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1.
Proc Natl Acad Sci U S A ; 114(41): E8685-E8694, 2017 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-28973887

RESUMO

The molecular underpinnings of invasion, a hallmark of cancer, have been defined in terms of individual mediators but crucial interactions between these mediators remain undefined. In xenograft models and patient specimens, we identified a c-Met/ß1 integrin complex that formed during significant invasive oncologic processes: breast cancer metastases and glioblastoma invasive resistance to antiangiogenic VEGF neutralizing antibody, bevacizumab. Inducing c-Met/ß1 complex formation through an engineered inducible heterodimerization system promoted features crucial to overcoming stressors during metastases or antiangiogenic therapy: migration in the primary site, survival under hypoxia, and extravasation out of circulation. c-Met/ß1 complex formation was up-regulated by hypoxia, while VEGF binding VEGFR2 sequestered c-Met and ß1 integrin, preventing their binding. Complex formation promoted ligand-independent receptor activation, with integrin-linked kinase phosphorylating c-Met and crystallography revealing the c-Met/ß1 complex to maintain the high-affinity ß1 integrin conformation. Site-directed mutagenesis verified the necessity for c-Met/ß1 binding of amino acids predicted by crystallography to mediate their extracellular interaction. Far-Western blotting and sequential immunoprecipitation revealed that c-Met displaced α5 integrin from ß1 integrin, creating a complex with much greater affinity for fibronectin (FN) than α5ß1. Thus, tumor cells adapt to microenvironmental stressors induced by metastases or bevacizumab by coopting receptors, which normally promote both cell migration modes: chemotaxis, movement toward concentrations of environmental chemoattractants, and haptotaxis, movement controlled by the relative strengths of peripheral adhesions. Tumor cells then redirect these receptors away from their conventional binding partners, forming a powerful structural c-Met/ß1 complex whose ligand-independent cross-activation and robust affinity for FN drive invasive oncologic processes.


Assuntos
Neoplasias da Mama/secundário , Resistencia a Medicamentos Antineoplásicos , Glioblastoma/secundário , Integrina beta1/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , Inibidores da Angiogênese/farmacologia , Animais , Apoptose/efeitos dos fármacos , Bevacizumab/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Adesão Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Feminino , Fibronectinas/metabolismo , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Humanos , Integrina beta1/genética , Camundongos , Invasividade Neoplásica , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-met/genética , Transdução de Sinais/efeitos dos fármacos , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
2.
JCI Insight ; 2(2): e88815, 2017 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-28138554

RESUMO

Clinical trials revealed limited response duration of glioblastomas to VEGF-neutralizing antibody bevacizumab. Thriving in the devascularized microenvironment occurring after antiangiogenic therapy requires tumor cell adaptation to decreased glucose, with 50% less glucose identified in bevacizumab-treated xenografts. Compared with bevacizumab-responsive xenograft cells, resistant cells exhibited increased glucose uptake, glycolysis, 13C NMR pyruvate to lactate conversion, and survival in low glucose. Glucose transporter 3 (GLUT3) was upregulated in bevacizumab-resistant versus sensitive xenografts and patient specimens in a HIF-1α-dependent manner. Resistant versus sensitive cell mitochondria in oxidative phosphorylation-selective conditions produced less ATP. Despite unchanged mitochondrial numbers, normoxic resistant cells had lower mitochondrial membrane potential than sensitive cells, confirming poorer mitochondrial health, but avoided the mitochondrial dysfunction of hypoxic sensitive cells. Thin-layer chromatography revealed increased triglycerides in bevacizumab-resistant versus sensitive xenografts, a change driven by mitochondrial stress. A glycogen synthase kinase-3ß inhibitor suppressing GLUT3 transcription caused greater cell death in bevacizumab-resistant than -responsive cells. Overexpressing GLUT3 in tumor cells recapitulated bevacizumab-resistant cell features: survival and proliferation in low glucose, increased glycolysis, impaired oxidative phosphorylation, and rapid in vivo proliferation only slowed by bevacizumab to that of untreated bevacizumab-responsive tumors. Targeting GLUT3 or the increased glycolysis reliance in resistant tumors could unlock the potential of antiangiogenic treatments.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Bevacizumab/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Glioblastoma/tratamento farmacológico , Transportador de Glucose Tipo 3/genética , Glicólise , Inibidores da Angiogênese/farmacologia , Animais , Bevacizumab/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Glioblastoma/irrigação sanguínea , Glioblastoma/genética , Glioblastoma/metabolismo , Glucose/metabolismo , Transportador de Glucose Tipo 3/efeitos dos fármacos , Humanos , Espectroscopia de Ressonância Magnética , Camundongos , Camundongos Nus , Transplante de Neoplasias , Fosforilação Oxidativa , Ácido Pirúvico/metabolismo , Regulação para Cima
3.
Am J Kidney Dis ; 69(2): 192-199, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27522513

RESUMO

BACKGROUND: Cardiac surgery-related acute kidney injury (AKI) is a common postoperative complication that greatly increases morbidity and mortality. There are currently no effective interventions to prevent AKI associated with cardiac surgery. Experimental data have shown that administration of the mineralocorticoid receptor blocker spironolactone prevents renal injury induced by ischemia-reperfusion in rats. The objective of this study was to test whether short-term perioperative administration of oral spironolactone could reduce the incidence of AKI in cardiac surgical patients. STUDY DESIGN: Randomized, double-blinded, placebo-controlled trial. SETTING & PARTICIPANTS: Data were collected from April 2014 through July 2015 at the National Heart Institute in Mexico. 233 patients were included; 115 and 118 received spironolactone or placebo, respectively. INTERVENTION: Spironolactone or placebo once at a dose of 100mg 12 to 24 hours before surgery and subsequently 3 further doses of 25mg in postoperative days 0, 1, and 2 were administered. OUTCOMES: Patients were followed up for 7 days or until discharge from the intensive care unit (ICU). The primary end point was AKI incidence defined by KDIGO criteria. Secondary end points included requirement of renal replacement therapy, ICU length of stay, and ICU mortality. Data were analyzed according to the intention-to-treat principle. RESULTS: Mean age was 53.2±15 years, mean serum creatinine level was 0.9±0.2mg/dL, median Thakar score for estimation of AKI risk was 2 (IQR, 1-3), and 25% had diabetes. The incidence of AKI was higher for the spironolactone group (43% vs 29%; P=0.02). No significant differences were found for secondary end points. LIMITATIONS: Single center, AKI was mostly driven by AKI stage 1, planned sample size was not achieved, and there was no renin-angiotensin-aldosterone system washout period. CONCLUSIONS: Our trial demonstrated that spironolactone was not protective for AKI associated with cardiac surgery and there may be a trend toward risk.


Assuntos
Injúria Renal Aguda/etiologia , Injúria Renal Aguda/prevenção & controle , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/prevenção & controle , Espironolactona/uso terapêutico , Método Duplo-Cego , Feminino , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade
4.
Clin Cancer Res ; 19(7): 1773-83, 2013 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-23307858

RESUMO

PURPOSE: To identify mediators of glioblastoma antiangiogenic therapy resistance and target these mediators in xenografts. EXPERIMENTAL DESIGN: We conducted microarray analysis comparing bevacizumab-resistant glioblastomas (BRG) with pretreatment tumors from the same patients. We established novel xenograft models of antiangiogenic therapy resistance to target candidate resistance mediator(s). RESULTS: BRG microarray analysis revealed upregulation versus pretreatment of receptor tyrosine kinase c-Met, which underwent further investigation because of its prior biologic plausibility as a bevacizumab resistance mediator. BRGs exhibited increased hypoxia versus pretreatment in a manner correlating with their c-Met upregulation, increased c-Met phosphorylation, and increased phosphorylation of c-Met-activated focal adhesion kinase and STAT3. We developed 2 novel xenograft models of antiangiogenic therapy resistance. In the first model, serial bevacizumab treatment of an initially responsive xenograft generated a xenograft with acquired bevacizumab resistance, which exhibited upregulated c-Met expression versus pretreatment. In the second model, a BRG-derived xenograft maintained refractoriness to the MRI tumor vasculature alterations and survival-promoting effects of bevacizumab. Growth of this BRG-derived xenograft was inhibited by a c-Met inhibitor. Transducing these xenograft cells with c-Met short hairpin RNA inhibited their invasion and survival in hypoxia, disrupted their mesenchymal morphology, and converted them from bevacizumab-resistant to bevacizumab-responsive. Engineering bevacizumab-responsive cells to express constitutively active c-Met caused these cells to form bevacizumab-resistant xenografts. CONCLUSION: These findings support the role of c-Met in survival in hypoxia and invasion, features associated with antiangiogenic therapy resistance, and growth and therapeutic resistance of xenografts resistant to antiangiogenic therapy. Therapeutically targeting c-Met could prevent or overcome antiangiogenic therapy resistance.


Assuntos
Inibidores da Angiogênese/farmacologia , Resistencia a Medicamentos Antineoplásicos , Neovascularização Patológica/genética , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/metabolismo , Transcriptoma , Inibidores da Angiogênese/uso terapêutico , Animais , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Bevacizumab , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Análise por Conglomerados , Resistencia a Medicamentos Antineoplásicos/genética , Ativação Enzimática/genética , Regulação Neoplásica da Expressão Gênica , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/mortalidade , Humanos , Camundongos , Invasividade Neoplásica/genética , Neovascularização Patológica/tratamento farmacológico , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Interferência de RNA , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Rev Invest Clin ; 65(6): 467-75, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24687353

RESUMO

INTRODUCTION: Acute kidney injury (AKI) associated with cardiac surgery is a common postoperative complication that increases the morbidity and mortality substantially. However, there is limited information of AKI after cardiac surgery in our institution. MATERIAL AND METHODS: We conducted a prospective, observational, and longitudinal analysis of adult patients that underwent to cardiac surgery requiring cardiopulmonary bypass and aortic cross clamp. Patients with preoperative chronic renal insufficiency that were on dialysis, with AKI detected up to 24 h before the procedure, or that received contrast agents 72 h before surgery were excluded. AKI was defined by the AKIN classification. Patients were followed up to 7 days after surgery or before if discharged from the intensive care unit. We analyzed age, sex, body mass index (BMI), co-morbilities, previous cardiac surgery, left ventricular ejection fraction, New York Heart Association class, type of procedure, cardiopulmonary bypass time, cross clamp time and bleeding. RESULTS: Our analysis included 164 patients submitted to cardiac surgery. In the follow up, 84% did not have AKI, 11% had AKIN 1 and 2 accompanied by increase in serum creatinine and 6% had AKIN 3. Patients with AKI were older, had a higher preoperative creatinine, plasma glucose level, and a lower left ventricular ejection fraction. All together patients with AKIN had a longer hospital stay and a higher mortality (p < 0.001). The preoperative use of insulin was associated with the development of AKI, and there was a higher number of patients with a New York Heart Association class III and IV for heart failure in the more sever forms of AKI (p = 0.01). The logistic regression analysis revealed that patients with a high preoperative blood urea nitrogen (> 20 mg/dL) creatinine level (> 1 mg/dL), uric acid (> 7 mg/dL) and lower albumin (< 4 g/dL) or lower intraoperative hemoglobin (< 8 g/dL) had a higher risk for postoperative AKI. CONCLUSIONS: The prevalence of AKI in our Institute is of 17%. Patients with AKIN 2 and 3 had a higher mortality and a longer stay in the intensive care unit. The major risk factors for AKI development were identified.


Assuntos
Injúria Renal Aguda/epidemiologia , Procedimentos Cirúrgicos Cardíacos , Complicações Pós-Operatórias/epidemiologia , Injúria Renal Aguda/sangue , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/terapia , Adulto , Fatores Etários , Idoso , Glicemia/análise , Índice de Massa Corporal , Ponte Cardiopulmonar , Creatinina/sangue , Complicações do Diabetes/tratamento farmacológico , Complicações do Diabetes/epidemiologia , Procedimentos Cirúrgicos Eletivos , Feminino , Seguimentos , Humanos , Unidades de Terapia Intensiva/estatística & dados numéricos , Tempo de Internação/estatística & dados numéricos , Masculino , México/epidemiologia , Pessoa de Meia-Idade , Complicações Pós-Operatórias/sangue , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/terapia , Estudos Prospectivos , Terapia de Substituição Renal/estatística & dados numéricos , Fatores de Risco , Albumina Sérica/análise , Fatores Sexuais , Volume Sistólico
6.
Autophagy ; 8(6): 979-81, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22714142

RESUMO

While anti-angiogenic therapy was initially greeted enthusiastically by the cancer community, initial successes with this therapeutic modality were tempered by the failure of angiogenesis inhibitors to produce sustained clinical responses in most patients, with resistance to the inhibitors frequently developing. We recently reported that hypoxia increases after the devascularization caused by anti-angiogenic therapy, consistent with the goals of these therapies, but that some tumor cells become resistant and survive the hypoxic insult elicited by anti-angiogenic therapy through autophagy by activating both AMPK and HIF1A pathways. These findings suggest that modulating the autophagy pathway may someday allow anti-angiogenic therapy to fulfill its therapeutic potential. However, further work will clearly be needed to develop more potent and specific autophagy inhibitors and to better understand the regulators of autophagy in malignant cells.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Autofagia , Resistencia a Medicamentos Antineoplásicos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Inibidores da Angiogênese/farmacologia , Animais , Autofagia/efeitos dos fármacos , Hipóxia Celular/efeitos dos fármacos , Ensaios Clínicos como Assunto , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Modelos Biológicos , Neoplasias/irrigação sanguínea , Células-Tronco Neoplásicas/patologia , Microambiente Tumoral/efeitos dos fármacos
7.
Mol Cell ; 37(5): 620-32, 2010 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-20227367

RESUMO

To sustain tumor growth, cancer cells must be able to adapt to fluctuations in energy availability. We have identified a single microRNA that controls glioma cell proliferation, migration, and responsiveness to glucose deprivation. Abundant glucose allows relatively high miR-451 expression, promoting cell growth. In low glucose, miR-451 levels decrease, slowing proliferation but enhancing migration and survival. This allows cells to survive metabolic stress and seek out favorable growth conditions. In glioblastoma patients, elevated miR-451 is associated with shorter survival. The effects of miR-451 are mediated by LKB1, which it represses through targeting its binding partner, CAB39 (MO25 alpha). Overexpression of miR-451 sensitized cells to glucose deprivation, suggesting that its downregulation is necessary for robust activation of LKB1 in response to metabolic stress. Thus, miR-451 is a regulator of the LKB1/AMPK pathway, and this may represent a fundamental mechanism that contributes to cellular adaptation in response to altered energy availability.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Neoplasias Encefálicas/enzimologia , Glioblastoma/enzimologia , MicroRNAs/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Estresse Fisiológico , Quinases Proteína-Quinases Ativadas por AMP , Proteínas Quinases Ativadas por AMP/genética , Adaptação Fisiológica , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Células COS , Proteínas de Ligação ao Cálcio/metabolismo , Movimento Celular , Proliferação de Células , Sobrevivência Celular , Chlorocebus aethiops , Ativação Enzimática , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Glioblastoma/mortalidade , Glioblastoma/patologia , Glucose/deficiência , Células HeLa , Humanos , Prognóstico , Proteínas Serina-Treonina Quinases/genética , Transdução de Sinais/genética , Estresse Fisiológico/genética , Fatores de Tempo , Transfecção
8.
Blood ; 108(4): 1334-8, 2006 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-16670263

RESUMO

Drug development in human chronic lymphocytic leukemia (CLL) has been limited by lack of a suitable animal model to adequately assess pharmacologic properties relevant to clinical application. A recently described TCL-1 transgenic mouse develops a chronic B-cell CD5(+) leukemia that might be useful for such studies. Following confirmation of the natural history of this leukemia in the transgenic mice, we demonstrated that the transformed murine lymphocytes express relevant therapeutic targets (Bcl-2, Mcl-1, AKT, PDK1, and DNMT1), wild-type p53 status, and in vitro sensitivity to therapeutic agents relevant to the treatment of human CLL. We then demonstrated the in vivo clinical activity of low-dose fludarabine in transgenic TCL-1 mice with active leukemia. These studies demonstrated both early reduction in blood-lymphocyte count and spleen size and prolongation of survival (P = .046) compared with control mice. Similar to human CLL, an emergence of resistance was noted with fludarabine treatment in vivo. Overall, these studies suggest that the TCL-1 transgenic leukemia mouse model has similar clinical and therapeutic response properties to human CLL and may therefore serve as a useful in vivo tool to screen new drugs for subsequent development in CLL.


Assuntos
Antineoplásicos/farmacologia , Transformação Celular Neoplásica/genética , Leucemia Linfocítica Crônica de Células B/genética , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas Proto-Oncogênicas/genética , Vidarabina/análogos & derivados , Animais , Antineoplásicos/uso terapêutico , Antígenos CD5/metabolismo , Transformação Celular Neoplásica/efeitos dos fármacos , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Leucemia Linfocítica Crônica de Células B/sangue , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Camundongos , Camundongos Transgênicos , Proteínas de Neoplasias/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Células Tumorais Cultivadas , Vidarabina/farmacologia , Vidarabina/uso terapêutico
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