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Cancer is a leading cause of death worldwide, accounting for nearly 10 million deaths in 2020 and ranking as the second-leading cause of death in economically developed countries [...].
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Transforming growth factor-beta1 (TGF-ß) regulates a plethora of cell-intrinsic processes that modulate tumor progression in a context-dependent manner. Thus, although TGF-ß acts as a tumor suppressor in the early stages of tumorigenesis, in late stages, this factor promotes tumor progression and metastasis. In addition, TGF-ß also impinges on the tumor microenvironment by modulating the immune system. In this aspect, TGF-ß exhibits a potent immunosuppressive effect, which allows both cancer cells to escape from immune surveillance and confers resistance to immunotherapy. While TGF-ß inhibits the activation and antitumoral functions of T-cell lymphocytes, dendritic cells, and natural killer cells, it promotes the generation of T-regulatory cells and myeloid-derived suppressor cells, which hinder antitumoral T-cell activities. Moreover, TGF-ß promotes tumor-associated macrophages and neutrophils polarization from M1 into M2 and N1 to N2, respectively. Altogether, these effects contribute to the generation of an immunosuppressive tumor microenvironment and support tumor promotion. This review aims to analyze the relevant evidence on the complex role of TGF-ß in cancer immunology, the current outcomes of combined immunotherapies, and the anti-TGF-ß therapies that may improve the success of current and new oncotherapies.
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Linfocitos T Reguladores , Factor de Crecimiento Transformador beta1 , Humanos , Células Asesinas Naturales , Carcinogénesis , Inmunoterapia , Factor de Crecimiento Transformador beta/fisiología , Microambiente TumoralRESUMEN
Glutamine synthetase (GS) activity is conserved from prokaryotes to humans, where the ATP-dependent production of glutamine from glutamate and ammonia is essential for neurotransmission and ammonia detoxification. Here, we show that mammalian GS uses glutamate and methylamine to produce a methylated glutamine analog, N5-methylglutamine. Untargeted metabolomics revealed that liver-specific GS deletion and its pharmacological inhibition in mice suppress hepatic and circulating levels of N5-methylglutamine. This alternative activity of GS was confirmed in human recombinant enzyme and cells, where a pathogenic mutation in the active site (R324C) promoted the synthesis of N5-methylglutamine over glutamine. N5-methylglutamine is detected in the circulation, and its levels are sustained by the microbiome, as demonstrated by using germ-free mice. Finally, we show that urine levels of N5-methylglutamine correlate with tumor burden and GS expression in a ß-catenin-driven model of liver cancer, highlighting the translational potential of this uncharacterized metabolite.
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Glutamina , Neoplasias , Humanos , Ratones , Animales , Glutamina/metabolismo , Glutamato-Amoníaco Ligasa/genética , Glutamato-Amoníaco Ligasa/metabolismo , Amoníaco , Ácido Glutámico/metabolismo , Hígado/metabolismo , Neoplasias/metabolismo , Homeostasis , MamíferosRESUMEN
Bone marrow mesenchymal stromal cells (MSCs) have immunomodulatory and regenerative potential. However, culture conditions govern their metabolic processes and therapeutic efficacy. Here we show that culturing donor-derived MSCs in Plasmax™, a physiological medium with the concentrations of nutrients found in human plasma, supports their proliferation and stemness, and prevents the nutritional stress induced by the conventional medium DMEM. The quantification of the exchange rates of metabolites between cells and medium, untargeted metabolomics, stable isotope tracing and transcriptomic analysis, performed at physiologically relevant oxygen concentrations (1%O2), reveal that MSCs rely on a high rate of glucose to lactate conversion, coupled with parallel anaplerotic fluxes from glutamine and glutamate to support citrate synthesis and secretion. These distinctive traits of MSCs shape the metabolic microenvironment of the bone marrow niche and can influence nutrient cross-talks under physiological and pathological conditions.
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Células de la Médula Ósea , Células Madre Mesenquimatosas , Citratos/metabolismo , Glucosa/metabolismo , Ácido Glutámico/metabolismo , Humanos , Células Madre Mesenquimatosas/metabolismoRESUMEN
Besides transformed cells, the tumors are composed of various cell types that contribute to undesirable tumor progression. Tumor-associated macrophages (TAMs) are the most abundant innate immune cells in the tumor microenvironment (TME). Within the TME, TAMs exhibit high plasticity and undergo specific functional metabolic alterations according to the availability of tumor tissue oxygen and nutrients, thus further contributing to tumorigenesis and cancer progression. Here, we review the main functional TAM metabolic patterns influenced by TME, including glycolysis, amino acid, and fatty acid metabolism. Moreover, this review discusses antitumor immunotherapies that affect TAM functionality by inducing cell repolarizing and metabolic profiles towards an antitumoral phenotype. Also, new macrophage-based cell therapeutic technologies recently developed using chimeric antigen receptor bioengineering are exposed, which may overcome all solid tumor physical barriers impeding the current adoptive cell therapies and contribute to developing novel cancer immunotherapies.
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Metabolismo Energético/efectos de los fármacos , Terapia Genética , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inmunoterapia Adoptiva , Neoplasias/terapia , Linfocitos T/trasplante , Microambiente Tumoral , Macrófagos Asociados a Tumores/efectos de los fármacos , Animales , Terapia Genética/efectos adversos , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inmunoterapia Adoptiva/efectos adversos , Neoplasias/genética , Neoplasias/inmunología , Neoplasias/metabolismo , Fenotipo , Receptores Quiméricos de Antígenos/genética , Receptores Quiméricos de Antígenos/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo , Microambiente Tumoral/inmunología , Macrófagos Asociados a Tumores/inmunología , Macrófagos Asociados a Tumores/metabolismoRESUMEN
Glutamoptosis is the induction of apoptotic cell death as a consequence of the aberrant activation of glutaminolysis and mTORC1 signaling during nutritional imbalance in proliferating cells. The role of the bioenergetic sensor AMPK during glutamoptosis is not defined yet. Here, we show that AMPK reactivation blocks both the glutamine-dependent activation of mTORC1 and glutamoptosis in vitro and in vivo. We also show that glutamine is used for asparagine synthesis and the GABA shunt to produce ATP and to inhibit AMPK, independently of glutaminolysis. Overall, our results indicate that glutamine metabolism is connected with mTORC1 activation through two parallel pathways: an acute alpha-ketoglutarate-dependent pathway; and a secondary ATP/AMPK-dependent pathway. This dual metabolic connection between glutamine and mTORC1 must be considered for the future design of therapeutic strategies to prevent cell growth in diseases such as cancer.
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Apoptosis/fisiología , Proliferación Celular/fisiología , Glutamina/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Transducción de Señal/fisiología , Proteínas Quinasas Activadas por AMP/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Antineoplásicos/farmacología , Línea Celular Tumoral , Células HCT116 , Células HEK293 , Humanos , Masculino , Ratones Endogámicos NOD , Ratones Noqueados , Ratones SCID , Sirolimus/análogos & derivados , Sirolimus/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
Alterations to the gut microbiome are associated with various neurological diseases, yet evidence of causality and identity of microbiome-derived compounds that mediate gut-brain axis interaction remain elusive. Here, we identify two previously unknown bacterial metabolites 3-methyl-4-(trimethylammonio)butanoate and 4-(trimethylammonio)pentanoate, structural analogs of carnitine that are present in both gut and brain of specific pathogen-free mice but absent in germ-free mice. We demonstrate that these compounds are produced by anaerobic commensal bacteria from the family Lachnospiraceae (Clostridiales) family, colocalize with carnitine in brain white matter, and inhibit carnitine-mediated fatty acid oxidation in a murine cell culture model of central nervous system white matter. This is the first description of direct molecular inter-kingdom exchange between gut prokaryotes and mammalian brain cells, leading to inhibition of brain cell function.
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Carnitina , Clostridiales/metabolismo , Microbioma Gastrointestinal , Mucosa Intestinal , Sustancia Blanca/metabolismo , Animales , Carnitina/análogos & derivados , Carnitina/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Masculino , RatonesRESUMEN
Purpose: Nilotinib plus doxorubicin showed to be synergistic regarding apoptosis in several sarcoma cell lines. A phase I/II trial was thus designed to explore the feasibility of nilotinib as coadjuvant of doxorubicin by inhibiting MRP-1/P-gp efflux activity. The phase I part of the study is presented here.Patients and Methods: Nilotinib 400 mg/12 hours was administered in fixed dose from day 1 to 6, and doxorubicin on day 5 of each cycle. Three dose escalation levels for doxorubicin at 60, 65, and 75 mg/m2 were planned. Cycles were repeated every 3 weeks for a total of 4 cycles. Eligible subtypes were retroperitoneal liposarcoma, leiomyosarcoma, and unresectable/metastatic high-grade chondrosarcoma.Results: Thirteen patients were enrolled: 7 chondrosarcoma, 4 liposarcoma, and 2 leiomyosarcoma. In 46 cycles administered, the most relevant grade 3/4 adverse effects per patient were neutropenia 54%, febrile neutropenia 15%, and asthenia 8%. No cardiac toxicity was observed. Only one dose-limiting toxicity (febrile neutropenia) was reported in the third dose level. With regard to efficacy, 1 partial response (1 liposarcoma), 9 stable diseases (5 chondrosarcoma, 2 liposarcoma, 1 leiomyosarcoma), and 3 progressive diseases (2 chondrosarcoma and 1 leiomyosarcoma) were present. ABCB1 and ABCC1 RNA expression levels decreased by 58.47-fold and 1.47-fold, respectively, on day 5 of the cycle.Conclusions: Combination of MRP-1/P-gp inhibitor, nilotinib, as coadjuvant with doxorubicin is feasible; it appears not to add substantial toxicity compared with doxorubicin alone. Pharmacodynamic study supports this concept. The recommended dose for the phase II part for doxorubicin was 75 mg/m2 Clin Cancer Res; 24(21); 5239-49. ©2018 AACR.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Sarcoma/tratamiento farmacológico , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Apoptosis/efectos de los fármacos , Biomarcadores de Tumor , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Quimioterapia Adyuvante , Doxorrubicina/administración & dosificación , Doxorrubicina/farmacocinética , Evaluación Preclínica de Medicamentos , Femenino , Humanos , Masculino , Ratones , Clasificación del Tumor , Estadificación de Neoplasias , Pirimidinas/administración & dosificación , Pirimidinas/farmacocinética , Sarcoma/diagnóstico , Sarcoma/metabolismo , Sarcoma/mortalidadRESUMEN
A master promoter of cell growth, mammalian target of rapamycin (mTOR) is upregulated in a large percentage of cancer cells. Still, targeting mTOR using rapamycin has a limited outcome in patients. Our recent results highlight the additional role of mTOR as a tumor suppressor, explaining these modest results in the clinic.
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Glutaminolysis plays a critical role in nutrient sufficiency and cell signaling activation in mammalian cells. Unexpectedly, our recent investigations revealed that the unbalanced activation of glutaminolysis during nutritional restriction causes a particular form of apoptotic cell death, that we termed "glutamoptosis." We found that the inhibition of autophagy is a key step to allow glutamoptosis-mediated cell death. Thus, autophagy controls glutamoptosis during nutritional imbalance.
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Apoptosis , Autofagia , Glutamina/farmacología , Estado Nutricional , Animales , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Humanos , Ácidos Cetoglutáricos/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Modelos BiológicosRESUMEN
A master coordinator of cell growth, mTORC1 is activated by different metabolic inputs, particularly the metabolism of glutamine (glutaminolysis), to control a vast range of cellular processes, including autophagy. As a well-recognized tumour promoter, inhibitors of mTORC1 such as rapamycin have been approved as anti-cancer agents, but their overall outcome in patients is rather poor. Here we show that mTORC1 also presents tumour suppressor features in conditions of nutrient restrictions. Thus, the activation of mTORC1 by glutaminolysis during nutritional imbalance inhibits autophagy and induces apoptosis in cancer cells. Importantly, rapamycin treatment reactivates autophagy and prevents the mTORC1-mediated apoptosis. We also observe that the ability of mTORC1 to activate apoptosis is mediated by the adaptor protein p62. Thus, the mTORC1-mediated upregulation of p62 during nutrient imbalance induces the binding of p62 to caspase 8 and the subsequent activation of the caspase pathway. Our data highlight the role of autophagy as a survival mechanism upon rapamycin treatment.
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Apoptosis/fisiología , Glutamina/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/antagonistas & inhibidores , Anticuerpos , Autofagia , Línea Celular Tumoral , Medios de Cultivo/química , Regulación de la Expresión Génica/fisiología , Humanos , Plásmidos , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
The remarkable metabolic differences between cancer cells and normal cells result in the potential for targeted cancer therapy. The upregulation of glutaminolysis provides energetic advantages to cancer cells. The recently described link between glutaminolysis and autophagy, mediated by MTORC1, may constitute an attractive target for therapeutic strategies. A combination of therapies targeting simultane-ously cell signaling, cancer metabolism, and autophagy can solve therapy resistance and tumor relapse problems, commonly observed in patients treated with most of the current targeted therapies. In this review we summarize the mechanistic link between glutaminolysis and autophagy, and discuss the impacts of these processes on cancer progression and the potential for therapeutic intervention.