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Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare and heterogeneous tumors that present a wide spectrum of different clinical and biological characteristics. Currently, tumor grading, determined by Ki-67 staining and mitotic counts, represents the most reliable predictor of prognosis. This time-consuming approach fails to reach high reproducibility standards thus requiring novel approaches to support histological evaluation and prognosis. In this study, starting from a microarray analysis of paraffin-embedded tissue specimens, we defined the miRNAs signature for poorly differentiated NETs (G3) compared to well-differentiated NETs (G1 and G2) consisting of 56 deregulated miRNAs. We identified 8 miRNAs that were expressed in all GEP-NETs grades but at different level. Among these miRNAs, miR-96-5p expression level was progressively higher from grade 1 to grade 3; inversely, its target FoxO1 expression decreased from grade 1 to grade 3. Our results reveal that the miRNAs expression profile of GEP-NET is correlated with the tumor grade, showing a potential advantage of miRNA quantification that could aid clinicians in the classification of common GEP-NETs subtypes. These findings could reliably support the histological evaluation of GEP-NETs paving the way toward personalized treatment approaches.
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High serum levels of microbiota-derived uremic toxins, indoxyl sulfate (IS) and p-cresyl sulfate (PCS), are associated with chronic kidney disease (CKD) progression and cardiovascular complications. IS and PCS cannot be efficiently removed by conventional hemodialysis (HD), due to their high binding affinity for albumin. This study evaluates the efficacy of a divinylbenzene-polyvinylpyrrolidone (DVB-PVP) cartridge and a synbiotic to reduce uremic toxins in HD patients. First, the in vitro efficacy of DVB-PVP in adsorbing IS and PCS was evaluated. Second, a randomized, placebo-controlled pilot study in HD patients was carried out to establish whether the administration of a synbiotic, either individually and in association with DVB-PVP-HD, could reduce the production of uremic toxins. In vitro data showed that DVB-PVP resin removed a mean of 56% PCS and around 54% IS, after 6 h of perfusion. While, in the in vivo study, the DVB-PVP cartridge showed its adsorbing efficacy only for IS plasma levels. The combination of synbiotic treatment with DVB-PVP HD decreased IS and PCS both at pre- and post-dialysis levels. In conclusion, this study provides the first line of evidence on the synergistic action of gut microbiota modulation and an innovative absorption-based approach in HD patients, aimed at reducing plasma levels of IS and PCS.
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Cresóis/sangue , Indicã/sangue , Povidona/administração & dosagem , Diálise Renal , Ésteres do Ácido Sulfúrico/sangue , Simbióticos/administração & dosagem , Compostos de Vinila/administração & dosagem , Adsorção , Adulto , Cresóis/química , Feminino , Humanos , Indicã/química , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Povidona/química , Ésteres do Ácido Sulfúrico/química , Compostos de Vinila/químicaRESUMO
SCOPE: Dendritic cells (DCs) are the most potent antigen-presenting cells that play an important role in the crosstalk between the innate and the adaptive immune response. Quercetin exposure is identified as an effective strategy to suppress the inflammatory response induced by LPS. METHODS AND RESULTS: In this study, using a next-generation sequencing analysis, the effect of quercetin on microRNAs (miRNAs) expression in DCs is examined. A signature of 113 miRNAs that are differentially regulated in LPS-stimulated DCs after quercetin exposure is defined. It is demonstrated that the loss of function of miR-369-3p in LPS-stimulated DCs during quercetin exposure led to an increase of CCAAT/enhancer binding protein ß (C/EBP-ß) mRNA and protein and its downstream targets tumor necrosis factor-α (TNF-α) and interleukin 6 (IL6). Conversely, it is shown that the ectopic induction of miR-369-3p without quercetin suppresses the inflammatory response of LPS reducing C/EBP-ß, TNF-α, and IL6 production. In vivo, oral administration of quercetin in dextran-sulfate-sodium-induced colitis induces miR-369-3p expression. CONCLUSIONS: These findings indicate that quercetin-induced miR-369-3p regulates the inflammatory cascade in chronic inflammatory response and present promising therapeutic implications.
Assuntos
Proteína beta Intensificadora de Ligação a CCAAT/genética , Células Dendríticas/metabolismo , Expressão Gênica/efeitos dos fármacos , Inflamação/genética , MicroRNAs/fisiologia , Quercetina/farmacologia , Animais , Células da Medula Óssea/metabolismo , Proteína beta Intensificadora de Ligação a CCAAT/análise , Células Cultivadas/química , Células Dendríticas/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Inativação Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Interleucina-6/genética , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , RNA Mensageiro/análise , Fator de Necrose Tumoral alfa/genéticaRESUMO
[This corrects the article DOI: 10.3389/fimmu.2018.02355.].
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Inflammatory bowel diseases (IBD) are debilitating chronic inflammatory disorders that develop as a result of a defective immune response toward intestinal bacteria. Intestinal dysbiosis is associated with the onset of IBD and has been reported to persist even in patients in deep remission. We investigated the possibility of a dietary-induced switch to the gut microbiota composition using Winnie mice as a model of spontaneous ulcerative colitis and chow enriched with 1% Bronze tomato. We used the near isogenic tomato line strategy to investigate the effects of a diet enriched in polyphenols administered to mild but established chronic intestinal inflammation. The Bronze-enriched chow administered for two weeks was not able to produce any macroscopic effect on the IBD symptoms, although, at molecular level there was a significant induction of anti-inflammatory genes and intracellular staining of T cells revealed a mild decrease in IL17A and IFNγ production. Analysis of the microbial composition revealed that two weeks of Bronze enriched diet was sufficient to perturb the microbial composition of Winnie and control mice, suggesting that polyphenol-enriched diets may create unfavorable conditions for distinct bacterial species. In conclusion, dietary regimes enriched in polyphenols may efficiently support IBD remission affecting the intestinal dysbiosis.
Assuntos
Anti-Inflamatórios/administração & dosagem , Colite Ulcerativa/dietoterapia , Dieta , Disbiose/microbiologia , Microbioma Gastrointestinal/fisiologia , Solanum lycopersicum , Animais , Bactérias/classificação , Linfócitos T CD4-Positivos/metabolismo , Colite Ulcerativa/microbiologia , Modelos Animais de Doenças , Disbiose/dietoterapia , Frutas/química , Microbioma Gastrointestinal/genética , Inflamação/genética , Doenças Inflamatórias Intestinais/dietoterapia , Doenças Inflamatórias Intestinais/microbiologia , Interferon gama/biossíntese , Interleucina-17/biossíntese , Solanum lycopersicum/química , Camundongos , Camundongos Endogâmicos C57BL , Polifenóis/administração & dosagem , RNA Ribossômico 16S/análiseRESUMO
Dendritic cells (DCs) are the most potent antigen-presenting cells able to trigger the adaptive immune response to specific antigens. When non-self-antigens are captured, DCs switch from an "immature" to a "mature" state to fulfill their function. Among the several surface proteins involved in DCs maturation, the role of aquaporins (AQPs) is still poorly understood. Here we investigated the expression profile of Aqps in murine bone marrow derived dendritic cells (BMDCs). Among the Aqps analyzed, Aqp9 was the most expressed by DCs. Its expression level was significantly upregulated 6 h following LPS exposure. Chemical inhibition of Aqp9 led to a decreased inflammatory cytokines secretion. BMDCs from AQP9-KO mice release lower amount of inflammatory cytokines and chemokines and increased release of IL-10. Despite the reduced release of inflammatory cytokines, Aqp9-KO mice were not protected from DSS induced colitis. All together, our data indicate that AQP9 blockade can be an efficient strategy to reduce DCs inflammatory response but it is not sufficient to protect from acute inflammatory insults such as DSS induced colitis.
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Dendritic cells' (DCs) ability to present antigens and initiate the adaptive immune response confers them a pivotal role in immunological defense against hostile infection and, at the same time, immunological tolerance towards harmless components of the microbiota. Food products can modulate the inflammatory status of intestinal DCs. Among nutritionally-derived products, we investigated the ability of quercetin to suppress inflammatory cytokines secretion, antigen presentation, and DCs migration towards the draining lymph nodes. We recently identified the Slpi expression as a crucial checkpoint required for the quercetin-induced inflammatory suppression. Here we demonstrate that Slpi-KO DCs secrete a unique panel of cytokines and chemokines following quercetin exposure. In vivo, quercetin-enriched food is able to induce Slpi expression in the ileum, while little effects are detectable in the duodenum. Furthermore, Slpi expressing cells are more frequent at the tip compared to the base of the intestinal villi, suggesting that quercetin exposure could be more efficient for DCs projecting periscopes in the intestinal lumen. These data suggest that quercetin-enriched nutritional regimes may be efficient for suppressing inflammatory syndromes affecting the ileo-colonic tract.
Assuntos
Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Inflamação/tratamento farmacológico , Quercetina/farmacologia , Inibidor Secretado de Peptidases Leucocitárias/metabolismo , Animais , Antioxidantes/farmacologia , Células da Medula Óssea/efeitos dos fármacos , Células Cultivadas , Quimiocina CXCL1/genética , Quimiocina CXCL1/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Intestinos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Inibidor Secretado de Peptidases Leucocitárias/genéticaRESUMO
BACKGROUND: The importance of hemoproteins for life lies largely in their iron-mediated chemical properties. In the human body, there are about 4 g of iron, a precious resource preserved by sophisticated recycling mechanisms. Iron is also important for pathogen growth, so it is not surprising that immune cells developed mechanisms to reduce iron availability in cases of inflammation. In healthy conditions, macrophages degrade hemoproteins and export iron, while if inflammation develops, they retain cytoplasmic iron to reduce extracellular iron concentrations. Iron-rich macrophages possess a stronger inflammatory ability, which explains the chronic inflammatory response observed in states of iron overload. Inflammatory bowel syndromes are often characterized by intestinal blood loss and consequent anemia, but iron-supplementation therapies may exacerbate the inflammatory response. In chronically transfused patients iron overload is frequently observed; the iron can become toxic and in excess, even fatal if not treated with iron-chelating drugs. CONCLUSION: In the present review, we discuss the importance of iron homeostasis in states of health and inflammation, focusing on iron and iron-chelation treatment for IBD patients. Oral administration of natural ironchelating chemicals may be an effective adjuvant therapy for IBD patients, acting on numerous aspects of chronic inflammatory syndromes.
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Adjuvantes Imunológicos/uso terapêutico , Inflamação/tratamento farmacológico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Quelantes de Ferro/uso terapêutico , Humanos , Inflamação/imunologia , Inflamação/patologia , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/patologiaRESUMO
BACKGROUND: Fruits and vegetables are rich in plant polyphenols, whose consumption is encouraged in healthy dietary regimes due to their antioxidants and anti-inflammatory effects. These organic molecules exhibit numerous properties including phylochelation; the ability to complex metal ions, including highly reactive iron. Among polyphenols, we focused our attention on quercetin that previously demonstrated its ability to reduce dendritic cells (DCs) inflammatory cytokine secretion and antigen presentation following LPS exposure. Dendritic cell inflammatory response is also associated with modulation of several iron metabolism related genes. OBJECTIVE: To characterize the axis between quercetin exposure and iron extracellular transport that may explain polyphenol anti-inflammatory abilities. METHOD: Bone marrow derived DCs were exposed to 25µM of quercetin on day 7 and treated with 1 µg/mL of LPS on day 8. The relation between quercetin exposure and the expression level of genes involved in iron homeostasis was addressed by qPCR. The axis between iron export and quercetin exposure was confirmed in vitro and in vivo using quercetin gavage and quercetin-enriched diet. RESULTS: Here we demonstrate that DCs, exposed to quercetin, activate a pattern of genes that increase extracellular iron export, resulting in an overall decrease in the intracellular iron content and consequent diminished inflammatory abilities. This DCs phenotype is consistent with anti-inflammatory phenotype of the mucosal resident DCs, the ones most commonly exposed to polyphenols. CONCLUSIONS: Iron balance is a crucial checkpoint for DCs inflammatory abilities. Quercetin-enriched nutritional regimes that favor DCs extracellular iron transport could reduce the incidence of chronic inflammatory syndromes.
Assuntos
Anti-Inflamatórios/farmacologia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Homeostase/efeitos dos fármacos , Inflamação/tratamento farmacológico , Ferro/metabolismo , Quercetina/farmacologia , Animais , Células Cultivadas , Células Dendríticas/metabolismo , Inflamação/imunologia , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Renal cell carcinoma (RCC) accounts for more than 2% of neoplasias in humans worldwide. Renal biopsy is the gold standard among the diagnostic procedures, but it is invasive and not suitable for all patients. Therefore, new reliable and non-invasive biomarkers for RCC are required. Secretion of extracellular vesicles (EVs), containing RNA molecules that can be transferred between cells, appears to be a common feature of neoplasia. Consistently, cancer-derived EVs are increased in blood and urine. Therefore, urinary samples may be a non-invasive approach for discovering new diagnostic biomarkers. We enrolled 46 patients of whom 33 with clear cell renal cell carcinoma (ccRCC) and 22 healthy subjects (HS). Urinary EVs were isolated by differential centrifugation. Microarray analysis led to the identification of RNA molecules that were validated using RT-qPCR. We found that urinary exosomal shuttle RNA (esRNA) pattern was significantly different in ccRCC patients compared to HS and to non-clear cell RCC (non-ccRCC) and we identified three esRNAs involved in the tumor biology that may be potentially suitable as non-invasive gene signature. GSTA1, CEBPA and PCBD1 esRNA levels were decreased in urine of patients compared with HS. This pattern was specific of the ccRCC and one month after partial or radical nephrectomy the esRNA levels increased to reach the normal level. This study suggests, for the first time, the potential use of the RNA content of urinary EVs to provide a non-invasive first step to diagnose the ccRCC.
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Dendritic cells (DCs) are professional antigen presenting cells (APCs) that in response to microbial infections generate long-lasting adaptive immune response. Following microbial uptake, DCs undergo a cascade of cellular differentiation that ultimately leads to "mature" DCs. Mature DCs produce a variety of inflammatory cytokines, including tumor necrosis factor-α (TNFß) a key cytokine for the inflammatory cascade. In numerous studies, polyphenols, including quercetin, demonstrated their ability to suppress TNFα secretion and protect from the onset of chronic inflammatory disorders. We show that murine bone marrow derived DCs express Slpi following quercetin exposure. Slpi is known to suppress LPS mediated NFκB activation, thus, it was hypothesized that its expression could be the key step for polyphenol induced inflammatory suppression. Slpi-KO DCs poorly respond to quercetin administration failing to reduce TNFα secretion in response to quercetin exposure. Supernatant from quercetin exposed DCs could also reduce LPS-mediated TNFα secretion by unrelated DCs, but this property is lost using an anti-Slpi antibody. In vivo, oral administration of quercetin is able to induce Slpi expression. Human biopsies from inflamed tract of the intestine reveal the presence of numerous SLPI+ cells and the expression level could be further increased by quercetin administration. We propose that quercetin induces Slpi expression that in turn reduces the inflammatory response. Our data encourages the development of nutritional strategies to improve the efficiency of current therapies for intestinal chronic inflammatory syndrome and reduce the risks of colorectal cancer development.
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Quercetina/farmacologia , Inibidor Secretado de Peptidases Leucocitárias/genética , Inibidor Secretado de Peptidases Leucocitárias/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Animais , Colo/efeitos dos fármacos , Colo/metabolismo , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Espaço Extracelular/metabolismo , Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Lipopolissacarídeos/imunologia , Masculino , CamundongosRESUMO
Glucose-6-phosphate isomerase (GPI), also known as phosphoglucose isomerase, was initially identified as the second glycolytic enzyme that catalyzes the interconversion of glucose-6-phosphate to fructose-6-phosphate. Later studies demonstrated that GPI was the same as the autocrine motility factor (AMF), and that it mediates its biological effects through the interaction with its surface receptor (AMFR/gp78). In this study, we assessed the role of GPI/AMF as a prognostic factor for clear cell renal cell carcinoma (ccRCC) cancer-specific (CSS) and progression-free survival (PFS). In addition, we evaluated the expression and localization of GPI/AMF and AMFR, using tissue microarray-based immunohistochemistry (TMA-IHC), indirect immunofluorescence (IF), and confocal microscopy analysis.Primary renal tumor and nonneoplastic tissues were collected from 180 patients who underwent nephrectomy for ccRCC. TMA-IHC and IF staining showed an increased signal for both GPI and AMFR in cancer cells, and their colocalization on plasma membrane. Kaplan-Meier curves showed significant differences in CSS and PFS among groups of patients with high versus low GPI expression. In particular, patients with high tissue levels of GPI had a 5-year survival rate of 58.8%, as compared to 92.1% for subjects with low levels (Pâ<â0.0001). Similar findings were observed for PFS (56.8% vs 93.3% at 5 years). At multivariate analysis, GPI was an independent adverse prognostic factor for CSS (HRâ=â1.26; Pâ=â0.001), and PFS (HRâ=â1.16; Pâ=â0.01).In conclusion, our data suggest that GPI could serve as a marker of ccRCC aggressiveness and a prognostic factor for CSS and PFS.
Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/mortalidade , Regulação Neoplásica da Expressão Gênica , Glucose-6-Fosfato Isomerase/metabolismo , Neoplasias Renais/mortalidade , Rim/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/metabolismo , Citocinas/genética , Citocinas/metabolismo , Feminino , Técnica Indireta de Fluorescência para Anticorpo , Glucose-6-Fosfato Isomerase/genética , Humanos , Imuno-Histoquímica/métodos , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , Masculino , Microscopia Confocal , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , Reação em Cadeia da Polimerase em Tempo Real , Estudos Retrospectivos , Análise de Sobrevida , Regulação para CimaRESUMO
Prostate cancer (PCa) is the second leading cause of cancer-related death in men; however, the molecular mechanisms leading to its development and progression are not yet fully elucidated. Of note, it has been recently shown that conditional stk11 knockout mice develop atypical hyperplasia and prostate intraepithelial neoplasia (PIN). We recently reported an inverse correlation between the activity of the STK11/AMPK pathway and the MAPK/p38 cascade in HIF1A-dependent malignancies. Furthermore, MAPK/p38 overactivation was detected in benign prostate hyperplasia, PIN and PCa in mice and humans. Here we report that STK11 expression is significantly decreased in PCa compared to normal tissues. Moreover, STK11 protein levels decreased throughout prostate carcinogenesis. To gain insight into the role of STK11-MAPK/p38 activity balance in PCa, we treated PCa cell lines and primary biopsies with a well-established MAPK14-MAPK11 inhibitor (SB202190), which has been extensively used in vitro and in vivo. Our results indicate that inhibition of MAPK/p38 significantly affects PCa cell survival in an STK11-dependent manner. Indeed, we found that pharmacologic inactivation of MAPK/p38 does not affect viability of STK11-proficient PCa cells due to the triggering of the AMPK-dependent autophagic pathway, while it induces apoptosis in STK11-deficient cells irrespective of androgen receptor (AR) status. Of note, AMPK inactivation or autophagy inhibition in STK11-proficient cells sensitize SB202190-treated PCa cells to apoptosis. On the other end, reconstitution of functional STK11 in STK11-deficient PCa cells abrogates apoptosis. Collectively, our data show that STK11 is a key factor involved in the early phases of prostate carcinogenesis, and suggest that it might be used as a predictive marker of therapeutic response to MAPK/p38 inhibitors in PCa patients.
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Metabolomic profiling offers a powerful methodology for understanding the perturbations of biochemical systems occurring during a disease process. During neoplastic transformation, prostate cells undergo metabolic reprogramming to satisfy the demands of growth and proliferation. An early event in prostate cell transformation is the loss of capacity to accumulate zinc. This change is associated with a higher energy efficiency and increased lipid biosynthesis for cellular proliferation, membrane formation and cell signaling. Moreover, recent studies have shown that sarcosine, an N-methyl derivative of glycine, was significantly increased during disease progression from normal to localized to metastatic prostate cancer. Mapping the metabolomic profiles to their respective biochemical pathways showed an upregulation of androgen-induced protein synthesis, an increased amino acid metabolism and a perturbation of nitrogen breakdown pathways, along with high total choline-containing compounds and phosphocholine levels. In this review, the role of emerging biomarkers is summarized, based on the current understanding of the prostate cancer metabolome.
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Biomarcadores Tumorais , Metaboloma , Metabolômica/métodos , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/metabolismo , Humanos , MasculinoRESUMO
The analysis of cancer metabolome has shown that proliferating tumor cells require a large quantities of different nutrients in order to support their high rate of proliferation. In this study we analyzed the metabolic profile of glycolysis and the pentose phosphate pathway (PPP) in human clear cell-renal cell carcinoma (ccRCC) and evaluate the role of these pathways in sustaining cell proliferation, maintenance of NADPH levels, and production of reactive oxygen species (ROS). Metabolomic analysis showed a clear signature of increased glucose uptake and utilization in ccRCC tumor samples. Elevated levels of glucose-6-phosphate dehydrogenase (G6PDH) in association with higher levels of PPP-derived metabolites, suggested a prominent role of this pathway in RCC-associated metabolic alterations. G6PDH inhibition, caused a significant decrease in cancer cell survival, a decrease in NADPH levels, and an increased production of ROS, suggesting that the PPP plays an important role in the regulation of ccRCC redox homeostasis. Patients with high levels of glycolytic enzymes had reduced progression-free and cancer-specific survivals as compared to subjects with low levels. Our data suggest that oncogenic signaling pathways may promote ccRCC through rerouting the sugar metabolism. Blocking the flux through this pathway may serve as a novel therapeutic target.
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Carcinoma de Células Renais/enzimologia , Glucosefosfato Desidrogenase/metabolismo , Glicólise/fisiologia , Neoplasias Renais/enzimologia , Metabolômica , Via de Pentose Fosfato/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/patologia , Proliferação de Células/fisiologia , Cromatografia Líquida , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , NADP/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Células Tumorais CultivadasRESUMO
Recently, several studies have investigated the presence of cancer stem cells in kidney cancer, performed characterization, and compared their profile with the normal stem cell counterparts. CD133, alone or in combination with other molecular markers, has been used to isolate normal and cancer stem cells from different sources, including renal carcinoma; however, it is still a matter of debate whether CD133+ cells really represent the main tumorigenic population within the heterogeneous pool of cancer cells that characterize this tumor. In this review, we summarize and discuss the current findings related to cancer stem cells isolation in renal cell carcinoma, focusing on controversies about their origin and the identification of a specific marker.
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Antígeno AC133/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/patologia , Neoplasias Renais/patologia , Células-Tronco Neoplásicas/metabolismo , Transformação Celular Neoplásica , Humanos , Células-Tronco Pluripotentes/patologia , Células Tumorais Cultivadas/citologiaRESUMO
Malignancies are one of the main causes of mortality in diabetic patients; however, to date, very limited data have been reported on the specific influence of type 2 diabetes mellitus (T2DM) on the survival of patients with renal cell carcinoma (RCC). In the present long-term retrospective study, we investigated whether T2DM may influence the overall survival (OS), cancer-specific survival (CSS), and progression-free survival (PFS) in patients with surgically treated RCC. Medical records of 924 patients treated by radical or partial nephrectomy for sporadic, unilateral RCC were reviewed. Patients with type-1 DM and with T2 DM receiving insulin treatment were excluded. Survival estimates were calculated according to the Kaplan-Meier method and compared with the log-rank test. Univariate and multivariate analyses were performed using the Cox regression model.Of the 924 RCC patients, 152 (16.5%) had T2DM. Mean follow-up was 68.5 months. Mean OS was 41.3 and 96.3 months in T2DM and non-T2DM patients, respectively (P < 0.0001).The estimated CSS rates at 1, 3, and 5 years in T2DM versus non-T2DM patients were 63.4% versus 76.7%, 30.4% versus 56.6%, and 16.3% versus 48.6%, respectively (P = 0.001). Mean PFS was significantly lower (31.5 vs 96.3 months; P < 0.0001) in the T2DM group. At multivariate analysis, T2DM was an independent adverse prognostic factor for OS (hazard ratio [HR] â= 3.44; 95% confidence interval [CI]:2.40-4.92), CSS (HR = 6.39; 95% CI: 3.78-10.79), and PFS (HR = 4.71; 95% CI: 3.11-7.15). In conclusion, our findings suggest that patients with RCC and pre-existing T2DM have a shorter OS, increased risk of recurrence, and higher risk for kidney cancer mortality than those without diabetes.
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Carcinoma de Células Renais/mortalidade , Diabetes Mellitus Tipo 2/complicações , Neoplasias Renais/mortalidade , Idoso , Carcinoma de Células Renais/complicações , Progressão da Doença , Intervalo Livre de Doença , Feminino , Humanos , Itália/epidemiologia , Neoplasias Renais/complicações , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de RiscoRESUMO
The effects of obstruction on renal function are the consequence of many factors that profoundly alter all components of glomerular function. Besides the acute effects on glomerular filtration rate and tubule function, a chronic obstruction induces tubular and interstitial injury that results from the activation of different pathways. The progression of tubulointerstitial injury leads to chronic renal damage characterized by tubular atrophy, inflammatory cell infiltration, and interstitial fibrosis. Obstructive nephropathy is an evolving disease in which the renal damage continues even after relief of the obstruction. In particular, it has been demonstrated that the time of relief is the most important factor in predicting long-term renal function deterioration. In this setting, the EGF/MCP-1 ratio, urinary NGAL, and urinary KIM-1 are useful early biomarkers of progressive renal damage and could have a potential role in predicting the long-term renal outcome. This minireview summarizes the role of these emerging urinary biomarkers of obstructive nephropathy based on the current understanding of the pathophysiology of renal injury.
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Injúria Renal Aguda/urina , Biomarcadores/urina , Nefropatias/urina , Obstrução Ureteral/urina , Injúria Renal Aguda/patologia , Proteínas de Fase Aguda/urina , Quimiocina CCL2/urina , Fator de Crescimento Epidérmico/urina , Taxa de Filtração Glomerular , Receptor Celular 1 do Vírus da Hepatite A , Humanos , Túbulos Renais/patologia , Lipocalina-2 , Lipocalinas/urina , Glicoproteínas de Membrana/urina , Proteínas Proto-Oncogênicas/urina , Receptores ViraisRESUMO
PURPOSE: In clear cell renal cell carcinoma tissue samples we identified and characterized a population of renal cell carcinoma derived CD133+/CD24+ cancer cells. We studied differences between these cells and their nonneoplastic counterpart, tubular adult renal progenitor cells. MATERIALS AND METHODS: CD133+/CD24+ renal cell carcinoma derived cells were isolated from 40 patients. The mesenchymal phenotype and stemness proteomic profile of these renal cell carcinoma derived cells were characterized. Colony forming efficiency and self-renewal ability were tested by limiting dilution. Tumorigenic properties were evaluated in vitro by soft agar assay. The angiogenic response was evaluated in vivo by the chorioallantoic membrane angiogenic assay. Microarray analysis was performed on 6 tubular adult renal progenitor cell and 6 renal cell carcinoma derived cell clones. Membrane protein expression was evaluated by flow cytometry and immunofluorescence staining. RESULTS: CD133+/CD24+ cells were isolated from normal and tumor kidney tissue. Fluorescence activated cell sorting revealed that renal cell carcinoma derived cells did not express mesenchymal stem cell markers. CD133+/CD24+ tumor cells were more undifferentiated than tubular adult renal progenitor cells. Renal cell carcinoma derived cells were clonigenic and could differentiate into adipocytes, epithelial and osteogenic cells. They could also regenerate tumor cells in vitro and induce angiogenesis in vivo. Gene expression profile identified CTR2 as a membrane marker for this neoplastic population. CTR2 was involved in renal cell carcinoma derived cell cisplatin resistance. CONCLUSIONS: Our results indicate the presence of a CD133+/CD24+/CTR2+ cancer cell population in clear cell renal cell carcinoma. These cells have some stem cell-like features, including in vitro self-maintenance and differentiating capabilities, and they can induce an angiogenic response in vivo.
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Carcinoma de Células Renais/química , Carcinoma de Células Renais/patologia , Proteínas de Transporte de Cátions/análise , Neoplasias Renais/química , Neoplasias Renais/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas SLC31 , Células Tumorais CultivadasRESUMO
CA 15-3, CA 125 and ß-2 microglobulin are three common tumor markers currently used for diagnosis, prognosis, assessment of therapeutic response, and/or to evaluate recurrence in breast and ovarian cancer and malignant lymphoproliferative disorders, respectively. In the present prospective study we assessed the role of these three serum proteins as biomarkers for renal cell carcinoma (RCC), as well as any association between tumor marker levels and clinical-pathological parameters. CA 15-3, CA 125, and ß-2 microglobulin were preoperatively measured in 332 patients who underwent nephrectomy for RCC. Estimates of cancer-specific survival (CSS) was calculated according to the Kaplan-Meier method. Multivariate analysis was performed to identify the most significant variables for predicting CSS. Preoperatively, 35.2% (n = 117), 9.6% (n = 32) and 30.4% (n = 101) of the patients had abnormal levels of CA 15-3, CA 125 and ß-2 microglobulin, respectively. Statistically significant differences resulted between CA 15-3, CA 125 and ß-2 microglobulin values and tumor size, Fuhrman grade, presence of lymph node, and visceral metastases. CSS was significantly decreased for patients with high levels of CA 15-3, CA 125, and ß-2 microglobulin (P < 0.0001, P < 0.0001, and P = 0.001, resp.). At multivariate analysis only age, the presence of visceral metastases, and high levels of CA 15-3 were independent adverse prognostic factors for CSS.