RESUMO
Tumor hypoxia, resulting from rapid tumor growth and aberrant vascular proliferation, exacerbates tumor aggressiveness and resistance to treatments like radiation and chemotherapy. To increase tumor oxygenation, we developed solid oxygen gas-entrapping materials (O2-GeMs), which were modeled after clinical brachytherapy implants, for direct tumor implantation. The objective of this study was to investigate the impact different formulations of solid O2-GeMs have on the entrapment and delivery of oxygen. Using a Parr reactor, we fabricated solid O2-GeMs using carbohydrate-based formulations used in the confectionary industry. In evaluating solid O2-GeMs manufactured from different sugars, the sucrose-containing formulation exhibited the highest oxygen concentration at 1 mg/g, as well as the fastest dissolution rate. The addition of a surface coating to the solid O2-GeMs, especially polycaprolactone, effectively prolonged the dissolution of the solid O2-GeMs. In vivo evaluation confirmed robust insertion and positioning of O2-GeMs in a malignant peripheral nerve sheath tumor, highlighting potential clinical applications.
Assuntos
Neoplasias , Oxigênio , Humanos , Hipóxia Tumoral/fisiologia , Neoplasias/tratamento farmacológicoRESUMO
BACKGROUND: A majority of relapse cases have been reported in colorectal cancer patients due to cancer stem cell progenitors. The factors responsible for chemoresistance have yet to be discovered and investigated as CSCs have reported escaping from chemotherapy's killing action. OBJECTIVE: In this study, we have investigated the effects of HIF-1α and TGF-ß2 in hypoxia conditions on the expression of GLI2, which is a potential factor for causing chemoresistance. Material and Methods. Colorectal samples of treated patients were collected from the Hospital Biological Sample Library. Culture of patient-derived TSs and fibroblasts was performed. The collected patient samples and cells were used for immunohistochemistry, quantitative PCR, and western blotting studies which were performed. RESULTS: It was reported that HIF-1α (hypoxia-inducible factor) and TGF-ß2 secreted from cancer-associated fibroblasts (CAFs) synergistically work to express GLI2 in cancer stem cells. Hence, it increased the stemness as well as resistance to chemotherapy. CONCLUSION: The HIF-1α/TGF-ß2-mediated GLI2 signaling was responsible for causing chemoresistance in the hypoxia environment. High expressions of HIF1α/TGF-ß2/GLI2 cause the relapsing of colorectal cancer, thus making this a potential biomarker for identifying the relapse and resistance in patients. The study uncovers the mechanism involved in sternness and chemotherapy resistance which will help in targeted treatment.
Assuntos
Neoplasias Colorretais/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Proteínas Nucleares/metabolismo , Fator de Crescimento Transformador beta2/metabolismo , Proteína Gli2 com Dedos de Zinco/metabolismo , Biomarcadores Tumorais/metabolismo , Fibroblastos Associados a Câncer/metabolismo , Neoplasias Colorretais/tratamento farmacológico , Biologia Computacional , Resistencia a Medicamentos Antineoplásicos , Humanos , Células-Tronco Neoplásicas/metabolismo , Proteínas Nucleares/antagonistas & inibidores , Pteridinas/farmacologia , Piridinas/farmacologia , Pirimidinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta2/antagonistas & inibidores , Células Tumorais Cultivadas , Hipóxia Tumoral/fisiologia , Microambiente Tumoral/fisiologia , Proteína Gli2 com Dedos de Zinco/antagonistas & inibidoresRESUMO
Breast cancer metastasis is the leading cause of cancer-related deaths. Hypoxia in the tumor mass is believed to trigger cell migration, which is involved in a crucial process of breast cancer metastasis. However, the molecular mechanisms underlying aggressive behavior under hypoxic conditions have not been fully elucidated. Here, we demonstrate the significant motility of MDA-MB-231 cells cultured under hypoxic conditions compared to that of cells cultured under normoxic conditions. MDA-MB-231 cells under hypoxic conditions showed a significant increase in Na+/H+ exchanger isoform 1 (NHE1) expression level, which was observed to co-locate in lamellipodia formation. Inhibition of NHE1 significantly suppressed the intracellular pH and the expression of mesenchymal markers, thereby blocking the high migration activity in hypoxia. Moreover, treatment with ciglitazone, a potent and selective peroxisome proliferator-activated receptor γ (PPARγ) agonist, modulated hypoxia-enhanced motion in cells via the repression of NHE1. These findings highlight that NHE1 is required for migratory activity through the enhancement of epithelial-mesenchymal transition (EMT) in MDA-MB-231 cells under hypoxic conditions, and we propose new drug repurposing strategies targeting hypoxia based on NHE1 suppression by effective usage of PPARγ agonists.
Assuntos
Neoplasias da Mama/metabolismo , Trocador 1 de Sódio-Hidrogênio/metabolismo , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/fisiologia , Transição Epitelial-Mesenquimal/fisiologia , Feminino , Humanos , Modelos Biológicos , PPAR gama/agonistas , Transdução de Sinais/efeitos dos fármacos , Tiazolidinedionas/farmacologia , Hipóxia Tumoral/fisiologia , Microambiente Tumoral/fisiologiaRESUMO
Epithelial ovarian cancer is predominantly diagnosed at advanced stages which creates significant therapeutic challenges. As a result, the 5-year survival rate is low. Within ovarian cancer, significant tumor heterogeneity exists, and the tumor microenvironment is diverse. Tumor heterogeneity leads to diversity in therapy response within the tumor, which can lead to resistance or recurrence. Advancements in therapy development and tumor profiling have initiated a shift from a "one-size-fits-all" approach towards precision patient-based therapies. Here, we review aspects of ovarian tumor heterogeneity that facilitate tumorigenesis and contribute to treatment failure. These tumor characteristics should be considered when designing novel therapies or characterizing mechanisms of treatment resistance. Individual patients vary considerably in terms of age, fertility and contraceptive use which innately affects the endocrine milieu in the ovary. Similarly, individual tumors differ significantly in their immune profile, which can impact the efficacy of immunotherapies. Tumor size, presence of malignant ascites and vascular density further alters the tumor microenvironment, creating areas of significant hypoxia that is notorious for increasing tumorigenesis, resistance to standard of care therapies and promoting stemness and metastases. We further expand on strategies aimed at improving oxygenation status in tumors to dampen downstream effects of hypoxia and set the stage for better response to therapy.
Assuntos
Carcinoma Epitelial do Ovário/terapia , Neoplasias Ovarianas/terapia , Hipóxia Tumoral/fisiologia , Microambiente Tumoral/fisiologia , Carcinoma Epitelial do Ovário/imunologia , Carcinoma Epitelial do Ovário/patologia , Feminino , Humanos , Imunoterapia , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/patologiaRESUMO
Hypoxia is associated with tumor radioresistance; therefore, a predictive marker for tumor hypoxia and a rational target to overcome it have been sought to realize personalized radiotherapy. Here, we show that serine protease inhibitor Kazal type I (SPINK1) meets these 2 criteria. SPINK1 expression was induced upon hypoxia (O2 < 0.1%) at the transcription initiation level in a HIF-dependent manner, causing an increase in secreted SPINK1 levels. SPINK1 proteins were detected both within and around hypoxic regions of xenografted and clinical tumor tissues, and their plasma levels increased in response to decreased oxygen supply to xenografts. Secreted SPINK1 proteins enhanced radioresistance of cancer cells even under normoxic conditions in EGFR-dependent and nuclear factor erythroid 2-related factor 2-dependent (Nrf2-dependent) manners and accelerated tumor growth after radiotherapy. An anti-SPINK1 neutralizing antibody exhibited a radiosensitizing effect. These results suggest that SPINK1 secreted from hypoxic cells protects the surrounding and relatively oxygenated cancer cells from radiation in a paracrine manner, justifying the use of SPINK1 as a target for radiosensitization and a plasma marker for predicting tumor hypoxia.
Assuntos
Tolerância a Radiação/genética , Inibidor da Tripsina Pancreática de Kazal/metabolismo , Hipóxia Tumoral/fisiologia , Células HeLa , Humanos , TransfecçãoRESUMO
Small extracellular vesicles (sEVs) operate as a signaling platform due to their ability to carry functional molecular cargos. However, the role of sEVs in hypoxic tumor microenvironment-mediated premetastatic niche formation remains poorly understood. Methods: Protein expression profile of sEVs derived from normoxic and hypoxic head and neck squamous cell carcinoma (HNSCC) cells were determined by Isobaric Tagging Technology for Relative Quantitation. In vitro invasion assay and in vivo colonization were performed to evaluate the role of sEV-delivering proteins. Results: We identified lysyl oxidase like 2 (LOXL2) which had the highest fold increase in hypoxic sEVs compared with normoxic sEVs. Hypoxic cell-derived sEVs delivered high amounts of LOXL2 to non-hypoxic HNSCC cells to elicit epithelial-to-mesenchymal transition (EMT) and induce the invasion of the recipient cancer cells. Moreover, LOXL2-enriched sEVs were incorporated by distant fibroblasts and activate FAK/Src signaling in recipient fibroblasts. Increased production of fibronectin mediated by FAK/Src signaling recruited myeloid-derived suppressor cells to form a premetastatic niche. Serum sEV LOXL2 can reflect a hypoxic and aggressive tumor type and can serve as an alternative to tissue LOXL2 as an independent prognostic factor of overall survival for patients with HNSCC. Conclusion: sEVs derived from the hypoxic tumor microenvironment of HNSCC can drive local invasion of non-hypoxic HNSCC cells and stimulate premetastatic niche formation by delivering LOXL2 to non-hypoxic HNSCC cells and fibroblasts to induce EMT and fibronectin production, respectively.
Assuntos
Aminoácido Oxirredutases/metabolismo , Neoplasias de Cabeça e Pescoço/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Aminoácido Oxirredutases/genética , Animais , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , China , Transição Epitelial-Mesenquimal/genética , Vesículas Extracelulares/metabolismo , Feminino , Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/genética , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Camundongos Nus , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Metástase Neoplásica/fisiopatologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Transcriptoma/genética , Hipóxia Tumoral/fisiologia , Microambiente Tumoral/fisiologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The annual global incidence of cervical cancer is approximately 604 000 cases/342 000 deaths, making it the fourth most common cancer in women. Cervical cancer is a major healthcare problem in low and middle income countries where 85% of new cases and deaths occur. Secondary prevention measures have reduced incidence and mortality in developed countries over the past 30 years, but cervical cancer remains a major cause of cancer deaths in women. For women who present with Fédération Internationale de Gynécologie et d'Obstétrique (FIGO 2018) stages IB3 or upwards, chemoradiation is the established treatment. Despite high rates of local control, overall survival is less than 50%, largely due to distant relapse. Reducing the health burden of cervical cancer requires greater individualization of treatment, identifying those at risk of relapse and progression for modified or intensified treatment. Hypoxia is a well known feature of solid tumors and an established therapeutic target. Low tumorous oxygenation increases the risk of local invasion, metastasis and treatment failure. While meta-analyses show benefit, many individual trials targeting hypoxia failed in part due to not selecting patients most likely to benefit. This review summarizes the available hypoxia-targeted strategies and identifies further research and new treatment paradigms needed to improve patient outcomes. The applications and limitations of hypoxia biomarkers for treatment selection and response monitoring are discussed. Finally, areas of greatest unmet clinical need are identified to measure and target hypoxia and therefore improve cervical cancer outcomes.
Assuntos
Quimiorradioterapia/métodos , Hipóxia Tumoral/fisiologia , Neoplasias do Colo do Útero/terapia , Biomarcadores/análise , Feminino , Saúde Global , Humanos , Tomografia por Emissão de Pósitrons , Hipóxia Tumoral/efeitos dos fármacos , Neoplasias do Colo do Útero/diagnóstico por imagem , Neoplasias do Colo do Útero/mortalidade , Neoplasias do Colo do Útero/patologiaRESUMO
Highly resolved spatial data of complex systems encode rich and nonlinear information. Quantification of heterogeneous and noisy data-often with outliers, artifacts, and mislabeled points-such as those from tissues, remains a challenge. The mathematical field that extracts information from the shape of data, topological data analysis (TDA), has expanded its capability for analyzing real-world datasets in recent years by extending theory, statistics, and computation. An extension to the standard theory to handle heterogeneous data is multiparameter persistent homology (MPH). Here we provide an application of MPH landscapes, a statistical tool with theoretical underpinnings. MPH landscapes, computed for (noisy) data from agent-based model simulations of immune cells infiltrating into a spheroid, are shown to surpass existing spatial statistics and one-parameter persistent homology. We then apply MPH landscapes to study immune cell location in digital histology images from head and neck cancer. We quantify intratumoral immune cells and find that infiltrating regulatory T cells have more prominent voids in their spatial patterns than macrophages. Finally, we consider how TDA can integrate and interrogate data of different types and scales, e.g., immune cell locations and regions with differing levels of oxygenation. This work highlights the power of MPH landscapes for quantifying, characterizing, and comparing features within the tumor microenvironment in synthetic and real datasets.
Assuntos
Neoplasias de Cabeça e Pescoço/diagnóstico por imagem , Macrófagos/citologia , Linfócitos T Reguladores/citologia , Hipóxia Tumoral/fisiologia , Microambiente Tumoral/imunologia , Contagem de Células/métodos , Biologia Computacional/métodos , Simulação por Computador , Análise de Dados , Neoplasias de Cabeça e Pescoço/imunologia , Humanos , Macrófagos/imunologia , Esferoides Celulares , Linfócitos T Reguladores/imunologiaRESUMO
Multimodal synergistic therapy has gained increasing attention in cancer treatment to overcome the limitations of monotherapy and achieve high anticancer efficacy. In this study, a synergistic phototherapy and hypoxia-activated chemotherapy nanoplatform based on natural melanin nanoparticles (MPs) loaded with the bioreduction prodrug tirapazamine (TPZ) and decorated with hyaluronic acid (HA) was developed. A self-reporting aggregation-induced emission (AIE)-active photosensitizer (PS) (BATTMN) was linked to the prepared nanoparticles by boronate ester bonds. The MPs and BATTMN-HA played roles as quenchers for PS and cancer targeting/photodynamic moieties, respectively. As a pH sensitive bond, the borate ester bonds between HA and BATTMN are hydrolysed in the acidic cancer environment, thereby separating BATTMN from the nanoparticles and leading to the induction of fluorescence for imaging-guided synergistic phototherapy/hypoxia-activated chemotherapy under dual irradiation. TPZ can be released upon activation by pH, near-infrared (NIR) and hyaluronidase (Hyal). Particularly, the hypoxia-dependent cytotoxicity of TPZ was amplified by oxygen consumption in the tumor intracellular environment induced by the AIE-active PS in photodynamic therapy (PDT). The nanoparticles developed in our research showed favorable photothermal conversion efficiency (η = 37%), desired cytocompatibility, and excellent synergistic therapeutic efficacy. The proposed nanoplatform not only extends the application scope of melanin materials with AIE-active PSs, but also offers useful insights into developing multistimulus as well as multimodal synergistic tumor treatment.
Assuntos
Antineoplásicos/uso terapêutico , Portadores de Fármacos/química , Melaninas/uso terapêutico , Nanopartículas/uso terapêutico , Neoplasias/tratamento farmacológico , Fármacos Fotossensibilizantes/uso terapêutico , Animais , Antineoplásicos/química , Ácidos Borônicos/química , Ácidos Borônicos/efeitos da radiação , Ácidos Borônicos/uso terapêutico , Terapia Combinada , Tratamento Farmacológico , Feminino , Humanos , Células MCF-7 , Melaninas/química , Melaninas/efeitos da radiação , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/química , Nanopartículas/efeitos da radiação , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/efeitos da radiação , Terapia Fototérmica , Pró-Fármacos/química , Pró-Fármacos/uso terapêutico , Tirapazamina/química , Tirapazamina/uso terapêutico , Hipóxia Tumoral/fisiologia , Ensaios Antitumorais Modelo de XenoenxertoAssuntos
Neoplasias das Glândulas Suprarrenais , Endocrinologia/tendências , Feocromocitoma , Neoplasias das Glândulas Suprarrenais/diagnóstico , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/terapia , Carcinogênese/metabolismo , Carcinogênese/patologia , Terapia Combinada/métodos , Terapia Combinada/tendências , Endocrinologia/métodos , Humanos , Terapia de Alvo Molecular/métodos , Terapia de Alvo Molecular/tendências , Mutação , Feocromocitoma/diagnóstico , Feocromocitoma/genética , Feocromocitoma/terapia , Cuidados Pré-Operatórios/métodos , Cuidados Pré-Operatórios/tendências , Prognóstico , Receptores Acoplados a Proteínas G/genética , Medição de Risco , Succinato Desidrogenase/genética , Hipóxia Tumoral/genética , Hipóxia Tumoral/fisiologiaRESUMO
PURPOSE: A major issue in radiotherapy is the relative resistance of hypoxic cells to radiation. Historic approaches to this problem include the use of oxygen mimetic compounds to sensitize tumour cells, which were unsuccessful. This review looks at modern approaches aimed at increasing the efficacy of targeting and radiosensitizing hypoxic tumour microenvironments relative to normal tissues and asks the question of whether non-targeted effects in radiobiology may provide a new "target". Novel techniques involve the integration of recent technological advancements such as nanotechnology, cell manipulation, and medical imaging. Particularly, the major areas of research discussed in this review include tumour hypoxia imaging through PET imaging to guide carbogen breathing, gold nanoparticles, macrophage-mediated drug delivery systems used for hypoxia-activate prodrugs, and autophagy inhibitors. Furthermore, this review outlines several features of these methods, including the mechanisms of action to induce radiosensitization, the increased accuracy in targeting hypoxic tumour microenvironments relative to normal tissue, preclinical/clinical trials, and future considerations. CONCLUSIONS: This review suggests that the four novel tumour hypoxia therapeutics demonstrate compelling evidence that these techniques can serve as powerful tools to increase targeting efficacy and radiosensitizing hypoxic tumour microenvironments relative to normal tissue. Each technique uses a different way to manipulate the therapeutic ratio, which we have labelled "oxygenate, target, use, and digest". In addition, by focusing on emerging non-targeted and out-of-field effects, new umbrella targets are identified, which instead of sensitizing hypoxic cells, seek to reduce the radiosensitivity of normal tissues.
Assuntos
Terapia de Alvo Molecular/métodos , Neoplasias/terapia , Hipóxia Tumoral/fisiologia , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Morte Celular , Humanos , Terapia de Alvo Molecular/tendências , Neoplasias/patologia , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico , Radiossensibilizantes/farmacologia , Radiossensibilizantes/uso terapêutico , Terapias em Estudo/métodos , Terapias em Estudo/tendênciasRESUMO
Background: Ovarian cancer (OC) has the highest mortality rate among gynecologic malignancy. Hypoxia is a driver of the malignant progression in OC, which results in poor prognosis. We herein aimed to develop a validated model that was based on the hypoxia genes to systematically evaluate its prognosis in tumor immune microenvironment (TIM). Results: We identified 395 hypoxia-immune genes using weighted gene co-expression network analysis (WGCNA). We then established a nine hypoxia-related genes risk model using least absolute shrinkage and selection operator (LASSO) Cox regression, which efficiently distinguished high-risk patients from low-risk ones. We found that high-risk patients were significantly related to poor prognosis. The high-risk group showed unique immunosuppressive microenvironment, lower antigen presentation, and higher levels of inhibitory cytokines. There were also significant differences in somatic copy number alterations (SCNAs) and mutations between the high- and low-risk groups, indicating immune escape in the high-risk group. Tumor immune dysfunction and exclusion (TIDE) and SubMap algorithms showed that low-risk patients are significantly responsive to programmed cell death protein-1 (PD-1) inhibitors. Conclusions: In this study, we highlighted the clinical significance of hypoxia in OC and established a hypoxia-related model for predicting prognosis and providing potential immunotherapy strategies.
Assuntos
Neoplasias Ovarianas/mortalidade , Hipóxia Tumoral/fisiologia , Variações do Número de Cópias de DNA , Feminino , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Nomogramas , Neoplasias Ovarianas/etiologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/imunologia , Prognóstico , Microambiente TumoralRESUMO
Hypoxia is an important feature of the tumor microenvironment, and is closely associated with cell proliferation, angiogenesis, metabolism and the tumor immune response. All these factors can further promote tumor progression, increase tumor aggressiveness, enhance tumor metastatic potential and lead to poor prognosis. In this review, these effects of hypoxia on tumor biology will be discussed, along with their significance for tumor detection and treatment.
Assuntos
Neoplasias/fisiopatologia , Hipóxia Tumoral/fisiologia , Microambiente Tumoral/fisiologia , Animais , Proliferação de Células , Glicólise , Humanos , Neoplasias/terapia , Neovascularização Patológica , Transdução de Sinais , Evasão TumoralRESUMO
Radiologic images provide a way to monitor tumor development and its response to therapies in a longitudinal and minimally invasive fashion. However, they operate on a macroscopic scale (average value per voxel) and are not able to capture microscopic scale (cell-level) phenomena. Nevertheless, to examine the causes of frequent fast fluctuations in tissue oxygenation, models simulating individual cells' behavior are needed. Here, we provide a link between the average data values recorded for radiologic images and the cellular and vascular architecture of the corresponding tissues. Using hybrid agent-based modeling, we generate a set of tissue morphologies capable of reproducing oxygenation levels observed in radiologic images. We then use these in silico tissues to investigate whether oxygen fluctuations can be explained by changes in vascular oxygen supply or by modulations in cellular oxygen absorption. Our studies show that intravascular changes in oxygen supply reproduce the observed fluctuations in tissue oxygenation in all considered regions of interest. However, larger-magnitude fluctuations cannot be recreated by modifications in cellular absorption of oxygen in a biologically feasible manner. Additionally, we develop a procedure to identify plausible tissue morphologies for a given temporal series of average data from radiology images. In future applications, this approach can be used to generate a set of tissues comparable with radiology images and to simulate tumor responses to various anti-cancer treatments at the tissue-scale level.
Assuntos
Modelos Biológicos , Neoplasias/diagnóstico por imagem , Neoplasias/metabolismo , Oxigênio/metabolismo , Hipóxia Celular/fisiologia , Biologia Computacional , Simulação por Computador , Humanos , Conceitos Matemáticos , Neoplasias/irrigação sanguínea , Radiografia , Análise de Sistemas , Hipóxia Tumoral/fisiologia , Microambiente Tumoral/fisiologiaRESUMO
Multiple myeloma (MM) is a refractory plasma cell tumor. In myeloma cells, the transcription factor IRF4, the master regulator of plasma cells, is aberrantly upregulated and plays an essential role in oncogenesis. IRF4 forms a positive feedback loop with MYC, leading to additional tumorigenic properties. In recent years, molecular targeted therapies have contributed to a significant improvement in the prognosis of MM. Nevertheless, almost all patients experience disease progression, which is thought to be a result of treatment resistance induced by various elements of the bone marrow microenvironment. Among these, the hypoxic response, one of the key processes for cellular homeostasis, induces hypoxia-adapted traits such as undifferentiation, altered metabolism, and dissemination, leading to drug resistance. These inductions are caused by ectopic gene expression changes mediated by the activation of hypoxia-inducible factors (HIFs). By contrast, the expression levels of IRF4 and MYC are markedly reduced by hypoxic stress. Notably, an anti-apoptotic capability is usually acquired under both normoxic and hypoxic conditions, but the mechanism is distinct. This fact strongly suggests that myeloma cells may survive by switching their dependent regulatory factors from IRF4 and MYC (normoxic bone marrow region) to HIF (hypoxic bone marrow microenvironment). Therefore, to achieve deep remission, combination therapeutic agents, which are complementarily effective against both IRF4-MYC-dominant and HIF-dominated fractions, may become an important therapeutic strategy for MM.
Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Fatores Reguladores de Interferon/metabolismo , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Hipóxia Tumoral/fisiologia , ADP-Ribosil Ciclase 1/antagonistas & inibidores , ADP-Ribosil Ciclase 1/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Células da Medula Óssea/fisiologia , Desdiferenciação Celular , Hipóxia Celular/fisiologia , Movimento Celular/fisiologia , Microambiente Celular/fisiologia , MicroRNA Circulante/metabolismo , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/fisiologia , Retroalimentação Fisiológica , Glicólise/fisiologia , Hexoquinase/metabolismo , Homeostase , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Fatores Imunológicos/uso terapêutico , Fatores Reguladores de Interferon/genética , Glicoproteínas de Membrana/antagonistas & inibidores , Glicoproteínas de Membrana/metabolismo , Terapia de Alvo Molecular/métodos , Mieloma Múltiplo/etiologia , Mieloma Múltiplo/genética , Proteínas de Neoplasias/metabolismo , Células-Tronco Neoplásicas/fisiologia , Oxigênio , Pressão Parcial , Inibidores de Proteassoma/uso terapêutico , Proteínas Proto-Oncogênicas c-myc/genética , Família de Moléculas de Sinalização da Ativação Linfocitária/antagonistas & inibidores , Regulação para CimaRESUMO
The dynamics of tumor growth and associated events cover multiple time and spatial scales, generally including extracellular, cellular and intracellular modifications. The main goal of this study is to model the biological and physical behavior of tumor evolution in presence of normal healthy tissue, considering a variety of events involved in the process. These include hyper and hypoactivation of signaling pathways during tumor growth, vessels' growth, intratumoral vascularization and competition of cancer cells with healthy host tissue. The work addresses two distinctive phases in tumor development-the avascular and vascular phases-and in each stage two cases are considered-with and without normal healthy cells. The tumor growth rate increases considerably as closed vessel loops (anastomoses) form around the tumor cells resulting from tumor induced vascularization. When taking into account the host tissue around the tumor, the results show that competition between normal cells and cancer cells leads to the formation of a hypoxic tumor core within a relatively short period of time. Moreover, a dense intratumoral vascular network is formed throughout the entire lesion as a sign of a high malignancy grade, which is consistent with reported experimental data for several types of solid carcinomas. In comparison with other mathematical models of tumor development, in this work we introduce a multiscale simulation that models the cellular interactions and cell behavior as a consequence of the activation of oncogenes and deactivation of gene signaling pathways within each cell. Simulating a therapy that blocks relevant signaling pathways results in the prevention of further tumor growth and leads to an expressive decrease in its size (82% in the simulation).
Assuntos
Modelos Biológicos , Neoplasias/irrigação sanguínea , Neoplasias/patologia , Algoritmos , Animais , Proliferação de Células/fisiologia , Biologia Computacional , Simulação por Computador , Humanos , Terapia de Alvo Molecular , Invasividade Neoplásica/patologia , Invasividade Neoplásica/fisiopatologia , Neoplasias/terapia , Neovascularização Patológica , Transdução de Sinais/fisiologia , Análise de Sistemas , Hipóxia Tumoral/fisiologia , Fator A de Crescimento do Endotélio Vascular/fisiologiaRESUMO
Hypoxia is a common phenomenon in most malignant tumors, especially in pancreatic cancer (PC). Hypoxia is the result of unlimited tumor growth and plays an active role in promoting tumor survival, progression, and invasion. As the part of the hypoxia microenvironment in PC is gradually clarified, hypoxia is becoming a key determinant and an important therapeutic target of pancreatic cancer. To adapt to the severe hypoxia environment, cells have changed their metabolic phenotypes to maintain their survival and proliferation. Enhanced glycolysis is the most prominent feature of cancer cells' metabolic reprogramming in response to hypoxia. It provides the energy source for hypoxic cancer cells (although it provides less than oxidative phosphorylation) and produces metabolites that can be absorbed and utilized by normoxic cancer cells. In addition, the uptake of glutamine and fatty acids by hypoxic cancer cells is also increased, which is also conducive to tumor progression. Their metabolites are pooled in the hexosamine biosynthesis pathway (HBP). As a nutrition sensor, HBP, in turn, can coordinate glucose and glutamine metabolism. Its end product, UDP-GlcNAc, is the substrate of protein post-translational modification (PTM) involved in various signaling pathways supporting tumor progression. Adaptive metabolic changes of cancer cells promote their survival and affect tumor immune cells in the tumor microenvironment (TME), which contributes to tumor immunosuppressive microenvironment and induces tumor immunotherapy resistance. Here, we summarize the hypoxic microenvironment, its effect on metabolic reprogramming, and its contribution to immunotherapy resistance in pancreatic cancer.
Assuntos
Reprogramação Celular/fisiologia , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/metabolismo , Hipóxia Tumoral/fisiologia , Microambiente Tumoral/fisiologia , Animais , Humanos , Carga Tumoral/fisiologiaRESUMO
The increasing demands for personalized targeted therapy directed against renal cell carcinoma have driven a search for predictive markers. Novel therapies targeting HIF-1α in renal cell carcinoma have been developed, and HIF-1α has been suggested as a novel predictive marker of response to therapy. The surgical resection of a kidney tumor induces tissue ischemia, and HIF-1α is an oxygen-sensitive transcription factor, which is known to be upregulated during hypoxia. This study investigated the impact of intra-surgical and post-surgical ischemia on protein expression levels of HIF-1α and three related biomarkers (VEGF, GLUT-1, and CAIX) in 20 patients with renal cell carcinoma with immunohistochemistry and Western blotting. Surgical ischemia did not have a significant impact on protein expression levels of any of the investigated markers. Long-post-surgical ischemia resulted in reduced expression levels of HIF-1α, probably due to autolysis. Our results suggest that HIF-1α is a stable protein, with expression levels not affected by intra-surgical ischemia, and hence, HIF-1α is suited for marker analysis.
Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/irrigação sanguínea , Carcinoma de Células Renais/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Renais/irrigação sanguínea , Neoplasias Renais/metabolismo , Idoso , Idoso de 80 Anos ou mais , Anidrase Carbônica IX/metabolismo , Carcinoma de Células Renais/cirurgia , Feminino , Transportador de Glucose Tipo 1/metabolismo , Humanos , Isquemia/genética , Isquemia/metabolismo , Neoplasias Renais/cirurgia , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Nefrectomia , Prognóstico , Estudos Prospectivos , Análise Serial de Tecidos , Hipóxia Tumoral/genética , Hipóxia Tumoral/fisiologia , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Nogo-B is an important regulator of tumor angiogenesis. Expression of Nogo-B is remarkably upregulated in multiple tumor types, especially hepatocellular carcinoma (HCC). Here, we show the transcriptional regulation mechanisms of Nogo-B in liver cancer. In response to hypoxia, expression of Nogo-B significantly increased in HCC tissues and cells. The distal hypoxia-responsive element in the promoter was essential for transcriptional activation of Nogo-B under hypoxic conditions, which is the specific site for hypoxia inducible factor-1α (HIF-1α) binding. In addition, Nogo-B expression was associated with c-Fos expression in HCC tissues. Nogo-B expression was induced by c-Fos, yet inhibited by a dominant negative mutant A-Fos. Deletion and mutation analysis of the predicted activator protein-1 binding sites revealed that functional element mediated the induction of Nogo-B promoter activity, which was confirmed by ChIP. These results indicate that HIF-1α and c-Fos induce the expression of Nogo-B depending on tumor microenvironments, such as hypoxia and low levels of nutrients, and play a role in upregulation of Nogo-B in tumor angiogenesis.
Assuntos
Carcinoma Hepatocelular/metabolismo , Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Hepáticas/metabolismo , Proteínas Nogo/metabolismo , Fator de Transcrição AP-1/metabolismo , Animais , Sítios de Ligação/genética , Carcinoma Hepatocelular/irrigação sanguínea , Deleção de Genes , Artéria Hepática , Humanos , Ligadura , Neoplasias Hepáticas/irrigação sanguínea , Masculino , Mutação , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neovascularização Patológica , Proteínas Nogo/genética , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-fyn/metabolismo , Distribuição Aleatória , Ratos Sprague-Dawley , Fator de Transcrição AP-1/genética , Ativação Transcricional , Hipóxia Tumoral/fisiologia , Microambiente Tumoral , Regulação para CimaRESUMO
Bone marrow-derived human mesenchymal stem cells (hMSCs) are recruited to damaged or inflamed tissues where they contribute to tissue repair. This multi-step process involves chemokine-directed invasion of hMSCs and on-site release of factors that influence target cells or tumor tissues. However, the underlying molecular mechanisms are largely unclear. Previously, we described that microRNA let-7f controls hMSC differentiation. Here, we investigated the role of let-7f in chemotactic invasion and paracrine anti-tumor effects. Incubation with stromal cell-derived factor-1α (SDF-1α) or inflammatory cytokines upregulated let-7f expression in hMSCs. Transfection of hMSCs with let-7f mimics enhanced CXCR4-dependent invasion by augmentation of pericellular proteolysis and release of matrix metalloproteinase-9. Hypoxia-induced stabilization of the hypoxia-inducible factor 1 alpha in hMSCs promoted cell invasion via let-7f and activation of autophagy. Dependent on its endogenous level, let-7f facilitated hMSC motility and invasion through regulation of the autophagic flux in these cells. In addition, secreted let-7f encapsulated in exosomes was increased upon upregulation of endogenous let-7f by treatment of the cells with SDF-1α, hypoxia, or induction of autophagy. In recipient 4T1 tumor cells, hMSC-derived exosomal let-7f attenuated proliferation and invasion. Moreover, implantation of 3D spheroids composed of hMSCs and 4T1 cells into a breast cancer mouse model demonstrated that hMSCs overexpressing let-7f inhibited tumor growth in vivo. Our findings provide evidence that let-7f is pivotal in the regulation of hMSC invasion in response to inflammation and hypoxia, suggesting that exosomal let-7f exhibits paracrine anti-tumor effects.