Epstein-Barr virus-induced metabolic rearrangements in human B-cell lymphomas

Tumor metabolism has been the object of several studies in the past, leading to the pivotal observation of a consistent shift toward aerobic glycolysis (so-called Warburg effect). More recently, several additional investigations proved that tumor metabolism is profoundly affected during tumorigenesis, including glucose, lipid and amino-acid metabolism. It is noticeable that metabolic reprogramming can represent a suitable therapeutic target in many cancer types. Epstein-Barr virus (EBV) was the first virus linked with cancer in humans when Burkitt lymphoma (BL) was described. Besides other well-known effects, it was recently demonstrated that EBV can induce significant modification in cell metabolism, which may lead or contribute to neoplastic transformation of human cells. Similarly, virus-induced tumorigenesis is characterized by relevant metabolic abnormalities directly induced by the oncoviruses. In this article, the authors critically review the most recent literature concerning EBV-induced metabolism alterations in lymphomas

Targeted therapies in breast cancer

Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, Universidade de Lisboa, Faculdade de Farmácia, 2017Breast cancer is a disease responsible for millions of deaths annually. It’s a very heterogenous disease due to the different mutations on each case. Breast cancer doesn’t have existing cure, and it’s currently approached through therapeutic schemes involving radiotherapy, chemotherapy and surgical procedure. Both radiotherapy as chemotherapy act adjunctly allowing further removal through lumpectomy or mastectomy. Current chemotherapy can’t distinguish between healthy and malignant cells, causing patient suffering through adverse effects. So, there’s a demand to find out novel therapies more efficient e selective. However, many researchers claim to found novel selective approaches, that ultimately aren’t. Potentially new drugs on research will be analysed, and an efficient and viable drug design is proposed to cure breast cancer.O cancro da mama é uma doença responsável por milhões de mortes anualmente. É uma doença muito heterogenia devido às diferentes mutações existentes em cada caso. O cancro da mama não tem uma cura existente, ele é tratado através de uma série de esquemas terapêuticos que envolve radioterapia, quimioterapia e cirurgia. Tanto a radio como a quimioterapia são unicamente adjuvantes de modo a permitir a remoção do cancro através de uma lumpectomia ou mastectomia. A quimioterapia corrente usada não consegue distinguir células malignas de células saudáveis e isso remete para reações adversas sentidas pelo doente que tornam a terapia dolorosa. Existe, portanto, uma demanda de novas opções terapêuticas mais eficazes e seletivas. Contundo, muito investigadores referem descobrir novas terapêuticas seletivas que acabam por não o ser. Faz-se uma crítica a potenciais novos fármacos em investigação, mas também se propõe a síntese de fármacos mais eficazes e viáveis na cura do cancro da mama

Involvement of ion channels and transporters in carcinoma angiogenesis and metastasis

International audienceAngiogenesis is a finely tuned process, which is the result of the equilibrium between pro- and antiangiogenic factors. In solid tumor angiogenesis, the balance is highly in favor of the production of new, but poorly functional blood vessels, initially intended to provide growing tumors with nutrients and oxygen. Among the numerous proteins involved in tumor development, several types of ion channels are overexpressed in tumor cells, as well as in stromaland endothelial cells. Ion channels thus actively participate in the different hallmarks of cancer, especially in tumor angiogenesis and metastasis. Indeed, from their strategic localization in the plasma membrane, ion channels are key operators of cell signaling, as they sense and respond to environmental changes. This review aims to decipher how ion channels of different families are intricately involved in the fundamental angiogenesis and metastasis hallmarks, which lead from a nascent tumor to systemic dissemination. An overview of the possible use of ion channelsas therapeutic targets will also be given, showing that ion channel inhibitors orspecific antibodies may provide effective tools, in the near future, in the treatmentof carcinomas

Epstein-Barr virus-encoded EBNA1 inhibits the canonical NF-κB pathway in carcinoma cells by inhibiting IKK phosphorylation

Background The Epstein-Barr virus (EBV)-encoded EBNA1 protein is expressed in all EBV-associated tumours, including undifferentiated nasopharyngeal carcinoma (NPC), where it is indispensable for viral replication, genome maintenance and viral gene expression. EBNA1's transcription factor-like functions also extend to influencing the expression of cellular genes involved in pathways commonly dysregulated during oncogenesis, including elevation of AP-1 activity in NPC cell lines resulting in enhancement of angiogenesis in vitro. In this study we sought to extend these observations by examining the role of EBNA1 upon another pathway commonly deregulated during carcinogenesis; namely NF-κB. Results In this report we demonstrate that EBNA1 inhibits the canonical NF-κB pathway in carcinoma lines by inhibiting the phosphorylation of IKKα/β. In agreement with this observation we find a reduction in the phosphorylation of IκBα and reduced phosphorylation and nuclear translocation of p65, resulting in a reduction in the amount of p65 in nuclear NF-κB complexes. Similar effects were also found in carcinoma lines infected with recombinant EBV and in the EBV-positive NPC-derived cell line C666-1. Inhibition of NF-κB was dependent upon regions of EBNA1 essential for gene transactivation whilst the interaction with the deubiquitinating enzyme, USP7, was entirely dispensable. Furthermore, in agreement with EBNA1 inhibiting p65 NF-κB we demonstrate that p65 was exclusively cytoplasmic in 11 out of 11 NPC tumours studied. Conclusions Inhibition of p65 NF-κB in murine and human epidermis results in tissue hyperplasia and the development of squamous cell carcinoma. In line with this, p65 knockout fibroblasts have a transformed phenotype. Inhibition of p65 NF-κB by EBNA1 may therefore contribute to the development of NPC by inducing tissue hyperplasia. Furthermore, inhibition of NF-κB is employed by viruses as an immune evasion strategy which is also closely linked to oncogenesis during persistent viral infection. Our findings therefore further implicate EBNA1 in playing an important role in the pathogenesis of NPC

Proteoma salivar em pacientes com cancro da cabeça e do pescoço

Mestrado em Bioquímica - Bioquímica ClínicaAfter irreversible mutations in a cell, this can enter in a tumourogenese state evolving from a normal state to a hyperplasic originating a carcinoma in situ followed by an invasive carcinoma. There is also different aetiologic agents like tobacco, alcohol, a deficient diet and oral hygiene or viral infections that will promote the occurrence of mutations and the development of a possible invasive carcinoma. Head and neck cancers represent 5% of all cancers in Portugal with a mortality rate of about 50%, being a huge problem in public health. This way it becomes important to discover a new diagnosis method to discover and identify head and neck cancers as soon as possible to provide an effective treatment. Saliva, composed by proteins have been recently investigated and proved to be a very useful sample in the detection of different types of diseases when associated with Molecular Biology techniques. Recent proteomic and peptidomic analysis showed that increased expression levels of proteins or proteases in saliva could indicate diferent health status. This work addresses the first exploratory study regarding salivary proteases and peptidome with head and neck cancer patients. Results lead us to think in each way animal viruses are implicated in some human cancers and if they're latency state help in the development of cancer. Proteolytic analysis revealed that maybe it would be possible to detect larynx and oropharynx cancers in previous stages but we need further studies to comprise that.Após mutações irreversíveis numa célula, esta pode entrar em num estado tumourogenese evoluindo de um estado normal para um hiperplasico originando um carcinoma in situ, seguido de um carcinoma invasivo. Existem também diferentes agentes etiológicos como o tabaco, álcool, uma dieta deficiente e higiene oral ou infecções virais que podem promover a ocorrência de mutações e o desenvolvimento de um possível carcinoma invasivo. O Cancro da cabeça e pescoço representa 5% de todos os cancros em Portugal, com uma taxa de mortalidade de cerca de 50%, sendo por isso um grande problema na saúde pública. Desta forma, torna-se importante descobrir um novo método de diagnóstico para detectar e identificar cancros da cabeça e do pescoço, o mais rapidamente possível para proporcionar um tratamento eficaz. A saliva, composta por proteínas tem sido recentemente investigada e provou ser uma amostra muito útil na detecção de diferentes tipos de doenças, quando associado com técnicas de biologia molecular. Análises proteomicas e peptidomicas recentes mostraram que o aumento dos níveis de expressão de proteínas ou proteases na saliva pode indicar o estado de saúde em que se encontra o individuo. Este trabalho aborda o primeiro estudo exploratório sobre Proteinas e péptidos salivares com pacientes com cancro de cabeça e pescoço. Os resultados nos levam-nos a indagar se os vírus animais estão implicados de alguma forma neste tipo de cancros e se eles apesar estado de latência ajudam no desenvolvimento do cancro. A análise protolitica revelou que talvez fosse possível detectar cancros da laringe e orofaringe em estádios iniciais, no entanto precisamos de mais estudos que verifiquem estes dados

Recent Advances in Lung Cancer Therapy Based on Nanomaterials: A Review

Lung cancer is one of the commonest cancers with a significant mortality rate for both genders, particularly in men. Lung cancer is recognized as one of the leading causes of death worldwide, which threatens the lives of over 1.6 million people every day. Although cancer is the leading cause of death in industrialized countries, conventional an-ticancer medications are unlikely to increase patients' life expectancy and quality of life significantly. In recent years, there are significant advances in the development and applications of nanotechnology in cancer treatment. The superiority of nanostructured approaches is that they act more selectively than traditional agents. This progress led to the development of a novel field of cancer treatment known as nanomedicine. Various formulations based on nanocarriers, including lipids, polymers, liposomes, nanoparticles and dendrimers have opened new horizons in lung cancer therapy. The application and expan-sion of nano-agents lead to an exciting and challenging research era in pharmaceutical science, especially for the delivery of emerging anti-cancer agents. The objective of this review is to discuss the recent advances in three types of nanoparticle formulations for lung cancer treatments modalities, including liposomes, polymeric micelles, and den-drimers for efficient drug delivery. Afterward, we have summarized the promising clinical data on nanomaterials based therapeutic approaches in ongoing clinical studies

Role of TRAP1 in the adaptive metabolic response under hypoxic conditions in human colorectal carcinoma

La riprogrammazione del metabolismo energetico, che alimenta la veloce crescita e la proliferazione cellulare mediante aggiustamenti delle risorse energetiche, è considerata un caratteristica emergente del cancro. La caratteristica comune di questo alterato metabolismo delle cellule tumorali è l'aumento dell'assorbimento del glucosio e la fermentazione del glucosio in lattato. Questo fenomeno si osserva anche in presenza di ossigeno e mitocondri perfettamente funzionanti. Inoltre, i tumori maligni solidi contengono aree normalmente ipossiche caratterizzate da bassi livelli di ossigeno, e ciò si traduce in una sostanziale riprogrammazione dell'espressione dei geni coinvolti nel metabolismo cellulare, un processo principalmente guidato da HIF1-alfa. TRAP1 è un chaperone molecolare HSP90 upregolato nei carcinomi del colon-retto umani (CRC) e responsabile della soppressione della fosforilazione ossidativa (OXPHOS) e dell'adattamento allo stress. Al fine di caratterizzare il ruolo di TRAP1 nel metabolismo glicolitico e nella risposta metabolica adattativa in condizioni ipossiche, sono stati utilizzati organoidi CRC derivati da pazienti, cellule di CRC umane e campioni di CRC. È stata osservata una correlazione lineare tra i livelli di TRAP1 e l'assorbimento del 18F-fluoro-2-desossiglucosio (18F-FDG) in PET e espressione di GLUT1 nei CRC umani. Coerentemente, TRAP1 aumenta l'espressione di GLUT1, l'uptake di glucosio e la produzione di lattato e downregula l’OXPHOS nelle linee cellulari di CRC, condizione che risulta essere esacerbata in ipossia, che di favorisce per sé il metabolismo glicolitico. È interessante notare che TRAP1 è coinvolto nella regolazione e stabilizzazione di HIF1-alpha indotta dall'ipossia, essendo l’espressione di quest’ultimo parzialmente compromessa nelle cellule CRC silenziate per TRAP1 deprivate di ossigeno. Coerentemente, a livello trascrizionale, la riprogrammazione del metabolismo del cancro guidata da HIF1α è parzialmente bloccata quando TRAP1 è downregulato, con una riduzione dei livelli di espressione di tutti i geni HIF1alfa inducibili sia nelle cellule HCT116 che negli organoidi CRC derivati dai pazienti sottoposti a lunghe esposizioni di ipossia. Questi dati ci consentono di ipotizzare che il livello di espressione di TRAP1 nel carcinoma del colon-retto sia un fattore chiave per l'attivazione del programma genetico di HIF-1α a carattere oncogenico, ampliando il panorama delle risposte adattative mediate da TRAP1 nel carcinoma del colon-retto. Pertanto, questo concetto supporta l'ipotesi che il targeting TRAP1 potrebbe costituire un nuovo approccio antitumorale.Energy metabolism reprogramming, which fuels fast cell growth and proliferation by adjustments of energetic resources, is considered as an emerging hallmark of cancer. The common feature of this altered metabolism of cancer cells is increased glucose uptake and fermentation of glucose to lactate. This phenomenon is observed even in the presence of oxygen and completely functioning mitochondria. Moreover, solid malignant tumors contain normally hypoxic areas characterized by low levels of oxygen, and this results in a substantial reprogramming of the expression of number of genes involved in cellular metabolism, a process mostly driven by HIF1 alpha. TRAP1 is a HSP90 molecular chaperone upregulated in human colorectal carcinomas (CRCs) and responsible for suppression of oxidative phosphorylation (OXPHOS) and adaptation to stress. In order to characterize the role of TRAP1 in glycolytic metabolism and adaptive metabolic response under hypoxic conditions, patients-derived CRC organoids, human CRC cells and CRC samples were used. A linear correlation was observed between TRAP1 levels and 18F-Fluoro-2-Deoxy-Glucose (18F-FDG) uptake upon PET scan or GLUT1 expression in human CRCs. Consistently, TRAP1 enhances GLUT1 expression, glucose uptake and lactate production and downregulates OXPHOS in CRC cell lines, and this condition was more pronounced under hypoxia, which by itself favors glycolytic metabolism. Interestingly, TRAP1 is involved in regulating hypoxia-induced HIF1alpha stabilization, being its expression partially impaired in TRAP1-silenced CRC cells exposed to hypoxia. Consistently, at transcriptional level, the reprogramming of cancer metabolism driven by HIF1α is partially blocked when TRAP1 is downregulated, with a reduction in expression levels of all transcripts induced by long-term exposure to hypoxia in both HCT116 cells and patients-derived CRC organoids. These data allow us to hypothesize that TRAP1 expression level in colorectal cancer is a key factor for the activation of the oncogenic HIF-1α genetic program, widening the panorama of TRAP1-mediated adaptive responses in carcinoma of the colorectal. Thus, this concept supports the hypothesis that TRAP1 targeting could constitute a new antitumor approach

Biodistribution, Uptake and Effects Caused by Cancer-derived Extracellular Vesicles

Extracellular vesicles (EVs) have recently emerged as important mediators of intercellular communication. They are released in the extracellular space by a variety of normal and cancerous cell types and have been found in all human body fluids. Cancer-derived EVs have been shown to carry lipids, proteins, mRNAs, non-coding and structural RNAs and even extra-chromosomal DNA, which can be taken up by recipient cells and trigger diverse physiological and pathological responses. An increasing body of evidence suggests that cancer-derived EVs mediate paracrine signalling between cancer cells. This leads to the increased invasiveness, proliferation rate and chemoresistance, as well as the acquisition of the cancer stem cell phenotype. This stimulates angiogenesis and the reprogramming of normal stromal cells into cancer-promoting cell types. Furthermore, cancer-derived EVs contribute to the formation of the pre-metastatic niche and modulation of anti-tumour immune response. However, as most of these data are obtained by in vitro studies, it is not entirely clear which of these effects are recapitulated in vivo. In the current review, we summarize studies that assess the tissue distribution, trafficking, clearance and uptake of cancer-derived EVs in vivo and discuss the impact they have, both locally and systemically

Transcending frontiers in prostate cancer: the role of oncometabolites on epigenetic regulation, CSCs, and tumor microenvironment to identify new therapeutic strategies

Prostate cancer, as one of the most prevalent malignancies in males, exhibits an approximate 5-year survival rate of 95% in advanced stages. A myriad of molecular events and mutations, including the accumulation of oncometabolites, underpin the genesis and progression of this cancer type. Despite growing research demonstrating the pivotal role of oncometabolites in supporting various cancers, including prostate cancer, the root causes of their accumulation, especially in the absence of enzymatic mutations, remain elusive. Consequently, identifying a tangible therapeutic target poses a formidable challenge. In this review, we aim to delve deeper into the implications of oncometabolite accumulation in prostate cancer. We center our focus on the consequential epigenetic alterations and impacts on cancer stem cells, with the ultimate goal of outlining novel therapeutic strategies