT1 expression and global levels of DNA methylation were evaluated in the same cell lines. The effectiveness of DNA demethylation was further assessed through the determination of promoter methylation and transcript levels of GSTP1, APC and RAR-β2, by quantitative methylation-specific PCR and RT-PCR, respectively. Results: RG108 led to a significant dose and time dependent growth inhibition and apoptosis induction in LNCaP, 22Rv1 and DU145. LNCaP and 22Rv1 also displayed decreased DNMT activity, DNMT1 expression and global DNA methylation. Interestingly, chronic treatment with RG108 significantly decreased GSTP1, APC and RAR-β2 promoter hypermethylation levels, although mRNA reexpression was only attained for GSTP1 and APC. Conclusions: RG108 is an effective tumor growth suppressor in most PCa cell lines tested. This effect is likely mediated by reversion of aberrant DNA methylation affecting cancer related-genes epigenetically silenced in PCa. However, additional mechanism might underlie the anti-tumor effects of RG108. In vivo studies are now mandatory to confirm these promising results and evaluate the potential of this compound for PCa therapy. © 2014 Bentham Science Publishers.

Graca I.,Polytechnic Institute of Porto | Vieira F.Q.,Polytechnic Institute of Porto | Torres-Ferreira J.,Portuguese Oncology Institute Porto | Martins M.G.,Portuguese Oncology Institute Porto | And 3 more authors.
Oncotarget | Year: 2014

Prostate cancer (PCa) is a major cause of cancer-related morbidity and mortality worldwide. Although early disease is often efficiently managed therapeutically, available options for advanced disease are mostly ineffective. Aberrant DNA methylation associated with gene-silencing of cancer-related genes is a common feature of PCa. Therefore, DNA methylation inhibitors might constitute an attractive alternative therapy. Herein, we evaluated the anti-cancer properties of hydralazine, a non-nucleoside DNA methyltransferases (DNMT) inhibitor, in PCa cell lines. In vitro assays showed that hydralazine exposure led to a significant dose and time dependent growth inhibition, increased apoptotic rate and decreased invasiveness. Furthermore, it also induced cell cycle arrest and DNA damage. These phenotypic effects were particularly prominent in DU145 cells. Following hydralazine exposure, decreased levels of DNMT1, DNMT3a and DNMT3b mRNA and DNMT1 protein were depicted. Moreover, a significant decrease in GSTP1, BCL2 and CCND2 promoter methylation levels, with concomitant transcript re-expression, was also observed. Interestingly, hydralazine restored androgen receptor expression, with upregulation of its target p21 in DU145 cell line. Protein array analysis suggested that blockage of EGF receptor signaling pathway is likely to be the main mechanism of hydralazine action in DU145 cells. Our data demonstrate that hydralazine attenuated the malignant phenotype of PCa cells, and might constitute a useful therapeutic tool.

Pinto F.,University of Minho | Pinto F.,Icvs 3Bs Pt Government Assoc Laboratory | Pertega-Gomes N.,University of Minho | Pertega-Gomes N.,Icvs 3Bs Pt Government Assoc Laboratory | And 13 more authors.
Clinical Cancer Research | Year: 2014

Purpose: Successful therapy of patients with prostate cancer is highly dependent on reliable diagnostic and prognostic biomarkers. Brachyury is considered a negative prognostic factor in colon and lung cancer; however, there are no reports on Brachyury's expression in prostate cancer.Experimental Design: In this study, we aimed to assess the impact of Brachyury expression in prostate tumorigenesis using a large series of human prostate samples comprising benign tissue, prostate intraepithelial neoplasia (PIN) lesions, localized tumor, and metastatic tissues. The results obtained were compared with what can be inferred from the Oncomine database. In addition, multiple in vitro models of prostate cancer were used to dissect the biologic role of Brachyury in prostate cancer progression.Results: We found that Brachyury is significantly overexpressed in prostate cancer and metastatic tumors when compared with normal tissues, both at protein and at mRNA levels. Brachyury expression in the cytoplasm correlates with highly aggressive tumors, whereas the presence of Brachyury in the nucleus is correlated with tumor invasion. We found that Brachyury-positive cells present higher viability, proliferation, migration, and invasion rates than Brachyury-negative cells. Microarray analysis further showed that genes co-expressed with Brachyury are clustered in oncogenic-related pathways, namely cell motility, cellcycle regulation, and cell metabolism.Conclusions: Collectively, the present study suggests that Brachyury plays an important role in prostate cancer aggressiveness and points, for the first time, to Brachyury as a significant predictor of poor prostate cancer prognosis. Our work paves the way for future studies assessing Brachyury as a possible prostate cancer therapeutic target. © 2014 American Association for Cancer Research.

de Mello R.A.,Portuguese Oncology Institute Porto | de Mello R.A.,University of Porto | Costa B.M.,University of Minho | Reis R.M.,University of Minho | And 4 more authors.
Recent Patents on Anti-Cancer Drug Discovery | Year: 2012

Lung cancer is a highly prevalent disease worldwide. Currently, there are more than 150 million patients with lung cancer in the world, with more than 1 million new cases diagnosed per year. Tumoral angiogenesis is an important hallmark of this disease, but despite being extensively studied, the complete angiogenic mechanisms are not fully elucidated. Recent studies have reported a correlation between pharmacological inhibition of these angiogenic mechanisms and improvement of overall survival in lung cancer patients, mainly for those in advanced stages. The family of vascular endothelial growth factor (VEGF) proteins has critical roles in tumoral angiogenesis. An interaction between VEGF-A and VEGF receptor 2 (VEGFR-2) is the main pathway of activation and maintenance of angiogenesis. In tumors, this process is intimately correlative with progression and metastasis. Some studies suggested that serum levels of VEGF are higher in patients with lung cancer, especially in some types of non-small cell lung cancer (NSCLC). Other studies revealed that genetic polymorphisms of VEGF correlate with susceptibility, prognosis, and therapeutic response of some patients with NSCLC. This paper aims to review the impact of angiogenesis, especially on VEGF pathways, in NSCLC, and highlights the relevance of known and new patents disclosed of anti-angiogenic therapies in these patients. © 2012 Bentham Science Publishers.

Carvalho J.R.,Portuguese Oncology Institute Porto | Filipe L.,Portuguese Oncology Institute Porto | Costa V.L.,Portuguese Oncology Institute Porto | Ribeiro F.R.,Portuguese Oncology Institute Porto | And 6 more authors.
Apoptosis | Year: 2010

Apoptosis is known to be involved in tumorigenesis and a defective ratio between cell proliferation and apoptosis may contribute to the emergence of a malignant phenotype. Transcriptional silencing of apoptosis-related genes associated with aberrant promoter methylation may impair the apoptotic machinery, ultimately leading to cancer development. Aberrant promoter methylation of numerous genes involved in many different pathways is frequent in prostate cancer. Our aim was to quantitatively assess the methylation status of several apoptosis-related genes in prostate adenocarcinoma (PCa) and its precursor lesion, high-grade prostatic intraepithelial neoplasia (HGPIN). First, 120 PCa and 39 HGPIN were screened for altered expression of BCL2, CASP8, CASP3, DAPK DR3, DR4, DR6, FAS, TMS1, TNFR2, using 28 benign prostate hyperplasias and 10 normal prostates as controls. Underexpressed genes were then assessed by quantitative methylation-specific PCR to determine the promoter methylation status. Finally, quantitative mRNA expression of aberrantly methylated genes was performed and methylation data was correlated with standard clinicopathologic parameters. DAPK, DR4 and TNFR2 were significantly overexpressed in HGPIN and PCa, whereas BCL2, TMS1, and FAS were downregulated. Although methylation levels were significantly higher for TMS1 and BCL2 (correlating with advanced stage), an inverse correlation with mRNA expression was found only for BCL2. We concluded that the apoptotic pathways are largely preserved in prostate carcinogenesis, in particular the extrinsic pathway, with the exception of FAS and TMS1, which are epigenetically downregulated. In addition, BCL2 was also found to be frequently silenced in PCa due to aberrant promoter methylation, thus supporting a future role for apoptosis-targeted therapy in prostate cancer. © 2010 Springer Science+Business Media, LLC.

Valente M.J.,University of Porto | Baltazar A.F.,Fernando Pessoa University | Henrique R.,Portuguese Oncology Institute Porto | Henrique R.,University of Porto | And 3 more authors.
Food and Chemical Toxicology | Year: 2011

This study reports for the first time the biological properties of Portuguese propolis. The antioxidant potential of propolis samples from Bornes (Northeast) and Fundão (Centre) regions of Portugal was evaluated by their ability to inhibit the 2,2'-azobis(2-amidinopropane) dihydrochloride (AAPH)-induced oxidative hemolysis and lipid peroxidation in human erythrocytes. Bornes and Fundão propolis strongly protected the erythrocyte membrane from hemolysis (IC50 of 6.3±0.7 and 10.4±2.7μg/ml, respectively), in a time- and concentration-dependent manner. This effect was found to be significantly higher than that presented by ascorbic acid (IC50 of 31.0±5.6μg/ml). In addition, human erythrocytes treated with propolis extracts showed concentration-dependent decrease in levels of malondialdehyde, a breakdown product of lipid peroxidation. Propolis extracts were also assayed for their anticancer properties on human renal cell carcinoma (RCC). Primary cultures of normal and cancerous renal cells derived from RCC patients, in addition to A-498 cell line, were treated with propolis extracts (0-100μg/ml). Cytotoxic and antiproliferative effects were determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Propolis extracts exhibited selective toxicity against malignant cells compared to normal cells. In vitro RCC growth was strongly inhibited by Bornes and Fundão propolis in a concentration-dependent manner. Our results indicate that Portuguese propolis constitutes an excellent source of effective natural antioxidant and chemopreventive agents. © 2010 Elsevier Ltd.

Areia M.,University of Porto | Areia M.,Portuguese Oncology Institute Coimbra | Carvalho R.,Portuguese Oncology Institute Coimbra | Cadime A.T.,Portuguese Oncology Institute Coimbra | And 4 more authors.
Helicobacter | Year: 2013

Background: Cost-effectiveness studies are highly dependent on the models, settings, and variables used and should be based on systematic reviews. We systematically reviewed cost-effectiveness studies that address screening for gastric cancer and/or surveillance of precancerous conditions and lesions. Materials and Methods: A systematic review of cost-effectiveness studies was performed by conducting a sensitive search in seven databases (PubMed, Scopus, Web of Science, Current Contents Connect, Centre for Reviews and Dissemination, Academic Search Complete, and CINAHL Plus), independently evaluated by two investigators. Articles were evaluated for type of study, perspective, model, intervention, incremental cost-effectiveness ratio, clinical or cost variables, and quality, according to published guidelines. Results: From 2395 abstracts, 23 articles were included: 19 concerning population screening and 4 on following up premalignant lesions. Studies on Helicobacter pylori screening concluded that serology was cost-effective, depending on cancer incidence and endoscopy cost (incremental cost-effectiveness ratio: 6264-25,881), and eradication after endoscopic resection was also cost-effective (dominant) based on one study. Studies on imaging screening concluded that endoscopy was more cost-effective than no screening (incremental cost-effectiveness ratio: 3376-26,836). Articles on follow-up of premalignant lesions reported conflicting results (incremental cost-effectiveness ratio: 1868-72,519 for intestinal metaplasia; 18,600-39,800 for dysplasia). Quality assessment revealed a unanimous lack of a detailed systematic review and fulfillment of a median number of 23 items (20-26) of 35 possible ones. Conclusions: The available evidence shows that Helicobacter pylori serology or endoscopic population screening is cost-effective, while endoscopic surveillance of premalignant gastric lesions presents conflicting results. Better implementation of published guidelines and accomplishment of systematic detailed reviews are needed. © 2013 John Wiley & Sons Ltd.

Bartosch C.,Portuguese Oncology Institute Porto | Bartosch C.,Mahatma Jyotiba Phule Rohilkhand University
International Journal of Gynecological Pathology | Year: 2016

Uterine leiomyosarcoma (U-LMS) is the most frequent malignant gynecologic mesenchymal tumor, often develops distant metastases and has a dismal prognosis. In this study we aim to characterize the body sites and time to metastasis in women with U-LMS. We evaluated 130 U-LMSs with distant metastases including a series of patients diagnosed at 2 tertiary centers, as well as cases published in the literature, found using a PubMed query. Data collected included clinic-pathologic features, time to first metastasis, and survival. Survival analysis was performed using univariable and multivariable Cox regression model. The most frequent metastatic sites were: lung (67.7%), cranial/intracranial (16.2%), skin/soft tissues (15.3%), and bone (13.8%). Other sites included thyroid, salivary gland, heart, liver, pancreas, adrenal gland, bowel, and breast. Metastases were histologically identical to primary tumors. Median time to first metastasis was highly variable (median: 24 mo; range, 1 mo to 26 y). Lung and peritoneum were the earlier metastatic sites; 21.4% of patients with U-LMS limited to the pelvis develop metastasis >5 yr after diagnosis. Lung metastases significantly associated with other distant metastases. Regarding treatment, only metastasectomy significantly influenced postmetastasis survival in multivariable analysis (hazard ratio: 0.49, P=0.015). In conclusion, U-LMS display highly variable sites of distant metastases. Metastases in unusual locations are sometimes the first to be detected, and not uncommonly, single and prone to surgical resection. There is also a wide range of time intervals to first metastasis, highlighting the need of long-term follow-up, high level of suspicion, and appropriate diagnostic confirmation. ©2016International Society of Gynecological Pathologists

Montezuma D.,Portuguese Oncology Institute Porto | Montezuma D.,Portuguese Oncology Institute | Azevedo R.,Portuguese Oncology Institute Porto | Lopes P.,Portuguese Oncology Institute Porto | And 5 more authors.
Virchows Archiv | Year: 2013

Accurate classification of lung cancer, as well as the differentiation between primary and metastatic carcinoma to the lung, mostly performed on biopsy or fine needle aspiration specimens, is critical for decisions on therapy and for determining prognosis. The limited amount of biopsy material available for morphological assessment has stimulated attempts to improve diagnostic accuracy through the use of immunohistochemistry (IHC), but an optimal IHC diagnostic algorithm has not been firmly established. We evaluated, on a retrospective series of biopsy specimens, the performance of a four-antibody IHC panel for accurate subclassification of non-small cell lung carcinoma (NSCLC) and for identification of metastatic carcinoma. Tumor morphology was assessed and IHC for CK7, CK20, TTF-1, and p63 was performed according to a two-step algorithm. Matched resection specimens served as gold standard and were compared with the corresponding biopsy. Of 443 biopsy specimens studied, 325 were diagnosed as primary carcinoma of the lung, 198 (44.7 %) as adenocarcinoma, 9 (2 %) as possibly adenosquamous carcinoma, 127 (28.7 %) as squamous cell carcinoma, and 40 (9 %) as NSCLC not further classifiable. Ten cases (2.3 %) were classified as adenocarcinoma of unknown origin and 58 (13 %) as metastasis. Importantly, of the primary lung adenocarcinomas, 35 (17.7 %) had been considered on clinical grounds as a metastasis from a previously diagnosed primary tumor. Of the 55 cases submitted to surgical resection in 47 (85.5 %) the biopsy diagnosis was confirmed, revealing substantial agreement (κ value = 0.757). Our two-step approach allows for accurate subclassification of NSCLC and also to distinguish between primary lung adenocarcinoma and metastasis, notably of colorectal adenocarcinoma, with crucial implications for appropriate patient management. © 2013 Springer-Verlag Berlin Heidelberg.

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