Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 735
Filtrar
1.
Med Sci (Paris) ; 36 Hors série n° 1: 56-60, 2020 Oct.
Artigo em Francês | MEDLINE | ID: mdl-33052096

RESUMO

Monoclonal antibody (mAb)-based immunotherapy is booming in oncology. In 2020, more than 40% of FDA (Food and Drug Administration)-approved antibodies (34 out of 84 antibodies, according to The Antibody Society) have an indication for cancer therapy. In contrast to standard chemotherapy, they demonstrate a much better safety profile for patients. Despite this, adverse side effects may occur due to the targeting of the antigen also expressed by healthy tissues. For this reason, emerging strategies aim at optimizing the antibody format and considering the particularities of the tumor microenvironment to confer a more specific action of the antibody at the tumor site.


Assuntos
Anticorpos Monoclonais , Antígenos de Neoplasias/isolamento & purificação , Terapia de Alvo Molecular/métodos , Neoplasias/imunologia , Neoplasias/terapia , Microambiente Tumoral/imunologia , Animais , Anticorpos Monoclonais/isolamento & purificação , Anticorpos Monoclonais/uso terapêutico , Especificidade de Anticorpos , Antígenos de Neoplasias/imunologia , Sistemas de Liberação de Medicamentos/métodos , Mapeamento de Epitopos/métodos , Humanos , Pró-Fármacos/uso terapêutico , Hipóxia Tumoral/imunologia
2.
Phytomedicine ; 78: 153318, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32896707

RESUMO

BACKGROUND: Hypoxia and HIF-1α are important regulators of tumour growth and angiogenesis and could be attractive targets for cancer therapeutics. Decursin is an active compound extracted from the roots of Angelica gigas and has been shown to have potent anti-cancer and anti-angiogenic activities. However, whether decursin regulates HIF-1α activity and immune responses under hypoxic conditions is not yet understood. PURPOSE: The aim of this study was to identify whether decursin exhibits anti-cancer activity by targeting HIF-1α. STUDY DESIGN: We investigated whether decursin regulates HIF-1α protein stability and increases its degradation. In addition, we determined if decursin increases immune responses in tumour microenvironment to identify its hypoxia-associated anti-cancer activities. MATERIALS AND METHODS: We performed the hypoxia-responsive element promoter-reporter assay, Western blot analysis, immune-fluorescence assay, semi-quantitative RT-PCR and ELISA for VEGF secretion, CCK-8 assay for cell proliferation, TUNEL assay for apoptosis and invasion assay in A549 human lung cancer or HCT116 human colon cancer cells. In vivo Lewis lung carcinoma (LLC) allograft mouse model was used to check tumour growth and immune responses in tumour microenvironment by immunohistochemistry analysis. RESULTS: We observed that decursin inhibited HIF-1 activation under hypoxia by down-regulating the protein level of its subunit HIF-1α. It increased oxygen-dependant hydroxylation and ubiquitination of HIF-1α to promote HIF-1α degradation. Decursin also decreased mRNA expression of HIF-1α target genes. Decursin suppressed cancer cell proliferation, induced apoptosis and inhibited cancer cell invasion under hypoxia in cancer cells. In the allograft mouse tumour model, decursin reduced the hypoxic area and HIF-1α and PD-L1 expression. Infiltrating T cells (CD3+), helper T cells (CD4+) and cytotoxic (CD8+) T cells were accumulated, but regulatory T cells (Foxp3) and myeloid-derived suppressor cell-mediated immune suppressors (Arg1) were attenuated by decursin. CONCLUSION: Our results suggest that decursin is a novel HIF-1α inhibitor that functions by promoting its proteasomal degradation and that it also helps improve T cell activation in tumour microenvironment; these findings provide new explanations about its anti-cancer and anti-angiogenic activity mechanisms.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Benzopiranos/farmacologia , Butiratos/farmacologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Células A549 , Animais , Apoptose/efeitos dos fármacos , Antígeno B7-H1/metabolismo , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Células HCT116 , Humanos , Camundongos Endogâmicos C57BL , Hipóxia Tumoral/efeitos dos fármacos , Ubiquitinação/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Int J Nanomedicine ; 15: 5687-5700, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32821097

RESUMO

Background and Purpose: Sonodynamic therapy (SDT) has been widely used for the noninvasive treatment of solid tumors, but the hypoxic tumor microenvironment limits its therapeutic effect. The current methods of reoxygenation to enhance SDT have limitations, prompting reconsideration of the design of therapeutic approaches. Here, we developed a tumor microenvironment-responsive nanoplatform by reducing oxygen consumption to overcome hypoxia-induced resistance to cancer therapy. Methods: A pH-responsive drug-loaded liposome (MI-PEOz-lip) was prepared and used to reduce oxygen consumption, attenuating hypoxia-induced resistance to SDT and thereby improving therapeutic efficiency. Photoacoustic imaging (PAI) and fluorescence imaging (FI) of MI-PEOz-lip were evaluated in vitro and in breast xenograft tumor models. The pH-sensitive functionality of MI-PEOz-lip was applied for pH-triggered cargo release, and its capacity was evaluated. The MI-PEOz-lip-mediated SDT effect was compared with other treatments in vivo. Results: MI-PEOz-lip was demonstrated to specifically accumulate in tumors. Metformin molecules in liposomes selectively accumulate in tumors by pH-responsive drug release to inhibit the mitochondrial respiratory chain while releasing IR780 to the tumor area. These pH-responsive liposomes demonstrated PAI and FI imaging capabilities in vitro and in vivo, providing potential for treatment guidance and monitoring. In particular, the prepared MI-PEOz-lip combined with ultrasound irradiation effectively inhibited breast tumors by producing toxic reactive singlet oxygen species (ROS), while the introduction of metformin inhibited mitochondrial respiration and reduced tumor oxygen consumption, resulting in excellent sonodynamic therapy performance compared with other treatments. Conclusion: In this study, we present a novel strategy to achieve high therapeutic efficacy of SDT by the rational design of multifunctional nanoplatforms. This work provides a new strategy that can solve the current problems of inefficient oxygen delivery strategies and weaken resistance to various oxygen-dependent therapies.


Assuntos
Mitocôndrias/metabolismo , Neoplasias/patologia , Neoplasias/terapia , Hipóxia Tumoral , Terapia por Ultrassom , Animais , Antineoplásicos/farmacologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Respiração Celular/efeitos dos fármacos , Humanos , Concentração de Íons de Hidrogênio , Lipossomos , Metformina/farmacologia , Camundongos , Oxigênio/metabolismo , Técnicas Fotoacústicas , Distribuição Tecidual/efeitos dos fármacos , Microambiente Tumoral
4.
Nat Commun ; 11(1): 3704, 2020 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-32709869

RESUMO

FGF-2 displays multifarious functions in regulation of angiogenesis and vascular remodeling. However, effective drugs for treating FGF-2+ tumors are unavailable. Here we show that FGF-2 modulates tumor vessels by recruiting NG2+ pricytes onto tumor microvessels through a PDGFRß-dependent mechanism. FGF-2+ tumors are intrinsically resistant to clinically available drugs targeting VEGF and PDGF. Surprisingly, dual targeting the VEGF and PDGF signaling produces a superior antitumor effect in FGF-2+ breast cancer and fibrosarcoma models. Mechanistically, inhibition of PDGFRß ablates FGF-2-recruited perivascular coverage, exposing anti-VEGF agents to inhibit vascular sprouting. These findings show that the off-target FGF-2 is a resistant biomarker for anti-VEGF and anti-PDGF monotherapy, but a highly beneficial marker for combination therapy. Our data shed light on mechanistic interactions between various angiogenic and remodeling factors in tumor neovascularization. Optimization of antiangiogenic drugs with different principles could produce therapeutic benefits for treating their resistant off-target cancers.


Assuntos
Inibidores da Angiogênese/farmacologia , Fator 2 de Crescimento de Fibroblastos/efeitos dos fármacos , Fator 2 de Crescimento de Fibroblastos/metabolismo , Neoplasias/tratamento farmacológico , Fator de Crescimento Derivado de Plaquetas/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/efeitos dos fármacos , Animais , Biomarcadores Tumorais , Pressão Sanguínea , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Permeabilidade Capilar , Proliferação de Células , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Quimioterapia Combinada , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias/patologia , Neovascularização Patológica/tratamento farmacológico , Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptor beta de Fator de Crescimento Derivado de Plaquetas , Transdução de Sinais/efeitos dos fármacos , Hipóxia Tumoral , Microambiente Tumoral/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/metabolismo
5.
PLoS One ; 15(7): e0236245, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32706818

RESUMO

We have previously demonstrated that endothelial targeting of gold nanoparticles followed by external beam irradiation can cause specific tumor vascular disruption in mouse models of cancer. The induced vascular damage may lead to changes in tumor physiology, including tumor hypoxia, thereby compromising future therapeutic interventions. In this study, we investigate the dynamic changes in tumor hypoxia mediated by targeted gold nanoparticles and clinical radiation therapy (RT). By using noninvasive whole-body fluorescence imaging, tumor hypoxia was measured at baseline, on day 2 and day 13, post-tumor vascular disruption. A 2.5-fold increase (P<0.05) in tumor hypoxia was measured two days after combined therapy, resolving by day 13. In addition, the combination of vascular-targeted gold nanoparticles and radiation therapy resulted in a significant (P<0.05) suppression of tumor growth. This is the first study to demonstrate the tumor hypoxic physiological response and recovery after delivery of vascular-targeted gold nanoparticles followed by clinical radiation therapy in a human non-small cell lung cancer athymic Foxn1nu mouse model.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Nanopartículas Metálicas/uso terapêutico , Hipóxia Tumoral , Células A549 , Animais , Carcinoma Pulmonar de Células não Pequenas/irrigação sanguínea , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Ouro/uso terapêutico , Humanos , Neoplasias Pulmonares/irrigação sanguínea , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/radioterapia , Camundongos , Camundongos Nus , Imagem Óptica/métodos , Hipóxia Tumoral/efeitos dos fármacos , Hipóxia Tumoral/efeitos da radiação , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Br J Radiol ; 93(1115): 20200087, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32551913

RESUMO

Prostate cancer (PCa) is a clinically heterogeneous disease and has poor patient outcome when tumours progress to castration-resistant and metastatic states. Understanding the mechanistic basis for transition to late stage aggressive disease is vital for both assigning patient risk status in the localised setting and also identifying novel treatment strategies to prevent progression. Subregions of intratumoral hypoxia are found in all solid tumours and are associated with many biologic drivers of tumour progression. Crucially, more recent findings show the co-presence of hypoxia and genomic instability can confer a uniquely adverse prognosis in localised PCa patients. In-depth informatic and functional studies suggests a role for hypoxia in co-operating with oncogenic drivers (e.g. loss of PTEN) and suppressing DNA repair capacity to alter clonal evolution due to an aggressive mutator phenotype. More specifically, hypoxic suppression of homologous recombination represents a "contextual lethal" vulnerability in hypoxic prostate tumours which could extend the application of existing DNA repair targeting agents such as poly-ADP ribose polymerase inhibitors. Further investigation is now required to assess this relationship on the background of existing genomic alterations relevant to PCa, and also characterise the role of hypoxia in driving early metastatic spread. On this basis, PCa patients with hypoxic tumours can be better stratified into risk categories and treated with appropriate therapies to prevent progression.


Assuntos
Instabilidade Genômica/fisiologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Hipóxia Tumoral/fisiologia , Reparo do DNA/efeitos dos fármacos , Reparo do DNA/genética , Progressão da Doença , Recombinação Homóloga/fisiologia , Humanos , Masculino , Inibidores da Síntese de Ácido Nucleico/farmacologia
7.
Int J Nanomedicine ; 15: 3719-3727, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32547024

RESUMO

Purpose: Most solid tumors contain areas of chronic hypoxia. Gold nanoparticles (GNP) have been extensively explored as enhancers of external beam radiation; however, GNP have lower cellular uptake in hypoxic conditions than under normoxic conditions. Conversely, the chelator diacetyl-bis (N(4)-methylthiosemicarbazonato) copper II (CuATSM) deposits copper in hypoxic regions, allowing for dose enhancement in previously inaccessible regions. Methods: External beam sources with different spectra were modeled using a Monte Carlo code (EGSnrc) to evaluate radioenhancement in a layered model with metal solutions. Also considered was a simple concentric layered tumor model containing a hypoxic core with each layer varying in concentrations of either copper or gold according to hypoxic conditions. Low energy external photon beams were then projected onto the tumor to determine the regional dose enhancement dependent on hypoxic conditions. Results: Dose enhancement was more pronounced for beam spectra with low energy photons (225 kVp) and was highly dependent on metal concentrations from 0.1 g/kg to 100 g/kg. Increasing the depth of the metallic solution layer from 1 cm to 6 cm decreased dose enhancement. A small increase in the dose enhancement factor (DEF) of 1.01 was predicted in the hypoxic regions of the tumor model with commonly used diagnostic concentrations of CuATSM. At threshold concentrations of toxic subcutaneous injection levels, the DEF increases to 1.02, and in simulation of a high concentration of CuATSM, the DEF increased to 1.07. High concentration treatments are also considered, as well as synergistic combinations of GNP/CuATSM treatments. Conclusion: The research presented is novel utilization of CuATSM to target hypoxic regions and act as a radiosensitizer by the nature of its ability to deposit copper metal in reduced tissue. We demonstrate CuATSM at high concentrations with low energy photons can increase dose deposition in hypoxic tumor regions.


Assuntos
Ouro/química , Nanopartículas Metálicas/química , Método de Monte Carlo , Compostos Organometálicos/farmacocinética , Fótons , Tiossemicarbazonas/farmacocinética , Hipóxia Tumoral , Relação Dose-Resposta à Radiação , Modelos Biológicos , Imagens de Fantasmas , Radiossensibilizantes/farmacologia , Hipóxia Tumoral/efeitos dos fármacos , Hipóxia Tumoral/efeitos da radiação
8.
Br J Radiol ; 93(1112): 20190250, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32462907

RESUMO

OBJECTIVE: As a fractionated course of radiotherapy proceeds tumour shrinkage leads to resolution of hypoxia and the initiation of accelerated proliferation of radioresistant cancer cells with better repair capacity. We hypothesise that, in tumours with significant hypoxia, improved tumour control could be achieved with biphasic fractionation schedules that either use acceleration after 3-4 weeks of conventional radiotherapy or deliver a higher proportional dose towards the end of a course of treatment. We conducted a modelling study based on the concept of biological effective dose (BED) comparing such novel regimens with conventional fractionation. METHODS: The comparator conventional fractionation schedule 70 Gy in 35 fractions delivered over 7 weeks was tested against the following novel regimens, both of which were designed to be isoeffective in terms of late normal tissue toxicity.40 Gy in 20 fractions over 4 weeks followed by 22.32 Gy in 6 consecutive daily fractions (delayed acceleration)30.4 Gy in 27 fractions over 4 weeks followed by 40 Gy in 15 fractions over 3 weeks (temporal dose redistribution)The delayed acceleration regimen is exactly identical to that of the comparator schedule over the first 28 days and the BED gains with the novel schedule are achieved during the second phase of treatment when reoxygenation is complete. For the temporal redistribution regimen, it was assumed that the reoxygenation fraction progressively increases during the first 4 weeks of treatment and an iterative approach was used to calculate the final tumour BED for varying hypoxic fractions. RESULTS: Novel fractionation with delayed acceleration or temporal fractionation results in tumour BED gains equivalent to 3.5-8 Gy when delivered in 2 Gy fractions. CONCLUSION: In hypoxic tumours, novel fractionation strategies result in significantly higher tumour BED in comparison to conventional fractionation. ADVANCES IN KNOWLEDGE: We demonstrate that novel biphasic fractionation regimens could overcome the effects of tumour hypoxia resulting in biological dose escalation.


Assuntos
Fracionamento da Dose de Radiação , Neoplasias/radioterapia , Hipóxia Tumoral , Humanos , Neoplasias/irrigação sanguínea , Neoplasias/metabolismo , Neoplasias/patologia , Radiobiologia , Hipóxia Tumoral/efeitos da radiação
9.
J Biomed Sci ; 27(1): 59, 2020 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-32370770

RESUMO

Over the past few years, long non-coding RNAs (lncRNAs) are recognized as key regulators of gene expression at chromatin, transcriptional and posttranscriptional level with pivotal roles in various biological and pathological processes, including cancer. Hypoxia, a common feature of the tumor microenvironment, profoundly affects gene expression and is tightly associated with cancer progression. Upon tumor hypoxia, the central regulator HIF (hypoxia-inducible factor) is upregulated and orchestrates transcription reprogramming, contributing to aggressive phenotypes in numerous cancers. Not surprisingly, lncRNAs are also transcriptional targets of HIF and serve as effectors of hypoxia response. Indeed, the number of hypoxia-associated lncRNAs (HALs) identified has risen sharply, illustrating the expanding roles of lncRNAs in hypoxia signaling cascade and responses. Moreover, through extra-cellular vesicles, lncRNAs could transmit hypoxia responses between cancer cells and the associated microenvironment. Notably, the aberrantly expressed cellular or exosomal HALs can serve as potential prognostic markers and therapeutic targets. In this review, we provide an update of the current knowledge about the expression, involvement and potential clinical impact of lncRNAs in tumor hypoxia, with special focus on their unique molecular regulation of HIF cascade and hypoxia-induced malignant progression.


Assuntos
Regulação Neoplásica da Expressão Gênica/fisiologia , RNA Longo não Codificante/genética , Transdução de Sinais , Hipóxia Tumoral/genética , Microambiente Tumoral/fisiologia , RNA Longo não Codificante/metabolismo
10.
Exp Oncol ; 42(1): 2-10, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32231198

RESUMO

Malignancy may be characterized as a state formed in the setting of specific tumor-host relationships at the molecular and cellular microenvironment levels. R.E. Kavetsky and his collaborators distinctly outlined the concept of tumor-host interaction. Tumor is a complicated biological system closely connected with the organism, where it arises and develops. Tumor cells are in the environment of different factors that form tumor microenvironment playing an active role in the disease progression. There are two types of tumor microenvironment: the metabolic microenvironment mediated by factors of tumor microphysiology (blood flow, vascular permeability, oxygenation, extracellular рН, interstitial fluid pressure, etc.) and the cellular-molecular microenvironment comprising interactions between tumor cells and non-tumor cells and the factors of the stromal compartment. Factors of tumor microphysio-logy can modify the interaction between tumor cells and surrounding non-tumor cells and molecular components and they form the tumor profile that influences the pressure of tumor on the host. The review presents the data concerning the role of metabolic microenvironment of tumor cells from the point of tumor-host interaction in order to employ these parameters to working out the methods of diagnosis and prognosis of disease outcome in patients with gastric cancer. Special attention has been paid to hypoxia as a key factor of metabolic microenvironment that positively affects tumor progression, stimulating its aggressiveness, metastasis and resistance to therapy and is regarded as a factor of unfavorable prognosis. It was shown that there is possible clinical relevance of tumor classification based on the level of tumor oxygenation that may be advantageous for selection of patients for individualized therapy that may give the hope for enhancement of treatment efficacy.


Assuntos
Neoplasias Gástricas/metabolismo , Hipóxia Tumoral/fisiologia , Microambiente Tumoral , Animais , Linhagem Celular Tumoral , Humanos , Fosfolipídeos/sangue , Neoplasias Gástricas/patologia
11.
Clin Nucl Med ; 45(6): e290-e293, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32332306

RESUMO

In the present case, we report the first experience of a patient with high-grade glioma who underwent dual F-FAZA PET/CT imaging for intratumoral hypoxia assessment, before treatment, and for therapy monitoring in the suspicious of recurrence, as part of a clinical research protocol. In addition, despite the diagnosis of glioblastoma, the patient at 3 years from diagnosis was alive and underwent C-methionine simultaneous PET/MRI for disease monitoring after treatment, showing stability of disease. The multitracer capability of PET in assessing different and complementary metabolic features along with the use of a last-generation scanner as PET/MRI in brain oncology are here enlighten.


Assuntos
Aminoácidos/metabolismo , Glioma/diagnóstico por imagem , Imagem por Ressonância Magnética , Metionina , Nitroimidazóis , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Hipóxia Tumoral , Adulto , Feminino , Glioma/metabolismo , Glioma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores
12.
Igaku Butsuri ; 40(1): 13-18, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32238677

RESUMO

Hypoxia has been known to be a feature associated with tumor radioresistance. So far, clinical strategies to overcome chronic hypoxia due to the limitation of the oxygen diffusion have been designed. However, intermittent or acute/cycling hypoxia, whose frequency can range between a few cycles per minutes to hours, is receiving increased attention, because this type of hypoxia has been reported to have an influence on tumor malignancy as well as treatment resistance via increased expression of pro-survival pathways. Therefore, a priori information on fluctuating hypoxia can be important in clinical treatment planning, but complicated dynamics makes it difficult to elucidate biological significance of intermittent hypoxia.Here, we illustrate the use of pulsed electron spin resonance imaging (ESRI) as a novel imaging method to directly monitor fluctuating oxygenation i.e. cycling hypoxia in transplanted tumors. A common resonator platform for both ESRI and magnetic resonance imaging (MRI) provided pO2 maps with anatomical guidance without positional movement. Oxygen images every 3 min in pO2 could visualize the rapid oxygen fluctuation and distinguish the cycling hypoxia and chronic hypoxia. Furthermore, we have examined the vascular renormalization process by longitudinally pO2 mapping during treatments with a multi-tyrosine kinase inhibitor sunitinib. Transient improvement in tumor oxygenation and the decrease of cycling tumor hypoxia were visualized by ESRI 2 to 4 days following antiangiogenic treatments. Radiation treatment during this time period of improved oxygenation by antiangiogenic therapy resulted in a synergistic delay in tumor growth.In conclusion, this ESRI technique combined with MRI, may offer a powerful clinical tool to noninvasively detect variable hypoxic status in tumors and to identify a window of vascular renormalization to maximize the effects of combination therapy with antiangiogenic drugs.


Assuntos
Neoplasias , Radiobiologia , Hipóxia Tumoral , Espectroscopia de Ressonância de Spin Eletrônica , Humanos , Hipóxia , Neoplasias/diagnóstico por imagem , Neoplasias/fisiopatologia , Oxigênio
13.
Oncogene ; 39(16): 3367-3380, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32111982

RESUMO

Overactivation of the cAMP signal transduction pathway plays a central role in the pathogenesis of endocrine tumors. Genetic aberrations leading to increased intracellular cAMP or directly affecting PKA subunit expression have been identified in inherited and sporadic endocrine tumors, but are rare indicating the presence of nongenomic pathological PKA activation. In the present study, we examined the impact of hypoxia on PKA activation using human growth hormone (GH)-secreting pituitary tumors as a model of an endocrine disease displaying PKA-CREB overactivation. We show that hypoxia activates PKA and enhances CREB transcriptional activity and subsequently GH oversecretion. This is due to a previously uncharacterized ability of HIF-1α to suppress the transcription of the PKA regulatory subunit 2B (PRKAR2B) by sequestering Sp1 from the PRKAR2B promoter. The present study reveals a novel mechanism through which the transcription factor HIF-1α transduces environmental signals directly onto PKA activity, without affecting intracellular cAMP concentrations. By identifying a point of interaction between the cellular microenvironment and intracellular enzyme activation, neoplastic, and nonneoplastic diseases involving overactivated PKA pathway may be more efficiently targeted.


Assuntos
Subunidade RIIbeta da Proteína Quinase Dependente de AMP Cíclico/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Neoplasias Hipofisárias/genética , Ativação Transcricional/genética , Linhagem Celular Tumoral , Subunidade RIIalfa da Proteína Quinase Dependente de AMP Cíclico/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Imunoglobulinas/genética , Fosforilação/genética , Neoplasias Hipofisárias/patologia , Transdução de Sinais/genética , Hipóxia Tumoral/genética
14.
RNA ; 26(5): 648-663, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32127384

RESUMO

Hypoxia is a hallmark of solid cancers, supporting proliferation, angiogenesis, and escape from apoptosis. There is still limited understanding of how cancer cells adapt to hypoxic conditions and survive. We analyzed transcriptome changes of human lung and breast cancer cells under chronic hypoxia. Hypoxia induced highly concordant changes in transcript abundance, but divergent splicing responses, underlining the cell type-specificity of alternative splicing programs. While RNA-binding proteins were predominantly reduced, hypoxia specifically induced muscleblind-like protein 2 (MBNL2). Strikingly, MBNL2 induction was critical for hypoxia adaptation by controlling the transcript abundance of hypoxia response genes, such as vascular endothelial growth factor A (VEGFA) MBNL2 depletion reduced the proliferation and migration of cancer cells, demonstrating an important role of MBNL2 as cancer driver. Hypoxia control is specific for MBNL2 and not shared by its paralog MBNL1. Thus, our study revealed MBNL2 as central mediator of cancer cell responses to hypoxia, regulating the expression and alternative splicing of hypoxia-induced genes.


Assuntos
Neoplasias da Mama/genética , Neoplasias Pulmonares/genética , Proteínas de Ligação a RNA/genética , Hipóxia Tumoral/genética , Fator A de Crescimento do Endotélio Vascular/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Transcriptoma/genética
15.
PLoS One ; 15(3): e0229290, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32187204

RESUMO

Preclinical studies have shown a larger inhibition of tumour growth when exercise begins prior to tumour implant (preventative setting) than when training begins after tumour implant (therapeutic setting). However, post-implantation exercise may alter the tumour microenvironment to make it more vulnerable to treatment by increasing tumour perfusion while reducing hypoxia. This has been shown most convincingly in breast and prostate cancer models to date and it is unclear whether other tumour types respond in a similar way. We aimed to determine whether tumour perfusion and hypoxia are altered with exercise in a melanoma model, and compared this with a breast cancer model. We hypothesised that post-implantation exercise would reduce tumour hypoxia and increase perfusion in these two models. Female, 6-10 week old C57BL/6 mice were inoculated with EO771 breast or B16-F10 melanoma tumour cells before randomisation to either exercise or non-exercising control. Exercising mice received a running wheel with a revolution counter. Mice were euthanised when tumours reached maximum ethical size and the tumours assessed for perfusion, hypoxia, blood vessel density and proliferation. We saw an increase in heart to body weight ratio in exercising compared with non-exercising mice (p = 0.0008), indicating that physiological changes occurred with this form of physical activity. However, exercise did not affect vascularity, perfusion, hypoxia or tumour growth rate in either tumour type. In addition, EO771 tumours had a more aggressive phenotype than B16-F10 tumours, as inferred from a higher rate of proliferation (p<0.0001), a higher level of tumour hypoxia (p = 0.0063) and a higher number of CD31+ vessels (p = 0.0005). Our results show that although a physiological training effect was seen with exercise, it did not affect tumour hypoxia, perfusion or growth rate. We suggest that exercise monotherapy is minimally effective and that future preclinical work should focus on the combination of exercise with standard cancer therapies.


Assuntos
Neoplasias da Mama/patologia , Melanoma Experimental/patologia , Condicionamento Físico Animal/métodos , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Animais , Neoplasias da Mama/irrigação sanguínea , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Feminino , Humanos , Melanoma Experimental/irrigação sanguínea , Melanoma Experimental/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Transplante de Neoplasias , Distribuição Aleatória , Corrida , Hipóxia Tumoral , Microambiente Tumoral
16.
Int J Nanomedicine ; 15: 1677-1691, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32214807

RESUMO

Background: Immune checkpoint blockades (ICBs) are a promising treatment for cancers such as melanoma by blocking important inhibitory pathways that enable tumor cells to evade immune attack. Programmed death ligand 1 monoclonal antibodies (aPDL1s) can be used as an ICB to significantly enhance the effectiveness of tumor immunotherapy by blocking the PD-1/PD-L1 inhibitory pathway. However, the effectiveness of aPDL1s may be limited by low selectivity in vivo and immunosuppressed tumor microenvironment including hypoxia. Purpose: To overcome the limitations, we develop a multifunctional immunoliposome, called CAT@aPDL1-SSL, with catalase (CAT) encapsulated inside to overcome tumor hypoxia and aPDL1s modified on the surface to enhance immunotherapeutic effects against melanoma. Methods: The multifunctional immunoliposomes (CAT@aPDL1-SSLs) are prepared using the film dispersion/post-insertion method. The efficacy of CAT@aPDL1-SSLs is verified by multiple experiments in vivo and in vitro. Results: The results of this study suggest that the multifunctional immunoliposomes preserve and protect the enzyme activity of CAT and ameliorate tumor hypoxia. Moreover, the enhanced cellular uptake of CAT@aPDL1-SSLs in vitro and their in vivo biodistribution suggest that CAT@aPDL1-SSLs have great targeting ability,resulting in improved delivery and accumulation of immunoliposomes in tumor tissue.Finally, by activating and increasing the infiltration of CD8+ T cells at the tumor site, CAT@aPDL1-SSLs inhibit the growth of tumor and prolong survival time of mice,with low systemic toxicity. Conclusion: In conclusion, the multifunctional immunoliposomes developed and proposed in this study are a promising candidate for melanoma immunotherapy, and could potentially be combined with other cancer therapies like radiotherapy and chemotherapy to produce positive outcomes.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Antígeno B7-H1/imunologia , Catalase/imunologia , Lipossomos/química , Melanoma/tratamento farmacológico , Hipóxia Tumoral/efeitos dos fármacos , Animais , Anticorpos Monoclonais/farmacologia , Antineoplásicos Imunológicos/química , Antineoplásicos Imunológicos/farmacocinética , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Catalase/química , Linhagem Celular Tumoral , Feminino , Imunoterapia/métodos , Lipossomos/administração & dosagem , Lipossomos/farmacologia , Melanoma/patologia , Camundongos Endogâmicos C57BL , Fosfatidiletanolaminas/química , Polietilenoglicóis/química , Distribuição Tecidual , Microambiente Tumoral/efeitos dos fármacos
17.
Oxid Med Cell Longev ; 2020: 6724810, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32215176

RESUMO

Transient receptor potential melastatin subfamily member 7 (TRPM7) was essential in the growth and metastatic ability of prostate cancer cells. However, the effects and the relevant molecular mechanisms of TRPM7 on metastasis of prostate cancer under hypoxic atmosphere remain unclear. This study investigated the role of TRPM7 in the metastatic ability of androgen-independent prostate cancer cells under hypoxia. First, data mining was carried out to disclose the relationship between the TRPM7 gene level and the survival of prostate cancer patients. Specific siRNAs were used to knockdown target genes. Western blotting and qPCR were employed to determine protein and gene expression, respectively. The gene transcription activity was evaluated by luciferase activity assay of promoter gene. The protein interaction was determined by coimmunoprecipitation. Wound healing and transwell assays were employed to evaluated cell migration and invasion, respectively. Open access database results showed that high expression of TRPM7 was closely related to the poor survival of prostate cancer patients. Hypoxia simultaneously increased TRPM7 expression and induced HIF-1α accumulation in androgen-independent prostate cancer cells. Knockdown of TRPM7 significantly promoted HIF-1α degradation through the proteasome and inhibited EMT changes in androgen-independent prostate cancer cells under hypoxic condition. Moreover, TRPM7 knockdown increased the phosphorylation of RACK1 and strengthened the interaction between RACK1 and HIF-1α but attenuated the binding of HSP90 to HIF-1α. Whereas knockdown of RACK1 increased the binding of HSP90 to HIF-1α. Furthermore, both TRPM7 and HIF-1α knockdown significantly suppressed hypoxia-induced Annexin A1 protein expression, and suppression of HIF-1α/Annexin A1 signaling significantly inhibited hypoxia-induced cell migration and invasion of androgen-independent prostate cancer cells. Our findings demonstrate that TRPM7 knockdown promotes HIF-1α degradation via an oxygen-independent mechanism involving increased binding of RAKC1 to HIF-1α, and TRPM7-HIF-1α-Annexin A1 signaling axis plays a crucial role in the EMT, cell migration, and invasion of androgen-independent prostate cancer cells under hypoxic conditions.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , Proteínas Serina-Treonina Quinases/genética , Receptores de Quinase C Ativada/metabolismo , Canais de Cátion TRPM/genética , Anexina A1/genética , Anexina A1/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Masculino , Fosforilação , Prognóstico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Ligação Proteica , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Canais de Cátion TRPM/metabolismo , Hipóxia Tumoral
18.
Gene ; 741: 144552, 2020 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-32165297

RESUMO

Hypoxia, as a form of stress, plays a critical role in oncogenesis, including metabolic reprogramming. Mitochondrial, the centers of energy production, re-balance mitochondria dynamic to maintain cell survival during high levels of environmental stresses. NDRG1 is a hypoxia-inducible protein that is involved in various human cancers, including HCC. However, little is known about whether NDRG1 participants in the quality control of mitochondrial in times of stress. Here, we firstly showed that how NDRG1 exerted its role through mediating mitochondrial dynamic in HCC cells under hypoxia. Initially, we identified that NDRG1 expression varies with oxygen content. NDRG1 silencing notably induced cell apoptosis under hypoxia, while no obviously change of wildtype cells in hypoxia compared with that in normoxia. Further analysis revealed that NDRG1 silencing in HCC cells led to increase of pro apoptotic protein BAX and decrease in anti-apoptotic proteins Bcl-2 and Bclx, which meant mitochondrial damage were induced. In the analysis of mitochondria, we found that more released cytochrome c located in cytosolic with NDRG1 knockdown in hypoxia, which may be due to mitochondria division. And the following experiment proved that more fragmented mitochondria were presented in NDRG1 silencing cells, as well as destroyed mitochondrial membrane potential with evidence by JC-1 was verified. Moreover, these trends could be reversed by Mdivi1. Further research showed that NDRG1 silencing disrupt hypoxia-enhanced aerobic glycolysis through effectively decreased glucose uptake, lactate output and ECAR value. In sum, we provide the first direct evidence that NDRG1-driven change in mitochondrial dynamics and aerobic glycolysis maintain cells survival in HCC during hypoxia.


Assuntos
Carcinoma Hepatocelular/genética , Proteínas de Ciclo Celular/genética , Reprogramação Celular/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasias Hepáticas/genética , Apoptose/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Sobrevivência Celular/genética , Citocromos c/genética , Regulação Neoplásica da Expressão Gênica/genética , Glicólise/genética , Humanos , Neoplasias Hepáticas/patologia , Potencial da Membrana Mitocondrial/genética , Dinâmica Mitocondrial/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Hipóxia Tumoral/genética , Proteína bcl-X/genética
19.
J Pathol ; 250(5): 593-611, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32086807

RESUMO

In this review article, we examine the importance of low levels of oxygen (hypoxia) in cancer biology. We provide a brief description of how mammalian cells sense oxygen. The hypoxia-inducible factor (HIF) pathway is currently the best characterised oxygen-sensing system, but recent work has revealed that mammals also use an oxygen-sensing system found in plants to regulate the abundance of some proteins and peptides with an amino-terminal cysteine residue. We discuss how the HIF pathway is affected during the growth of solid tumours, which develop in microenvironments with gradients of oxygen availability. We then introduce the concept of 'pseudohypoxia', a state of constitutive, oxygen-independent HIF system activation that occurs due to oncogenic stimulation in a number of specific tumour types that are of immediate relevance to diagnostic histopathologists. We provide an overview of the different methods of quantifying tumour hypoxia, emphasising the importance of pre-analytic factors in interpreting the results of tissue-based studies. Finally, we review recent approaches to targeting hypoxia/HIF system activation for therapeutic benefit, the application of which may require knowledge of which hypoxia signalling components are being utilised by a given tumour. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.


Assuntos
Neoplasias/patologia , Oxigênio/metabolismo , Hipóxia Tumoral/fisiologia , Microambiente Tumoral/fisiologia , Animais , Hipóxia Celular/fisiologia , Humanos , Hipóxia/patologia , Neoplasias/diagnóstico
20.
Sci Rep ; 10(1): 2661, 2020 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-32060400

RESUMO

Increasingly, in vivo imaging holds a strategic position in bio-pharmaceutical innovation. We will present the implementation of an integrated multimodal imaging setup enabling the assessment of multiple, complementary parameters. The system allows the fusion of information provided by: Near infrared fluorescent biomarkers, bioluminescence (for tumor proliferation status), Photoacoustic and Ultrasound imaging. We will study representative applications to the development of a smart prodrug, delivering a highly cytotoxic chemotherapeutic agent to cancer tumors. The results realized the ability of this embedded, multimodality imaging platform to firstly detect bioluminescent and fluorescent signals, and secondly, record ultrasound and photoacoustic data from the same animal. This study demonstrated that the prodrug was effective in three different models of hypoxia in human cancers compared to the parental cytotoxic agent and the vehicle groups. Monitoring by photoacoustic imaging during the treatments revealed that the prodrug exhibits an intrinsic capability to prevent the progression of tumor hypoxia. It is essential for onco-pharmacology studies to precisely document the hypoxic status of tumors both before and during the time course of treatments. This approach opens new perspectives for exploitation of preclinical mouse models of cancer, especially when considering associations between hypoxia, neoangiogenesis and antitumor activity.


Assuntos
Antineoplásicos/farmacologia , Imagem Multimodal , Pró-Fármacos/farmacologia , Animais , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Pró-Fármacos/uso terapêutico , Hipóxia Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA