Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 405.777
Filtrar
1.
Braz Oral Res ; 34: e006, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32022225

RESUMEN

Induced pluripotent stem (iPS) cells could be induced into ameloblast-like cells by ameloblasts serum-free conditioned medium (ASF-CM), and bone morphogenetic proteins (BMPs) might be essential during the regulation of this process. The present study investigates the signal transduction that regulates the ameloblastic differentiation of iPS cells induced by ASF-CM. Mouse iPS cells were characterized and then cultured for 14 days in epithelial cell medium (control) or ASF-CM. Bone morphogenetic protein receptor II (BMPR-II) siRNA, inhibitor of Smad1/5 phosphorylation activated by activin receptor-like kinase (ALK) receptors, and inhibitors of mitogen-activated protein kinases (MAPKs) phosphorylation were used to treat the iPS cells in combination with ASF-CM. Real-time PCR, western blotting, and immunofluorescent staining were used to evaluate the expressions of ameloblast markers ameloblastin, enamelin, and cytokeratin-14. BMPR-II gene and protein levels increased markedly in ASF-CM-treated iPS cells compared with the controls, while the mRNA levels of Bmpr-Ia and Bmpr-Ib were similar between the ASF-CM and control groups. ASF-CM stimulation significantly increased the gene and protein expression of ameloblastin, enamelin and cytokeratin-14, and phosphorylated SMAD1/5, p38 MAPK, and ERK1/2 MAPK compared with the controls. Knockdown of BMPR-II and inhibition of Smad1/5 phosphorylation both could significantly reverse the increased expression of ameloblastin, enamelin, and cytokeratin-14 induced by ASF-CM, while neither inhibition of p38 nor ERK1/2 phosphorylation had significant reversing effects. We conclude that smad1/5 signaling transduction, activated by ALK receptors, regulates the ameloblastic differentiation of iPS cells induced by ameloblast-conditioned medium.


Asunto(s)
Ameloblastos/citología , Células Madre Pluripotentes Inducidas/citología , Transducción de Señal/fisiología , Proteína Smad1/fisiología , Receptores de Activinas/análisis , Receptores de Activinas/fisiología , Western Blotting , Receptores de Proteínas Morfogenéticas Óseas de Tipo II/análisis , Receptores de Proteínas Morfogenéticas Óseas de Tipo II/fisiología , Diferenciación Celular/genética , Diferenciación Celular/fisiología , Células Cultivadas , Medio de Cultivo Libre de Suero , Técnica del Anticuerpo Fluorescente , Expresión Génica , Sistema de Señalización de MAP Quinasas/fisiología , Fosforilación , Interferencia de ARN , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteína Smad1/análisis , Factores de Tiempo , Proteínas Quinasas p38 Activadas por Mitógenos/análisis , Proteínas Quinasas p38 Activadas por Mitógenos/fisiología
2.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(1): 88-92, 2020 Feb.
Artículo en Chino | MEDLINE | ID: mdl-32027258

RESUMEN

OBJECTIVE: To study the effects of dihydroartemisinin (DHA) on the proliferation and apoptosis of acute myeloid leukemia (AML) cells. METHODS: The effects of DHA on the proliferation of acute myeloid leukemia cells and the inhibitory effect of Z-VAD-FMK on the DHA-induced cell apoptosis were detected by CCK-8 assay. The expression level of cleaved-caspased 3 was detected by indirect immunofluorescence. Western blot was used to quantify the protein expression of PTEN, p-Akt, AKT, ß-actin, and the apoptosis-associated proteins, such as C-PARP, Cleaved-caspase3 and Caspase3 respectively. RESULTS: DHA induced the AML cell apoptosis with concentration-dependent manner (rKasumi-1=-0.959, rKG-1=-0.956). The DHA could induce the accumulation of cleaved-caspase 3 and C-PARP in AML cells, activate PTEN gene and inhibited Akt phosphorylation. Apoptosis inhibitor Z-VAD-FMK could partially restored the activity of DHA-inhibited cell proliferation. CONCLUSION: Dihydroartemisinin induces AML cell apoptosis by inhibition of PTEN/AKT pathway. Dihydroartemisinin is expected to be a safe and effective drug for treatment of acute myeloid leukemia.


Asunto(s)
Leucemia Mieloide Aguda , Apoptosis , Artemisininas , Línea Celular Tumoral , Proliferación Celular , Humanos , Fosfohidrolasa PTEN , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal
3.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(1): 171-176, 2020 Feb.
Artículo en Chino | MEDLINE | ID: mdl-32027272

RESUMEN

OBJECTIVE: To investigate the inhibitory effect of adiponectin receptor agonist AdipoRon on proliferation of myeloma cell lines and its possible mechanism. METHODS: The myeloma cell lines Sp2/0-Ag14 and MPC-11 were treated with different concentration of AdipoRon. The cell proliferation was detected by CCK-8. Western blot was used to determine the protein level of the signaling pathway. RT-PCR was used to quantify the mRNA copy number of adiponectin receptor AdipoR1 and AdipoR2 in the bone marrow cells from 21 patients with multiple myeloma (MM). Twenty-three normal bone marrow samples were served as control. RESULTS: AdipoRon significantly inhibited the proliferation of MM cell lines Sp2/0-Ag14 and MPC-11 in a concentration-dependent and time-dependent manner. Western blot showed that AdipoRon induced an increase of the expression levels of apoptosis-related proteins cleaved caspase-3 and cleaved PARP. AdipoRon upregulated p-AMPK and its downstream p-ACC in MPC-11. In addition, AdipoRon upregulated LC3-II/LC3-I level and down-regulated the protein level of p62. The expression level of AdipoR1 in MM cells was significantly higher than that in normal controls, and the expression level of AdipoR2 in MM cells was significantly lower than that in normal controls. CONCLUSION: Adiponectin receptors are expressed differentially between MM patients and normal subjects. AdipoRon, an adiponectin receptor agonist, can inhibit myeloma cell proliferation and induce apoptosis, and AMPK/autophagy pathway may be one of its mechanisms.


Asunto(s)
Autofagia , Mieloma Múltiple , Proteínas Quinasas Activadas por AMP , Apoptosis , Proliferación Celular , Humanos , Piperidinas , Receptores de Adiponectina , Transducción de Señal
4.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(1): 354-358, 2020 Feb.
Artículo en Chino | MEDLINE | ID: mdl-32027303

RESUMEN

Abstract  Langerhans cell histiocytosis (LCH) is a disease originated from bone marrow dendritic cells, and classified as a tumor by the discovery of a recurrent somatic BRAF-V600E point mutation in the RAS-RAF-MEK-ERK signaling pathway. The clinical manifestations of LCH are mainly granulomatous lesions composed of clonal pathological tissue cells. According to the lesions and invasive risk organs, it is divided into single system diseases, multi-system diseases with risk-free organ infiltration and multi-system diseases with risk organ infiltration. The diagnosis was based on immunohistochemical pathological dendritic cell-specific markers CD1α++and/or CD207+,therefore, according to risk stratification, the regiment and intensity of combination chemotherapy and targeted therapy are drawn up. Prognosis is associates with risk organ infiltration, initial treatment response, and BRAF mutations. Due to the low incidence and lack of systematic knowledge, the clinical understanding of this disease is insufficient, thus the rates of misdiagnosis and therapeutic error are high. In this review, the pathogenesis, clinical manifestations, diagnostic and treatment are summarized. So on to provide a theroretical basis for clinical diagnosis and treatment of the diseases.


Asunto(s)
Histiocitosis de Células de Langerhans , Células Dendríticas , Humanos , Sistema de Señalización de MAP Quinasas , Mutación , Proteínas Proto-Oncogénicas B-raf , Transducción de Señal
5.
Adv Exp Med Biol ; 1202: 1-12, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32034706

RESUMEN

ATP is a cotransmitter with glutamate, noradrenaline, GABA, acetylcholine and dopamine in the brain. There is a widespread presence of both adenosine (P1) and P2 nucleotide receptors in the brain on both neurons and glial cells. Adenosine receptors play a major role in presynaptic neuromodulation, while P2X ionotropic receptors are involved in fast synaptic transmission and synaptic plasticity. P2Y G protein-coupled receptors are largely involved in presynaptic activities, as well as mediating long-term (trophic) signalling in cell proliferation, differentiation and death during development and regeneration. Both P1 and P2 receptors participate in neuron-glial interactions. Purinergic signalling is involved in control of cerebral vascular tone and remodelling and has been implicated in learning and memory, locomotor and feeding behaviour and sleep. There is increasing interest in the involvement of purinergic signalling in the pathophysiology of the CNS, including trauma, ischaemia, epilepsy, neurodegenerative diseases, neuropsychiatric and mood disorders, and cancer, including gliomas.


Asunto(s)
Encéfalo/metabolismo , Receptores Purinérgicos/metabolismo , Transducción de Señal , Transmisión Sináptica , Adenosina Trifosfato/metabolismo , Animales , Humanos
6.
Adv Exp Med Biol ; 1202: 13-33, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32034707

RESUMEN

Purines and pyrimidines are fundamental signaling molecules in controlling the survival and proliferation of astrocytes, as well as in mediating cell-to-cell communication between glial cells and neurons in the healthy brain. The malignant transformation of astrocytes towards progressively more aggressive brain tumours (from astrocytoma to anaplastic glioblastoma) leads to modifications in both the survival and cell death pathways which overall confer a growth advantage to malignant cells and resistance to many cytotoxic stimuli. It has been demonstrated, however, that, in astrocytomas, several purinergic (in particular adenosinergic) pathways controlling cell survival and death are still effective and, in some cases, even enhanced, providing invaluable targets for purine-based chemotherapy, that still represents an appropriate pharmacological approach to brain tumours. In this chapter, the current knowledge on both receptor-mediated and receptor-independent adenosine pathways in astrocytomas will be reviewed, with a particular emphasis on the most promising targets which could be translated from in vitro studies to in vivo pharmacology. Additionally, we have included new original data from our laboratory demonstrating a key involvement of MAP kinases in the cytostastic and cytotoxic effects exerted by an adenosine analogue, 2-CdA, which with the name of Cladribine is already clinically utilized in haematological malignancies. Here we show that 2-CdA can activate multiple intracellular pathways leading to cell cycle block and cell death by apoptosis of a human astrocytoma cell line that bears several pro-survival genetic mutations. Although in vivo data are still lacking, our results suggest that adenosine analogues could therefore be exploited to overcome resistance to chemotherapy of brain tumours.


Asunto(s)
Adenosina/metabolismo , Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , Transducción de Señal , Adenosina/análogos & derivados , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Resistencia a Antineoplásicos/efectos de los fármacos , Glioma/tratamiento farmacológico , Glioma/patología , Humanos , Transducción de Señal/efectos de los fármacos
7.
Adv Exp Med Biol ; 1202: 35-65, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32034708

RESUMEN

The chapter is focused on the mechanism of action of metabotropic P2Y nucleotide receptors: P2Y1, P2Y2, P2Y12, P2Y14 and the ionotropic P2X7 receptor in glioma C6 cells. P2Y1 and P2Y12 both respond to ADP, but while P2Y1 links to PLC and elevates cytosolic Ca2+ concentration, P2Y12 negatively couples to adenylate cyclase, maintaining cAMP at low level. In glioma C6, these two P2Y receptors modulate activities of ERK1/2 and PI3K/Akt signaling and the effects depend on physiological conditions of the cells. During prolonged serum deprivation, cell growth is arrested, the expression of the P2Y1 receptor strongly decreases and P2Y12 becomes a major player responsible for ADP-evoked signal transduction. The P2Y12 receptor activates ERK1/2 kinase phosphorylation (a known cell proliferation regulator) and stimulates Akt activity, contributing to glioma invasiveness. In contrast, P2Y1 has an inhibitory effect on Akt pathway signaling. Furthermore, the P2X7 receptor, often responsible for apoptotic fate, is not involved in Ca2+elevation in C6 cells. The shift in nucleotide receptor expression from P2Y1 to P2Y12 during serum withdrawal, the cross talk between both receptors and the lack of P2X7 activity shows the precise self-regulating mechanism, enhancing survival and preserving the neoplastic features of C6 cells.


Asunto(s)
Glioma/metabolismo , Nucleótidos/metabolismo , Receptores Purinérgicos P2/metabolismo , Transducción de Señal , Adenosina Difosfato/metabolismo , Línea Celular Tumoral , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Glioma/patología , Humanos , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo
8.
Adv Exp Med Biol ; 1202: 87-108, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32034710

RESUMEN

Among the pathological alterations that give tumor cells invasive potential, purinergic signaling is emerging as an important component. Studies performed in in vitro, in vivo and ex vivo glioma models indicate that alterations in the purinergic signaling are involved in the progression of these tumors. Gliomas have low expression of all E-NTPDases, when compared to astrocytes in culture. Nucleotides induce glioma proliferation and ATP, although potentially neurotoxic, does not evoke cytotoxic action on the majority of glioma cells in culture. The importance of extracellular ATP for glioma pathobiology was confirmed by the reduction in glioma tumor size by apyrase, which degrades extracellular ATP to AMP, and the striking increase in tumor size by over-expression of an ecto-enzyme that degrades ATP to ADP, suggesting the effect of extracellular ATP on the tumor growth depends on the nucleotide produced by its degradation. The participation of purinergic receptors on glioma progression, particularly P2X7, is involved in the resistance to ATP-induced cell death. Although more studies are necessary, the purinergic signaling, including ectonucleotidases and receptors, may be considered as future target for glioma pharmacological or gene therapy.


Asunto(s)
Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Progresión de la Enfermedad , Glioma/metabolismo , Glioma/patología , Receptores Purinérgicos/metabolismo , Transducción de Señal , Nucleótidos de Adenina/metabolismo , Animales , Humanos
9.
Adv Exp Med Biol ; 1202: 109-128, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32034711

RESUMEN

This chapter describes signaling pathways, stimulated by the P2Y2 nucleotide receptor (P2Y2R), that regulate cellular processes dependent on actin cytoskeleton dynamics in glioma C6 cells. P2Y2R coupled with G-proteins, in response to ATP or UTP, regulates the level of iphosphatidylinositol-4,5-bisphosphate (PIP2) which modulates a variety of actin binding proteins and is involved in calcium response and activates Rac1 and RhoA proteins. The RhoA/ROCK signaling pathway plays an important role in contractile force generation needed for the assembly of stress fibers, focal adhesions and for tail retraction during cell migration. Blocking of this pathway by a specific Rho-kinase inhibitor induces changes in F-actin organization and cell shape and decreases the level of phosphorylated myosin II and cofilin. In glioma C6 cells these changes are reversed after UTP stimulation of P2Y2R. Signaling pathways responsible for this compensation are calcium signaling which regulates MLC kinase activation via calmodulin, and the Rac1/PAK/LIMK cascade. Stimulation of the Rac1 mediated pathway via Go proteins needs additional interaction between αvß5 integrins and P2Y2Rs. Calcium free medium, or growing of the cells in suspension, prevents Gαo activation by P2Y2 receptors. Rac1 activation is necessary for cofilin phosphorylation as well as integrin activation needed for focal complexes formation and stabilization of lamellipodium. Inhibition of positive Rac1 regulation prevents glioma C6 cells from recovery of control cell like morphology.


Asunto(s)
Citoesqueleto/metabolismo , Glioma/metabolismo , Receptores Purinérgicos P2Y2/metabolismo , Transducción de Señal , Actinas/metabolismo , Animales , Línea Celular Tumoral , Glioma/patología , Humanos , Nucleótidos/metabolismo , Fosforilación
10.
Adv Exp Med Biol ; 1202: 129-149, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32034712

RESUMEN

Tumor cell invasiveness is a critical challenge in the clinical management of glioma patients. In addition, there is accumulating evidence that current therapeutic modalities, including anti-angiogenic therapy and radiotherapy, can enhance glioma invasiveness. Glioma cell invasion is stimulated by both autocrine and paracrine factors that act on a large array of cell surface-bound receptors. Key signaling elements that mediate receptor-initiated signaling in the regulation of glioblastoma invasion are Rho family GTPases, including Rac, RhoA and Cdc42. These GTPases regulate cell morphology and actin dynamics and stimulate cell squeezing through the narrow extracellular spaces that are typical of the brain parenchyma. Transient attachment of cells to the extracellular matrix is also necessary for glioblastoma cell invasion. Interactions with extracellular matrix components are mediated by integrins that initiate diverse intracellular signalling pathways. Key signaling elements stimulated by integrins include PI3K, Akt, mTOR and MAP kinases. In order to detach from the tumor mass, glioma cells secrete proteolytic enzymes that cleave cell surface adhesion molecules, including CD44 and L1. Key proteases produced by glioma cells include uPA, ADAMs and MMPs. Increased understanding of the molecular mechanisms that control glioma cell invasion has led to the identification of molecular targets for therapeutic intervention in this devastating disease.


Asunto(s)
Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Glioma/metabolismo , Glioma/patología , Invasividad Neoplásica , Transducción de Señal , Animales , Movimiento Celular , Glioblastoma/metabolismo , Glioblastoma/patología , Humanos , Integrinas/metabolismo
11.
Adv Exp Med Biol ; 1202: 179-201, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32034714

RESUMEN

Transforming growth factor beta (TGF-ß) signaling is involved in the regulation of proliferation, differentiation and survival/or apoptosis of many cells, including glioma cells. TGF-ß acts via specific receptors activating multiple intracellular pathways resulting in phosphorylation of receptor-regulated Smad2/3 proteins that associate with the common mediator, Smad4. Such complex translocates to the nucleus, binds to DNA and regulates transcription of many genes. Furthermore, TGF-ß-activated kinase-1 (TAK1) is a component of TGF-ß signaling and activates mitogen-activated protein kinase (MAPK) cascades. Negative regulation of TGF-ß/Smad signaling may occur through the inhibitory Smad6/7. While genetic alterations in genes related to TGF-ß signaling are relatively rare in gliomas, the altered expression of those genes is a frequent event. The increased expression of TGF-ß1-3 correlates with a degree of malignancy of human gliomas. TGF-ß may contribute to tumor pathogenesis in many ways: by direct support of tumor growth, by maintaining self-renewal of glioma initiating stem cells and inhibiting anti-tumor immunity. Glioma initiating cells are dedifferentiated cells that retain many stem cell-like properties, play a role in tumor initiation and contribute to its recurrence. TGF-ß1,2 stimulate expression of the vascular endothelial growth factor as well as the plasminogen activator inhibitor and some metalloproteinases that are involved in vascular remodeling, angiogenesis and degradation of the extracellular matrix. Inhibitors of TGF-ß signaling reduce viability and invasion of gliomas in animal models and show a great promise as novel, potential anti-tumor therapeutics.


Asunto(s)
Glioma/metabolismo , Glioma/patología , Transducción de Señal , Factor de Crecimiento Transformador beta/metabolismo , Animales , Carcinogénesis , Glioma/tratamiento farmacológico , Humanos , Fosforilación , Receptores de Factores de Crecimiento Transformadores beta/metabolismo
12.
Adv Exp Med Biol ; 1202: 223-241, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32034716

RESUMEN

Cannabinoids are a group of structurally heterogeneous but pharmacologically related compounds, including plant-derived cannabinoids, synthetic substances and endogenous cannabinoids, such as anandamide and 2-arachidonoylglycerol. Cannabinoids elicit a wide range of central and peripheral effects mostly mediated through cannabinoid receptors. There are two types of specific Gi/o-protein-coupled receptors cloned so far, called CB1 and CB2, although an existence of additional cannabinoid-binding receptors has been suggested. CB1 and CB2 differ in their predicted amino acid sequence, tissue distribution, physiological role and signaling mechanisms. Significant alterations of a balance in the cannabinoid system between the levels of endogenous ligands and their receptors occur during malignant transformation in various types of cancer, including gliomas. Cannabinoids exert anti-proliferative action in tumor cells. Induction of cell death by cannabinoid treatment relies on the generation of a pro-apoptotic sphingolipid ceramide and disruption of signaling pathways crucial for regulation of cellular proliferation, differentiation or apoptosis. Increased ceramide levels lead also to ER-stress and autophagy in drug-treated glioblastoma cells. Beyond blocking of tumor cells proliferation cannabinoids inhibit invasiveness, angiogenesis and the stem cell-like properties of glioma cells, showing profound activity in the complex tumor microenvironment. Advances in translational research on cannabinoid signaling led to clinical investigations on the use of cannabinoids in treatments of glioblastomas.


Asunto(s)
Cannabinoides/metabolismo , Glioma/metabolismo , Glioma/patología , Transducción de Señal , Animales , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Glioblastoma/metabolismo , Glioblastoma/patología , Humanos , Receptores de Cannabinoides/metabolismo , Microambiente Tumoral
13.
Adv Exp Med Biol ; 1202: 243-258, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32034717

RESUMEN

The observations that numerous cancers are characterized by impairment in arginine synthesis and that deficit of exogenous arginine specifically affects their growth and viability are the ground for arginine deprivation-based anticancer treatment strategy. This review addresses molecular mechanisms of the human glioblastoma cell response to arginine deprivation. Our earlier studies have shown that arginine deprivation specifically impairs glioblastoma cell motility, adhesion and invasiveness. These changes were evoked by alterations in the actin cytoskeleton organization resulting from a decreased arginylation of ß-actin isoform. Moreover, deficit of arginine induces prolonged endoplasmic reticulum (ER) stress and activation of the unfolded protein response, not leading, however, to a massive apoptosis in glioblastoma cells. Our current research indicates that cell death could be augmented by other compounds such as modulators of ER stress, for example arginine analogue of plant origin, canavanine. Implication of these studies on the development of new anti-glioma metabolic therapeutic modalities are discussed.


Asunto(s)
Arginina/deficiencia , Arginina/metabolismo , Glioblastoma/metabolismo , Glioblastoma/patología , Transducción de Señal , Animales , Arginina/análogos & derivados , Estrés del Retículo Endoplásmico/efectos de los fármacos , Glioblastoma/tratamiento farmacológico , Humanos , Transducción de Señal/efectos de los fármacos , Respuesta de Proteína Desplegada/efectos de los fármacos
14.
Adv Exp Med Biol ; 1223: 1-16, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32030682

RESUMEN

The tumor microenvironment (TME) has become a major concern of cancer research both from a basic and a therapeutic point of view. Understanding the effect of a signaling pathway-and thus the effect of its targeting-in every aspect of the microenvironment is a prerequisite to predict and analyze the effect of a therapy. The Notch signaling pathway is involved in every component of the TME as well as in the interaction between the different parts of the TME. This review aims at describing how Notch signaling is impacting the TME and the consequences this may have when modulating Notch signaling in a therapeutic perspective.


Asunto(s)
Neoplasias/metabolismo , Receptores Notch/metabolismo , Transducción de Señal , Microambiente Tumoral , Humanos
15.
Adv Exp Med Biol ; 1223: 17-30, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32030683

RESUMEN

Erythropoietin (EPO), the primary cytokine of erythropoiesis, stimulates both proliferation and differentiation of erythroid progenitors and their maturation to red blood cells. Basal EPO levels maintain the optimum levels of circulating red blood cells. However, during hypoxia, EPO secretion and its expression is elevated drastically in renal interstitial fibroblasts, thereby increasing the number of erythroid progenitors and accelerating their differentiation to mature erythrocytes. A tight regulation of this pathway is therefore of paramount importance. The biological response to EPO is commenced through the involvement of its cognate receptor, EPOR. The receptor-ligand complex results in homodimerization and conformational changes, which trigger downstream signaling events and cause activation or inactivation of critical transcription factors that promote erythroid expansion. In recent years, recombinant human EPO (rEPO) has been widely used as a therapeutic tool to treat a number of anemias induced by infection, and chemotherapy for various cancers. However, several studies have uncovered a tumor promoting ability of EPO in man, which likely occurs through EPOR or alternative receptor(s). On the other hand, some studies have demonstrated a strong anticancer activity of EPO, although the mechanism still remains unclear. A thorough investigation of EPOR signaling could yield enhanced understanding of the pathobiology for a variety of disorders, as well as the potential novel therapeutic strategies. In this chapter, in addition to the clinical relevance of EPO/EPOR signaling, we review its anticancer efficacy within various tumor microenvironments.


Asunto(s)
Eritropoyetina/metabolismo , Salud , Neoplasias/metabolismo , Receptores de Eritropoyetina/metabolismo , Transducción de Señal , Microambiente Tumoral , Eritropoyesis , Humanos
16.
Adv Exp Med Biol ; 1223: 31-67, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32030684

RESUMEN

Neuropilin-1 and neuropilin-2 form a small family of transmembrane receptors, which, due to the lack of a cytosolic protein kinase domain, act primarily as co-receptors for various ligands. Performing at the molecular level both the executive and organizing functions of a handyman as well as of a power broker, they are instrumental in controlling the signaling of various receptor tyrosine kinases, integrins, and other molecules involved in the regulation of physiological and pathological angiogenic processes. In this setting, the various neuropilin ligands and interaction partners on various cells of the tumor microenvironment, such as cancer cells, endothelial cells, cancer-associated fibroblasts, and immune cells, are surveyed. The suitability of various neuropilin-targeting substances and the intervention in neuropilin-mediated interactions is considered as a possible building block of tumor therapy.


Asunto(s)
Neoplasias/metabolismo , Neuropilina-1/metabolismo , Neuropilina-2/metabolismo , Microambiente Tumoral , Humanos , Neoplasias/irrigación sanguínea , Neoplasias/patología , Neovascularización Patológica , Transducción de Señal
17.
Adv Exp Med Biol ; 1223: 69-80, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32030685

RESUMEN

The mammalian target of rapamycin (mTOR) represents a critical hub for the regulation of different processes in both normal and tumor cells. Furthermore, it is now well established the role of mTOR in integrating and shaping different environmental paracrine and autocrine stimuli in tumor microenvironment (TME) constituents. Recently, further efforts have been employed to understand how the mTOR signal transduction mechanisms modulate the sensitivity and resistance to targeted therapies, also for its involvement of mTOR also in modulating angiogenesis and tumor immunity. Indeed, interest in mTOR targeting was increased to improve immune response against cancer and to develop new long-term efficacy strategies, as demonstrated by clinical success of mTOR and immune checkpoint inhibitor combinations. In this chapter, we will describe the role of mTOR in modulating TME elements and the implication in its targeting as a great promise in clinical trials.


Asunto(s)
Neoplasias/metabolismo , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismo , Microambiente Tumoral , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/inmunología , Microambiente Tumoral/efectos de los fármacos
18.
Adv Exp Med Biol ; 1223: 81-97, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32030686

RESUMEN

The involvement of inflammation in cancer progression is well-established. The immune system can play both tumor-promoting and -suppressive roles, and efforts to harness the immune system to help fight tumor growth are at the forefront of research. Of particular importance is the inflammatory profile at the site of the tumor, with respect to both the leukocyte population numbers, the phenotype of these cells, as well as the contribution of the tumor cells themselves. In this regard, the pro-inflammatory effects of pattern recognition receptor expression and activation in the tumor microenvironment have emerged as a relevant issue both for therapy and to understand tumor development.Pattern recognition receptors (PRRs) were originally recognized as components of immune cells, particularly innate immune cells, as detectors of pathogens. PRR signaling in immune cells activates them, inducing robust antimicrobial responses. In particular, toll-like receptors (TLRs) constitute a family of membrane-bound PRRs which can recognize pathogen-associated molecular patterns (PAMPs) carried by bacteria, virus, and fungi. In addition, PRRs can recognize products generated by stressed cells or damaged tissues, namely damage-associated molecular patterns or DAMPS. Taking into account the role of the immune system in fighting tumors together with the presence of immune cells in the microenvironment of different types of tumors, strategies to activate immune cells via PRR ligands have been envisioned as an anticancer therapeutic approach.In the last decades, it has been determined that PRRs are present and functional on nonimmune cells and that their activation in these cells contributes to the inflammation in the tumor microenvironment. Both tumor-promoting and antitumor effects have been observed when tumor cell PRRs are activated. This argues against nonspecific activation of PRR ligands in the tumor microenvironment as a therapeutic approach. Therefore, the use of PRR ligands for anticancer therapy might benefit from strategies that specifically deliver these ligands to immune cells, thus avoiding tumor cells in some settings. This review focuses on these aspects of TLR signaling in the tumor microenvironment.


Asunto(s)
Neoplasias/inmunología , Neoplasias/metabolismo , Transducción de Señal , Receptores Toll-Like/metabolismo , Microambiente Tumoral , Humanos , Receptores de Reconocimiento de Patrones/inmunología , Receptores de Reconocimiento de Patrones/metabolismo , Transducción de Señal/inmunología , Receptores Toll-Like/inmunología , Microambiente Tumoral/inmunología
19.
Adv Exp Med Biol ; 1223: 99-127, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32030687

RESUMEN

The Rho-ROCK signaling network has a range of specialized functions of key biological importance, including control of essential developmental processes such as morphogenesis and physiological processes including homeostasis, immunity, and wound healing. Deregulation of Rho-ROCK signaling actively contributes to multiple pathological conditions, and plays a major role in cancer development and progression. This dynamic network is critical in modulating the intricate communication between tumor cells, surrounding diverse stromal cells and the matrix, shaping the ever-changing microenvironment of aggressive tumors. In this chapter, we overview the complex regulation of the Rho-ROCK signaling axis, its role in health and disease, and analyze progress made with key approaches targeting the Rho-ROCK pathway for therapeutic benefit. Finally, we conclude by outlining likely future trends and key questions in the field of Rho-ROCK research, in particular surrounding Rho-ROCK signaling within the tumor microenvironment.


Asunto(s)
Neoplasias/metabolismo , Transducción de Señal , Microambiente Tumoral , Proteínas de Unión al GTP rho/metabolismo , Quinasas Asociadas a rho/metabolismo , Humanos , Neoplasias/enzimología
20.
Adv Exp Med Biol ; 1223: 129-153, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32030688

RESUMEN

Sphingosine-1-phosphate (S1P), together with other phosphosphingolipids, has been found to regulate complex cellular function in the tumor microenvironment (TME) where it acts as a signaling molecule that participates in cell-cell communication. S1P, through intracellular and extracellular signaling, was found to promote tumor growth, angiogenesis, chemoresistance, and metastasis; it also regulates anticancer immune response, modulates inflammation, and promotes angiogenesis. Interestingly, cancer cells are capable of releasing S1P and thus modifying the behavior of the TME components in a way that contributes to tumor growth and progression. Therefore, S1P is considered an important therapeutic target, and several anticancer therapies targeting S1P signaling are being developed and tested in clinics.


Asunto(s)
Lisofosfolípidos/metabolismo , Neoplasias/metabolismo , Transducción de Señal , Esfingosina/análogos & derivados , Microambiente Tumoral , Humanos , Neoplasias/patología , Esfingosina/metabolismo
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA