Metabolism within the tumor microenvironment and its implication on cancer progression: an ongoing therapeutic target

Since reprogramming energy metabolism is considered a new hallmark of cancer, tumor metabolism is again in the spotlight of cancer research. Many studies have been carried out and many possible therapies have been developed in the last years. However, tumor cells are not alone. A series of extracellular components and stromal cells, such as endothelial cells, cancer-associated fibroblasts, tumor-associated macrophages and tumor-infiltrating T cells, surround tumor cells in the so-called tumor microenvironment. Metabolic features of these cells are being studied in deep in order to find relationships between metabolism within the tumor microenvironment and tumor progression. Moreover, it cannot be forgotten that tumor growth is able to modulate host metabolism and homeostasis, so that tumor microenvironment is not the whole story. Importantly, the metabolic switch in cancer is just a consequence of the flexibility and adaptability of metabolism and should not be surprising. Treatments of cancer patients with combined therapies including anti-tumor agents with those targeting stromal cell metabolism, anti-angiogenic drugs and/or immunotherapy are being developed as promising therapeutics.Mª Carmen Ocaña is recipient of a predoctoral FPU grant from the Spanish Ministry of Education, Culture and Sport. Supported by grants BIO2014-56092-R (MINECO and FEDER), P12-CTS-1507 (Andalusian Government and FEDER) and funds from group BIO-267 (Andalusian Government). The "CIBER de Enfermedades Raras" is an initiative from the ISCIII (Spain). The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript

Chronic exposure of diesel exhaust particles induces alveolar enlargement in mice

Background\ud Diesel exhaust particles (DEPs) are deposited into the respiratory tract and are thought to be a risk factor for the development of diseases of the respiratory system. In healthy individuals, the timing and mechanisms of respiratory tract injuries caused by chronic exposure to air pollution remain to be clarified.\ud \ud \ud Methods\ud We evaluated the effects of chronic exposure to DEP at doses below those found in a typical bus corridor in Sao Paulo (150 μg/m3). Male BALB/c mice were divided into mice receiving a nasal instillation: saline (saline; n = 30) and 30 μg/10 μL of DEP (DEP; n = 30). Nasal instillations were performed five days a week, over a period of 90 days. Bronchoalveolar lavage (BAL) was performed, and the concentrations of interleukin (IL)-4, IL-10, IL-13 and interferon-gamma (INF-γ) were determined by ELISA-immunoassay. Assessment of respiratory mechanics was performed. The gene expression of Muc5ac in lung was evaluated by RT-PCR. The presence of IL-13, MAC2+ macrophages, CD3+, CD4+, CD8+ T cells and CD20+ B cells in tissues was analysed by immunohistochemistry. Bronchial thickness and the collagen/elastic fibers density were evaluated by morphometry. We measured the mean linear intercept (Lm), a measure of alveolar distension, and the mean airspace diameter (D0) and statistical distribution (D2).\ud \ud \ud Results\ud DEP decreased IFN-γ levels in BAL (p = 0.03), but did not significantly alter IL-4, IL-10 and IL-13 levels. MAC2+ macrophage, CD4+ T cell and CD20+ B cell numbers were not altered; however, numbers of CD3+ T cells (p ≤ 0.001) and CD8+ T cells (p ≤ 0.001) increased in the parenchyma. Although IL-13 (p = 0.008) expression decreased in the bronchiolar epithelium, Muc5ac gene expression was not altered in the lung of DEP-exposed animals. Although respiratory mechanics, elastic and collagen density were not modified, the mean linear intercept (Lm) was increased in the DEP-exposed animals (p ≤ 0.001), and the index D2 was statistically different (p = 0.038) from the control animals.\ud \ud \ud Conclusion\ud Our data suggest that nasal instillation of low doses of DEP over a period of 90 days results in alveolar enlargement in the pulmonary parenchyma of healthy mice.This work was supported by Coordenação de Aperfeiçoamento de Pessoal\ud de Nível Superior (CAPES) and Fundação de Amparo à Pesquisa do Estado\ud de São Paulo (FAPESP 2010/51377-9 and 2012/16279-1). Dr. Mauad is funded\ud by CNPq (National Research Council), Brazil

Gut microbiota and sirtuins in obesity-related inflammation and bowel dysfunction

Obesity is a chronic disease characterized by persistent low-grade inflammation with alterations in gut motility. Motor abnormalities suggest that obesity has effects on the enteric nervous system (ENS), which controls virtually all gut functions. Recent studies have revealed that the gut microbiota can affect obesity and increase inflammatory tone by modulating mucosal barrier function. Furthermore, the observation that inflammatory conditions influence the excitability of enteric neurons may add to the gut dysfunction in obesity. In this article, we discuss recent advances in understanding the role of gut microbiota and inflammation in the pathogenesis of obesity and obesity-related gastrointestinal dysfunction. The potential contribution of sirtuins in protecting or regulating the circuitry of the ENS under inflamed states is also considered

Effects of the participation of steroid-like compounds from air pollution in the airway epithelium of male and female mice

O epitélio nasal é a primeira porção do sistema respiratório a entrar em contato com o ambiente externo. Partículas da poluição do ar, principalmente os compostos orgânicos absorvidos, podem atuar como liberadores endócrinos. O receptor aril hidrocarboneto (AhR) é um importante competidor dos receptores de estrógeno-beta (ERbeta) que regulam a transcrição do gene para enzimas de metabolização xenobióticas (enzimas do citocromo P450). O objetivo deste estudo é identificar e quantificar ERbeta, AhR, CYP1A1, CYP1A2, CYP1B1 e o perfil de muco no epitélio nasal de camundongos machos e fêmeas em diferentes fases do ciclo estral. Camundongos BALB/c machos (n=32) e fêmeas (n=84) foram expostos ao ar ambiente e ao MP2,5 concentrado a 600 ug.m-³ em um concentrador de partículas ambientais (CPAs). As fêmeas foram divididas de acordo com as fases do ciclo estral: proestro, estro e diestro. O epitélio nasal foi avaliado por RT-PCR e imuno-histoquímica para análise de expressão de ERbeta (proteína), Erbeta-1 e Erbeta-2 (gene), AhR (proteína e gene) e Cyp1a1, Cyp1a2 and Cyp1b1 (gene). A quantificação de muco neutro - Periodic Acid Schiff\'s (PAS+) e ácido - Alcian Blue (AB+) foi avaliada por morfometria. As exposições foram realizadas durante 5 dias/semana, por 45 ± 55 dias. A expressão de Erbeta-2 RNAm apresentou diferenças em resposta à exposição ao CPAs (p=0,016), bem como uma diminuição em fêmeas, quando comparadas aos camundongos machos (p=0,036). A expressão de Cyp1b1 RNAm foi significantemente menor no grupo exposto ao CPAs, em relação ao grupo exposto ao ar ambiente nas fêmeas em diestro (p=0,036). A expressão de Erbeta foi aumentada no epitélio nasal de fêmeas em estro expostas ao CPAs (p=0,005) e a expressão de AhR foi menor em fêmeas em proestro expostas ao CPAs (p=0,048). A exposição ao CPAs levou ao aumento do conteúdo de muco ácido em camundongos machos (p=0,048), o qual diminuiu em fêmeas (p=0,040), quando comparados ao grupo ar ambiente. Este estudo mostrou que houve diferentes respostas à exposição à poluição do ar no epitélio nasal entre machos e fêmeas, e que essas diferenças podem estar relacionadas com a predisposição de fêmeas apresentarem maior suscetibilidade a doenças respiratórias das vias aéreasThe nasal epithelium is the first portion of the respiratory system to reach contact with the external environment. Air pollution particles, mainly the organic compounds absorbed into them, may act as endocrine releasers. The aryl hydrocarbon (AhR) receptor is an important competitor of estrogenic receptors-beta (ERbeta) that regulate transcription of gene coding for xenobiotic-metabolizing enzymes (cytochrome P450 enzymes). The aim of this study is to identify and quantify in the nasal epithelium of male and female mice in different estrous cycle phases related with ERbeta, AhR, CYP1A1, 1A2, 1B1 and the mucus profile. Male (n=32) and female (n=84) BALB/c mice were exposed to ambient air and PM2.5 concentrated at 600 ug.m-³ in an ambient particle concentrator with a particulate matter diameter of 2.5 um (PM2.5). Females were subdivided in three estrous cycles: proestrus, estrus and diestrus. Nasal epithelium was evaluated through RT-PCR and immunohistochemistry for the expression of ERbeta (protein), Erbeta-1 and Erbeta-2 (gene expression), AhR (protein and gene expression) and Cyp1a1, Cyp1a2 and Cyp1b1 (gene expression). Morphometry was applied for evaluation of mucus profile: acid - Alcian Blue (AB+) and neutral - Periodic Acid Schiff\'s (PAS+). Exposure happened for 5 days/week, for 45 ± 55 days. There were differences in Erbeta-2 mRNA in response to exposition to CPAs (p=0.016), and a significant decrease in female compared male mice (p=0.036). Cyp1b1 mRNA was significantly smaller in the CPAs-exposed group compared with the ambient air group in diestrus female mice (p=0.036). The ERbeta expression increased in the nasal epithelium of CPAs-exposed females in the estrus cycle (p=0.005), and the AhR expression decreased in the proestrus cycle of CPAs-exposed females (p=0.048). The exposure to the CPAs led to an increase in the acidic content of mucus in male mice (p=0.048), and decreased in female mice (p=0.040), compared to the ambient air group. This study showed there were different responses in the nasal epithelia of male and female mice exposed to air pollution, which could be related to the predisposition of the females to present more susceptibility to airway respiratory disease

Subchronic effects of diesel on nasal and airway epithelium in a murine model

A combustão do diesel (DEP) é a principal fonte de partículas ultrafinas (PUFs) relacionadas à poluição causada pelo tráfego. Indivíduos com doenças respiratórias crônicas estão propensos a exacerbações durante a exposição à poluição ambiente. Este estudo avaliou os efeitos de exposição subcrônica a uma baixa dose de partículas de combustão de diesel (DEP). 90 camundongos machos BALB/c foram divididos em 3 grupos: (a) Controle: instilação nasal de solução salina (n = 30); (b) DEP15: 15?g de DEP/10?l de solução salina (n = 30); e (c) DEP30: 30?g de DEP/10?l de solução salina (n = 30) durante cinco dias por semana, por 30 e 60 dias. Os animais foram anestesiados com pentobarbital de sódio (50mg/kg ip) e sacrificados por exanguinação. A contagem de células inflamatórias e as concentrações de interleucinas (IL) -4, -10, -13 e -17 no lavado broncoalveolar (LBA) foram avaliadas por ensaio imunoenzimático (Elisa). mRNA da MUC5ac foi avaliado por PCR em tempo real. A análise histológica do septo nasal e bronquíolos foi realizada para avaliar: (a) a espessura do epitélio brônquico e nasal, (b) o conteúdo de muco neutro e ácido na mucosa nasal. Nossos resultados mostraram que a instilação de DEP30 após 30 dias aumentou o número de células inflamatórias totais em relação ao controle (p=0,033). Ao comparar os resultados de DEP30 com o grupo Controle após 60 dias observamos os seguintes aumentos: (a) na expressão de MUC5AC nos pulmões (p = 0,016), no conteúdo de muco ácido no septo nasal (p = 0,017), nas células inflamatórias totais no LBA (p<0,001), no número de macrófagos no LBA (p=0,035) e na espessura do epitélio nasal (p=0,042). Nossos dados sugerem que dose baixa de DEP induz inflamação do trato respiratório com padrão tempo-dependente.Diesel exhaust is the major source of ultrafine particles (UFPs) in trafficrelated pollution. Subjects with chronic respiratory diseases have great risk of exacerbations during exposure to air pollution. This study evaluated the effects of sub-chronic exposure to a low dose of diesel exhaust particles (DEPs). Ninety male BALB/c mice were divided into 3 groups: (a) Control: nasal saline instillation (n=30); (b) DEP15: nasal instillation of 15?g of DEP/10?l of saline (n=30); and (c) DEP30: nasal instillation of 30?g of DEP/10?l of saline (n=30). Nasal instillations were performed five-days a week, during 30 e 60 days. Animals were anesthetized with pentobarbital sodium (50mg/kg i.p), and sacrificed by exsanguination. Bronchoalveolar lavage (BAL) was performed to assess inflammatory cell count and concetrations of interleukin (IL)-4, -10, -13 and -17 by enzyme-linked immunosorbent assay (ELISA). The RNAm MUC5ac gene expression was evaluated by real-time PCR. Histological analysis in nasal septum and bronchioles assessed: (a) bronchial and nasal epithelium thickness (b) acidic and neutral nasal mucous content. Our results showed that the instillation of DEP30 after 30 days increased the number of total inflammatory cells, as compared to the Control group (p = 0.033). The results of DEP30 after 60 days showed increases in: (a) the expression of MUC5AC in the lungs (p = 0.016); (b) acidic mucus production in the nasal septum (p = 0.017); (c) total inflammatory cells in the BAL fluid (p <0.001); (d) the number of macrophages in BALF (p = 0.035); and (d) nasal epithelium thickness (p = 0.042), as compared with control after 60 days. Our data suggest that a low dose of DEP induces inflammation of the respiratory tract in a time- dependent manner