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- Screening in vitro da actividade do taxol em linhagens celulares de cancro de cabeça e pescoçoPublication . Domingos, Célia; Silva, Eloiza Helena Tajara da; Power, DeborahO Taxol é um agente antimicrotúbulo, que promove e estabiliza a formação de polímeros de tubulina, resultando na inibição da reorganização dinâmica normal da rede de microtúbulos, necessária para as funções celulares mitóticas. Esta droga é amplamente utilizada para o tratamento de cancro de cabeça e pescoço de células escamosas (CCECP) e está disponível em três formas farmacêuticas, denominadas de medicamentos referência, genéricos e similares. O objetivo do presente estudo foi avaliar os efeitos das formas de genérico e similar do Taxol sobre a proliferação de células CCECP. Os resultados indicaram que ambas formas farmacêuticas, genérico e similar do Taxol tiveram efeitos comparáveis sobre a proliferação celular e apoptose Embora o Taxol seja um dos agentes quimioterápicos mais utilizados, o seu efeito tem uma variabilidade interindividual. Portanto, é importante identificar biomarcadores úteis para previsão da resposta a essa droga. As linhagens celulares constituem um bom modelo para avaliação do papel de quimioterápicos na secreção de fatores relacionados com a resposta terapêutica. Esses fatores podem incluir enzimas, citocinas, hormonas e outros mediadores solúveis, fundamentais para os processos de crescimento e diferenciação celulares, senescência, apoptose, angiogénese, invasão e metástase. Neste trabalho avaliou-se o efeito de metabolitos e proteínas produzidas pela influência do tratamento com Taxol, no microambiente do tumor, embora os resultados não sejam suficientemente conclusivos, parece que ocorrem alterações relacionadas com desenvolvimento e progressão tumoral.
- Cellular interactions in the tumor microenvironment: the role of secretomePublication . da Cunha, Bianca Rodrigues; Domingos, Célia; Stefanini, Ana Carolina Buzzo; Henrique, Tiago; Polachini, Giovana Mussi; Castelo-Branco, Pedro; Tajara, Eloiza HelenaOver the past years, it has become evident that cancer initiation and progression depends on several components of the tumor microenvironment, including inflammatory and immune cells, fibroblasts, endothelial cells, adipocytes, and extracellular matrix. These components of the tumor microenvironment and the neoplastic cells interact with each other providing pro and antitumor signals. The tumor-stroma communication occurs directly between cells or via a variety of molecules secreted, such as growth factors, cytokines, chemokines and microRNAs. This secretome, which derives not only from tumor cells but also from cancer-associated stromal cells, is an important source of key regulators of the tumorigenic process. Their screening and characterization could provide useful biomarkers to improve cancer diagnosis, prognosis, and monitoring of treatment responses.
- Cancer stem cells in prostate cancer: implications for targeted therapyPublication . Leao, Ricardo; Domingos, Célia; Figueiredo, Arnaldo; Hamilton, Robert; Tabori, Uri; Castelo-Branco, PedroProstate cancer (PCa) is the most frequently diagnosed cancer in men and the second most common cause of cancer-related mortality among men in the developed world. Conventional anti-PCa therapies include surgery, radiation, hormonal ablation, and chemotherapy. Despite increasing efforts, these therapies are not effective for patients with advanced and/or metastatic disease. In most cases, cancer therapies fail due to an incomplete depletion of tumor cells, resulting in tumor relapse. The cancer stem cell (CSC) hypothesis is an emerging model that explains many of the molecular characteristics of oncological disease as well as the tendency of cancers to relapse, metastasize, and develop resistance to conventional therapies. CSCs are a reservoir of cancer cells that exhibit properties of self-renewal and the ability to reestablish the heterogeneous tumor cell population. The existence of PCa stem cells offers a theoretical explanation for many uncertainties regarding PCa and also for treatment resistance and disease progression once clinical cure is achieved. Therapies targeting CSCs might therefore lead to more effective cancer treatments, divergent from a traditional anti-proliferative approach, based on tumor bulk reduction accompanied by CSC-specific inhibition. Here, we focus on reviewing the historical perspective as well as concepts regarding stem cells and CSCs in PCa. In addition, we will report possible strategies and new clinical approaches that address the CSC-based concept of tumorigenesis in PCa. (C) 2017 S. Karger AG, Basel
- A cancer specific hypermethylation signature of the TERT promoter predicts biochemical relapse in prostate cancer: A retrospective cohort studyPublication . Castelo-Branco, Pedro; Leao, Ricardo; Lipman, Tatiana; Campbell, Brittany; Lee, Donghyun; Price, Aryeh; Zhang, Cindy; Heidari, Abolfazl; Stephens, Derek; Boerno, Stefan; Coelho, Hugo; Domingos, Célia; Apolónio, Joana; Schaefer, Georg; Bristow, Robert G.; Schweiger, Michal R.; Hamilton, Robert; Zlotta, Alexandre; Figueiredo, Arnaldo; Klocker, Helmut; Sueltmann, Holger; Tabori, UriThe identification of new biomarkers to differentiate between indolent and aggressive prostate tumors is an important unmet need. We examined the role of THOR (TERT Hypermethylated Oncological Region) as a diagnostic and prognostic biomarker in prostate cancer (PCa).We analyzed THOR in common cancers using genome-wide methylation arrays. Methylation status of the whole TERT gene in benign and malignant prostate samples was determined by MeDIP-Seq. The prognostic role of THOR in PCa was assessed by pyrosequencing on discovery and validation cohorts from patients who underwent radical prostatectomy with long-term follow-up data.Most cancers (n = 3056) including PCa (n = 300) exhibited hypermethylation of THOR. THOR was the only region within the TERT gene that is differentially methylated between normal and malignant prostate tissue (p < 0.0001). Also, THOR was significantly hypermethylated in PCa when compared to paired benign tissues (n = 164, p < 0.0001). THOR hypermethylation correlated with Gleason scores and was associated with tumor invasiveness (p = 0.0147). Five years biochemical progression free survival (BPFS) for PCa patients in the discovery cohort was 87% (95% CI 73-100) and 65% (95% CI 52-78) for THOR non-hypermethylated and hypermethylated cancers respectively (p = 0.01). Similar differences in BPFS were noted in the validation cohort (p = 0.03). Importantly, THOR was able to predict outcome in the challenging (Gleason 6 and 7 (3 + 4)) PCa (p = 0.007). For this group, THOR was an independent risk factor for BPFS with a hazard-ratio of 3.685 (p = 0.0247). Finally, THOR hypermethylation more than doubled the risk of recurrence across all PSA levels (OR 2.5, p = 0.02).