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1.
Mol Cancer ; 21(1): 32, 2022 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-35090469

RESUMO

N6-methyladenosine (m6A) methylation, the most common form of internal RNA modification in eukaryotes, has gained increasing attention and become a hot research topic in recent years. M6A plays multifunctional roles in normal and abnormal biological processes, and its role may vary greatly depending on the position of the m6A motif. Programmed cell death (PCD) includes apoptosis, autophagy, pyroptosis, necroptosis and ferroptosis, most of which involve the breakdown of the plasma membrane. Based on the implications of m6A methylation on PCD, the regulators and functional roles of m6A methylation were comprehensively studied and reported. In this review, we focus on the high-complexity links between m6A and different types of PCD pathways, which are then closely associated with the initiation, progression and resistance of cancer. Herein, clarifying the relationship between m6A and PCD is of great significance to provide novel strategies for cancer treatment, and has a great potential prospect of clinical application.


Assuntos
Adenosina , Neoplasias , Adenosina/análogos & derivados , Adenosina/metabolismo , Apoptose/genética , Humanos , Metilação , Neoplasias/genética , Neoplasias/metabolismo
2.
Cell Commun Signal ; 20(1): 14, 2022 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-35090497

RESUMO

Programmed cell death 1 ligand 1 (PD-L1) is the ligand for programmed death protein-1 (PD-1), is associated with immunosuppression. Signaling via PD-1/PD-L1 will transmits negative regulatory signals to T cells, inducing T-cell inhibition, reducing CD8+ T-cell proliferation, or promoting T-cell apoptosis, which effectively reduces the immune response and leads to large-scale tumor growth. Accordingly, many antibody preparations targeting PD-1 or PD-L1 have been designed to block the binding of these two proteins and restore T-cell proliferation and cytotoxicity of T cells. However, these drugs are ineffective in clinical practice. Recently, numerous of studies have shown that, in addition to the surface of tumor cells, PD-L1 is also found on the surface of extracellular vesicles secreted by these cells. Extracellular vesicle PD-L1 can also interact with PD-1 on the surface of T cells, leading to immunosuppression, and has been proposed as a potential mechanism underlying PD-1/PD-L1-targeted drug resistance. Therefore, it is important to explore the production, regulation and tumor immunosuppression of PD-L1 on the surface of tumor cells and extracellular vesicles, as well as the potential clinical application of extracellular vesicle PD-L1 as tumor biomarkers and therapeutic targets. Video Abstract.


Assuntos
Vesículas Extracelulares , Neoplasias , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/metabolismo , Linfócitos T CD8-Positivos , Vesículas Extracelulares/metabolismo , Humanos , Neoplasias/metabolismo , Microambiente Tumoral
3.
J Cell Sci ; 135(15)2022 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-35929545

RESUMO

Quiescence, the ability to temporarily halt proliferation, is a conserved process that initially allowed survival of unicellular organisms during inhospitable times and later contributed to the rise of multicellular organisms, becoming key for cell differentiation, size control and tissue homeostasis. In this Review, we explore the concept of cancer as a disease that involves abnormal regulation of cellular quiescence at every step, from malignant transformation to metastatic outgrowth. Indeed, disrupted quiescence regulation can be linked to each of the so-called 'hallmarks of cancer'. As we argue here, quiescence induction contributes to immune evasion and resistance against cell death. In contrast, loss of quiescence underlies sustained proliferative signalling, evasion of growth suppressors, pro-tumorigenic inflammation, angiogenesis and genomic instability. Finally, both acquisition and loss of quiescence are involved in replicative immortality, metastasis and deregulated cellular energetics. We believe that a viewpoint that considers quiescence abnormalities that occur during oncogenesis might change the way we ask fundamental questions and the experimental approaches we take, potentially contributing to novel discoveries that might help to alter the course of cancer therapy.


Assuntos
Neoplasias , Carcinogênese , Transformação Celular Neoplásica , Humanos , Neoplasias/metabolismo , Neovascularização Patológica/metabolismo , Transdução de Sinais
4.
Nat Commun ; 13(1): 4527, 2022 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-35927264

RESUMO

Natural Killer (NK) cells, a subset of innate immune cells, undergo cancer-specific changes during tumor progression. Therefore, tracking NK cell activity in circulation has potential for cancer diagnosis. Identification of tumor associated NK cells remains a challenge as most of the cancer antigens are unknown. Here, we introduce tumor-associated circulating NK cell profiling (CNKP) as a stand-alone cancer diagnostic modality with a liquid biopsy. Metabolic profiles of NK cell activation as a result of tumor interaction are detected with a SERS functionalized OncoImmune probe platform. We show that the cancer stem cell-associated NK cell is of value in cancer diagnosis. Through machine learning, the features of NK cell activity in patient blood could identify cancer from non-cancer using 5uL of peripheral blood with 100% accuracy and localization of cancer with 93% accuracy. These results show the feasibility of minimally invasive cancer diagnostics using circulating NK cells.


Assuntos
Células Matadoras Naturais , Neoplasias , Humanos , Ativação Linfocitária , Neoplasias/diagnóstico , Neoplasias/metabolismo , Células-Tronco Neoplásicas
5.
Signal Transduct Target Ther ; 7(1): 264, 2022 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-35918322

RESUMO

Metastasis is the leading cause of cancer-related death. The interactions between circulating tumor cells and endothelial adhesion molecules in distant organs is a key step during extravasation in hematogenous metastasis. Surgery is a common intervention for most primary solid tumors. However, surgical trauma-related systemic inflammation facilitates distant tumor metastasis by increasing the spread and adhesion of tumor cells to vascular endothelial cells (ECs). Currently, there are no effective interventions to prevent distant metastasis. Here, we show that HECTD3 deficiency in ECs significantly reduces tumor metastasis in multiple mouse models. HECTD3 depletion downregulates expression of adhesion molecules, such as VCAM-1, ICAM-1 and E-selectin, in mouse primary ECs and HUVECs stimulated by inflammatory factors and inhibits adhesion of tumor cells to ECs both in vitro and in vivo. We demonstrate that HECTD3 promotes stabilization, nuclear localization and kinase activity of IKKα by ubiquitinating IKKα with K27- and K63-linked polyubiquitin chains at K296, increasing phosphorylation of histone H3 to promote NF-κB target gene transcription. Knockout of HECTD3 in endothelium significantly inhibits tumor cells lung colonization, while conditional knockin promotes that. IKKα kinase inhibitors prevented LPS-induced pulmonary metastasis. These findings reveal the promotional role of the HECTD3-IKKα axis in tumor hematogenous metastasis and provide a potential strategy for tumor metastasis prevention.


Assuntos
Células Endoteliais , Neoplasias , Animais , Células Endoteliais/metabolismo , Quinase I-kappa B/genética , Quinase I-kappa B/metabolismo , Inflamação/genética , Inflamação/metabolismo , Camundongos , Camundongos Knockout , Neoplasias/genética , Neoplasias/metabolismo , Ubiquitina-Proteína Ligases/metabolismo
6.
Front Immunol ; 13: 863317, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35936008

RESUMO

IgGFc-binding protein (FCGBP) is a mucin first detected in the intestinal epithelium. It plays an important role in innate mucosal epithelial defense, tumor metastasis, and tumor immunity. FCGBP forms disulfide-linked heterodimers with mucin-2 and members of the trefoil factor family. These formed complexes inhibit bacterial attachment to mucosal surfaces, affect the motility of pathogens, and support their clearance. Altered FCGBP expression levels may be important in the pathologic processes of Crohn's disease and ulcerative colitis. FCGBP is also involved in regulating the infiltration of immune cells into tumor microenvironments. Thus, the molecule is a valuable marker of tumor prognosis. This review summarizes the functional relevance and role of FCGBP in immune responses and disease development, and highlights the potential role in diagnosis and predicting tumor prognosis.


Assuntos
Mucinas , Neoplasias , Moléculas de Adesão Celular/metabolismo , Humanos , Imunidade nas Mucosas , Mucosa Intestinal , Mucinas/metabolismo , Neoplasias/metabolismo , Proteínas/metabolismo , Microambiente Tumoral
7.
Sci Transl Med ; 14(657): eabo7604, 2022 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-35947675

RESUMO

Upon chronic antigen exposure, CD8+ T cells become exhausted, acquiring a dysfunctional state correlated with the inability to control infection or tumor progression. In contrast, stem-like CD8+ T progenitors maintain the ability to promote and sustain effective immunity. Adenovirus (Ad)-vectored vaccines encoding tumor neoantigens have been shown to eradicate large tumors when combined with anti-programmed cell death protein 1 (αPD-1) in murine models; however, the mechanisms and translational potential have not yet been elucidated. Here, we show that gorilla Ad vaccine targeting tumor neoepitopes enhances responses to αPD-1 therapy by improving immunogenicity and antitumor efficacy. Single-cell RNA sequencing demonstrated that the combination of Ad vaccine and αPD-1 increased the number of murine polyfunctional neoantigen-specific CD8+ T cells over αPD-1 monotherapy, with an accumulation of Tcf1+ stem-like progenitors in draining lymph nodes and effector CD8+ T cells in tumors. Combined T cell receptor (TCR) sequencing analysis highlighted a broader spectrum of neoantigen-specific CD8+ T cells upon vaccination compared to αPD-1 monotherapy. The translational relevance of these data is supported by results obtained in the first 12 patients with metastatic deficient mismatch repair (dMMR) tumors vaccinated with an Ad vaccine encoding shared neoantigens. Expansion and diversification of TCRs were observed in post-treatment biopsies of patients with clinical response, as well as an increase in tumor-infiltrating T cells with an effector memory signature. These findings indicate a promising mechanism to overcome resistance to PD-1 blockade by promoting immunogenicity and broadening the spectrum and magnitude of neoantigen-specific T cells infiltrating tumors.


Assuntos
Linfócitos T CD8-Positivos , Neoplasias , Adenoviridae , Animais , Antígenos de Neoplasias/metabolismo , Humanos , Camundongos , Neoplasias/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo
8.
Sci Signal ; 15(746): eadc9816, 2022 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-35944067

RESUMO

Although oncogenic driver mutations in RAS occur in 20% of cancers, heterogeneity in the biologic outputs of different RAS mutants has hampered efforts to develop effective treatments for RAS-mutated cancers. In this issue of Science Signaling, Huynh et al. show that even among KRASQ61 mutants, the specific amino acid that is substituted substantially affects mutant KRAS biologic activity and oncogenicity.


Assuntos
Produtos Biológicos , Neoplasias , Humanos , Mutação , Neoplasias/genética , Neoplasias/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Transdução de Sinais
9.
Front Cell Infect Microbiol ; 12: 905906, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35937685

RESUMO

E3 ubiquitin ligases determine the substrate specificity and catalyze the ubiquitination of lysine residues. HUWE1 is a catalytic HECT domain-containing giant E3 ligase that contains a substrate-binding ring structure, and mediates the ubiquitination of more than 40 diverse substrates. HUWE1 serves as a central node in cellular stress responses, cell growth and death, signal transduction, etc. The expanding atlas of HUWE1 substrates presents a major challenge for the potential therapeutic application of HUWE1 in a particular disease. In addition, HUWE1 has been demonstrated to play contradictory roles in certain aspects of tumor progression in either an oncogenic or a tumor-suppressive manner. We recently defined novel roles of HUWE1 in promoting the activation of multiple inflammasomes. Inflammasome activation-mediated immune responses might lead to multifunctional effects on tumor therapy, inflammation, and autoimmune diseases. In this review, we summarize the known substrates and pleiotropic functions of HUWE1 in different types of cells and models, including its involvement in development, cancer, neuronal disorder and infectious disease. We also discuss the advances in cryo-EM-structural analysis for a functional-mechanistic understanding of HUWE1 in modulating the multitudinous diverse substrates, and introduce the possibility of revisiting the comprehensive roles of HUWE1 in multiple aspects within one microenvironment, which will shed light on the potential therapeutic application of targeting giant E3 ligases like HUWE1.


Assuntos
Deficiência Intelectual , Neoplasias , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Carcinogênese , Humanos , Deficiência Intelectual/metabolismo , Neoplasias/metabolismo , Espermatogênese , Microambiente Tumoral
10.
Cell Mol Life Sci ; 79(8): 413, 2022 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-35819633

RESUMO

Cancer immunotherapy is a rapidly developing and effective method for the treatment of a variety of malignancies in recent years. As a significant immune checkpoint, programmed cell death 1 ligand 1 (PD-L1) and its receptor programmed cell death protein 1 (PD-1) play the most significant role in cancer immune escape and cancer immunotherapy. Though PD-L1 have become an important target for drug development and there have been various approved drugs and clinic trials targeting it, and various clinical response rate and adverse reactions prevent many patients from benefiting from it. In recent years, combination trials have become the main direction of PD-1/PD-L1 antibodies development. Here, we summarized PD-L1 biofunctions and key roles in various cancers along with the development of PD-L1 inhibitors. The regulators that are involved in controlling PD-L1 expression including post-translational modification, mRNA level regulation as well as degradation and exosome secretory pathway of PD-L1 were focused. This systematic summary may provide comprehensive understanding of different regulations on PD-L1 as well as a broad prospect for the search of the important regulator of PD-L1. The regulatory factors of PD-L1 can be potential targets for immunotherapy and increase strategies of immunotherapy in combination.


Assuntos
Antígeno B7-H1 , Neoplasias , Antígeno B7-H1/metabolismo , Humanos , Imunoterapia/métodos , Neoplasias/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Processamento de Proteína Pós-Traducional
11.
Sci Prog ; 105(3): 368504221109212, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35775596

RESUMO

A kinase anchoring protein (AKAP) 12 is a scaffolding protein that improves the specificity and efficiency of spatiotemporal signal through assembling intracellular signal proteins into a specific complex. AKAP12 is a negative mitogenic regulator that plays an important role in controlling cytoskeletal architecture, maintaining endothelial integrity, regulating glial function and forming blood-brain barrier (BBB) and blood retinal barrier (BRB). Moreover, elevated or reduced AKAP12 contributes to a variety of diseases. Complex connections between AKAP12 and various diseases including chronic liver diseases (CLDs), inflammatory diseases and a series of cancers will be tried to delineate in this paper. We first describe the expression, distribution and physiological function of AKAP12. Then we summarize the current knowledge of different connections between AKAP12 expression and various diseases. Some research groups have found paradoxical roles of AKAP12 in different diseases and further confirmation is needed. This paper aims to assess the role of AKAP12 in physiology and diseases to help lay the foundation for the design of small molecules for specific AKAP12 to correct the pathological signal defects.


Assuntos
Proteínas de Ancoragem à Quinase A , Neoplasias , Proteínas de Ancoragem à Quinase A/genética , Proteínas de Ancoragem à Quinase A/metabolismo , Barreira Hematorretiniana/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Humanos , Neoplasias/genética , Neoplasias/metabolismo
12.
Int J Oncol ; 61(2)2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35796006

RESUMO

Primary cilia are hair­like organelles that are present on the majority of mammalian cells. They are regarded as the regulatory 'hub' of cell functions due to their indispensable roles for several signaling pathways, such as Hh and Wnt pathways. Originally, cilia defects were found to cause a panoply of human diseases commonly referred to as 'ciliopathies'. Evidence is accumulating that cilia defects are involved in the onset and development of cancer. Some proteins that cause cilia defects have been identified as oncogenes in multiple cancer types. Hence, understanding the pathways that cause cilia defects in cancer is of utmost importance for the development of novel cancer therapeutic targets. The present review article provides a critical overview of the molecular targets of primary cilia defects in cancer, and highlights their vast potential as therapeutic targets and novel biomarkers.


Assuntos
Cílios , Neoplasias , Animais , Humanos , Mamíferos , Neoplasias/genética , Neoplasias/metabolismo , Via de Sinalização Wnt
13.
Int Rev Cell Mol Biol ; 370: 33-64, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35798506

RESUMO

Dendritic cells (DCs) play a major role in cancer immunosurveillance as they bridge innate and adaptive immunity by detecting tumor-associated antigens and presenting them to T lymphocytes. The adoptive transfer of antigen loaded DCs has been proposed as an immunotherapeutic approach for the treatment of various types of cancer. Nevertheless, despite promising preclinical data, the therapeutic efficacy of DC transfer is still deceptive in cancer patients. Here we summarize recent findings in DC biology with a special focus on the development of actionable therapeutic strategies and discuss experimental and clinical approaches that aim at improving the efficacy of DC-based immunotherapies, including, but not limited to, optimized DC production and antigen loading, stimulated maturation, the co-treatment with additional immunotherapies, as well as the inhibition of DC checkpoints.


Assuntos
Vacinas Anticâncer , Neoplasias , Antígenos de Neoplasias/metabolismo , Células Dendríticas , Humanos , Imunoterapia , Neoplasias/metabolismo , Linfócitos T
14.
Front Immunol ; 13: 947568, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35865518

RESUMO

Signal transducer and activator of transcription 3 (STAT3) is a member of the Janus kinase (JAK)-STAT pathway, which is one of the key pathways contributing to cancer. STAT3 regulates transcription downstream of many cytokines including interleukin (IL)-6 and IL-10. In cancer, STAT3 is mainly described as a tumor promoter driving tumor cell proliferation, resistance to apoptosis, angiogenesis and metastasis and aberrant activation of STAT3 is associated with poor prognosis. STAT3 is also an important driver of immune evasion. Among many other immunosuppressive mechanisms, STAT3 aids tumor cells to escape natural killer (NK) cell-mediated immune surveillance. NK cells are innate lymphocytes, which can directly kill malignant cells but also regulate adaptive immune responses and contribute to the composition of the tumor microenvironment. The inborn ability to lyse transformed cells renders NK cells an attractive tool for cancer immunotherapy. Here, we provide an overview of the role of STAT3 in the dynamic interplay between NK cells and tumor cells. On the one hand, we summarize the current knowledge on how tumor cell-intrinsic STAT3 drives the evasion from NK cells. On the other hand, we describe the multiple functions of STAT3 in regulating NK-cell cytotoxicity, cytokine production and their anti-tumor responses in vivo. In light of the ongoing research on STAT3 inhibitors, we also discuss how targeting STAT3 would affect the two arms of STAT3-dependent regulation of NK cell-mediated anti-tumor immunity. Understanding the complexity of this interplay in the tumor microenvironment is crucial for future implementation of NK cell-based immunotherapies.


Assuntos
Células Matadoras Naturais , Neoplasias , Fator de Transcrição STAT3 , Citocinas/metabolismo , Humanos , Interleucina-6/metabolismo , Janus Quinases/metabolismo , Células Matadoras Naturais/imunologia , Neoplasias/imunologia , Neoplasias/metabolismo , Fator de Transcrição STAT3/metabolismo , Microambiente Tumoral
15.
Org Biomol Chem ; 20(28): 5500-5509, 2022 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-35786742

RESUMO

The tumor suppressor and master gene regulator protein p53 has been the subject of intense investigation for several decades due to its mutation in about half of all human cancers. However, mechanistic studies of p53 in cells are complicated by its many dynamic binding partners and heterogeneous post-translational modifications. The design of therapeutics that rescue p53 functions in cells requires a mechanistic understanding of its protein-protein interactions in specific protein complexes and identifying changes in p53 activity by diverse post-translational modifications. This review highlights the important roles that peptide and protein chemistry have played in biophysical and biochemical studies aimed at elucidating p53 regulation by several key binding partners. The design of various peptide inhibitors that rescue p53 function in cells and new opportunities in targeting p53-protein interactions are discussed. In addition, the review highlights the importance of a protein semisynthesis approach to comprehend the role of site-specific PTMs in p53 regulation.


Assuntos
Neoplasias , Proteína Supressora de Tumor p53 , Humanos , Mutação , Neoplasias/metabolismo , Peptídeos/química , Processamento de Proteína Pós-Traducional , Proteína Supressora de Tumor p53/metabolismo
16.
Bull Math Biol ; 84(8): 82, 2022 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-35792958

RESUMO

CD200 is a cell membrane protein that binds to its receptor, CD200 receptor (CD200R). The CD200 positive tumor cells inhibit the cellular functions of M1 and M2 macrophages and dendritic cells (DCs) through the CD200-CD200R complex, resulting in downregulation of Interleukin-10 and Interleukin-12 productions and affecting the activation of cytotoxic T lymphocytes. In this work, we provide two ordinary differential equation models, one complete model and one simplified model, to investigate how the binding affinities of CD200R and the populations of M1 and M2 macrophages affect the functions of the CD200-CD200R complex in tumor growth. Our simulations demonstrate that (i) the impact of the CD200-CD200R complex on tumor promotion or inhibition highly depends on the binding affinity of the CD200R on M2 macrophages and DCs to the CD200 on tumor cells, and (ii) a stronger binding affinity of the CD200R on M1 macrophages or DCs to the CD200 on tumor cells induces a higher tumor cell density in the CD200 positive tumor. Thus, the CD200 blockade would be an efficient treatment method in this case. Moreover, the simplified model shows that the binding affinity of CD200R on macrophages is the major factor to determine the treatment efficacy of CD200 blockade when the binding affinities of CD200R on M1 and M2 macrophages are significantly different to each other. On the other hand, both the binding affinity of CD200R and the population of macrophages are the major factors to determine the treatment efficacy of CD200 blockade when the binding affinities of CD200R on M1 and M2 macrophages are close to each other. We also analyze the simplified model to investigate the dynamics of the positive and trivial equilibria of the CD200 positive tumor case and the CD200 deficient tumor case. The bifurcation diagrams show that when M1 macrophages dominate the population, the tumor cell density of the CD200 positive tumor is higher than the one of CD200 deficient tumor. Moreover, the dynamics of tumor cell density change from tumor elimination to tumor persistence to oscillation, as the maximal proliferation rate of tumor cells increases.


Assuntos
Conceitos Matemáticos , Neoplasias , Transformação Celular Neoplásica , Humanos , Macrófagos/metabolismo , Modelos Biológicos , Neoplasias/metabolismo , Neoplasias/terapia
17.
PLoS One ; 17(7): e0271730, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35862357

RESUMO

Childhood cancer survivors (CCS) are predisposed to the onset of osteoporosis (OP). It is known that iron overload induces osteoclasts (OCs) overactivity and that the iron chelator Deferasirox (DFX) can counteract it. The Cannabinoid Receptor type 2 (CB2) and the transient receptor potential vanilloid type-1 (TRPV1) are potential therapeutic targets for OP. In this study we isolated OCs from peripheral blood of 20 CCS and investigated osteoclast biomarkers expression and iron metabolism evaluating iron release by OCs and the expression of several molecules involved in its regulation. Moreover, we analyzed the effects of CB2 and TRPV1 stimulation in combination with DFX on osteoclast activity and iron metabolism. We observed, for the first time, an osteoclast hyperactivation in CCS suggesting a role for iron in its development. Moreover, we confirmed the well-known role of CB2 and TRPV1 receptors in bone metabolism, suggesting the receptors as possible key biomarkers of bone damage. Moreover, we demonstrated a promising synergism between pharmacological compounds, stimulating CB2 or inhibiting/desensitizing TRPV1 and DFX, in counteracting osteoclast overactivity in CCS to improve their quality of life.


Assuntos
Ferro , Neoplasias , Osteoporose , Receptor CB2 de Canabinoide , Canais de Cátion TRPV , Biomarcadores/metabolismo , Sobreviventes de Câncer , Criança , Humanos , Ferro/metabolismo , Neoplasias/metabolismo , Osteoclastos/metabolismo , Osteoporose/metabolismo , Qualidade de Vida , Receptor CB2 de Canabinoide/metabolismo , Canais de Cátion TRPV/metabolismo
18.
J Hematol Oncol ; 15(1): 98, 2022 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-35864539

RESUMO

Mitochondria are essential for tumor growth and progression. However, the heavy demand for mitochondrial activity in cancer leads to increased production of mitochondrial reactive oxygen species (mtROS), accumulation of mutations in mitochondrial DNA, and development of mitochondrial dysfunction. If left unchecked, excessive mtROS can damage and unfold proteins in the mitochondria to an extent that becomes lethal to the tumor. Cellular systems have evolved to combat mtROS and alleviate mitochondrial stress through a quality control mechanism called the mitochondrial unfolded protein response (UPRmt). The UPRmt system is composed of chaperones and proteases, which promote protein folding or eliminate mitochondrial proteins damaged by mtROS, respectively. UPRmt is conserved and activated in cancer in response to mitochondrial stress to maintain mitochondrial integrity and support tumor growth. In this review, we discuss how mitochondria become dysfunctional in cancer and highlight the tumor-promoting functions of key components of the UPRmt.


Assuntos
Neoplasias , Resposta a Proteínas não Dobradas , DNA Mitocondrial , Humanos , Mitocôndrias/metabolismo , Proteínas Mitocondriais/genética , Neoplasias/metabolismo
19.
J Exp Clin Cancer Res ; 41(1): 227, 2022 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-35864520

RESUMO

CD8+ T cells play a central role in anti-tumor immunity. Naïve CD8+ T cells are active upon tumor antigen stimulation, and then differentiate into functional cells and migrate towards the tumor sites. Activated CD8+ T cells can directly destroy tumor cells by releasing perforin and granzymes and inducing apoptosis mediated by the death ligand/death receptor. They also secrete cytokines to regulate the immune system against tumor cells. Mitochondria are the central hub of metabolism and signaling, required for polarization, and migration of CD8+ T cells. Many studies have demonstrated that mitochondrial dysfunction impairs the anti-tumor activity of CD8+ T cells through various pathways. Mitochondrial energy metabolism maladjustment will cause a cellular energy crisis in CD8+ T cells. Abnormally high levels of mitochondrial reactive oxygen species will damage the integrity and architecture of biofilms of CD8+ T cells. Disordered mitochondrial dynamics will affect the mitochondrial number and localization within cells, further affecting the function of CD8+ T cells. Increased mitochondria-mediated intrinsic apoptosis will decrease the lifespan and quantity of CD8+ T cells. Excessively low mitochondrial membrane potential will cause the release of cytochrome c and apoptosis of CD8+ T cells, while excessively high will exacerbate oxidative stress. Dysregulation of mitochondrial Ca2+ signaling will affect various physiological pathways in CD8+ T cells. To some extent, mitochondrial abnormality in CD8+ T cells contributes to cancer development. So far, targeting mitochondrial energy metabolism, mitochondrial dynamics, mitochondria-mediated cell apoptosis, and other mitochondrial physiological processes to rebuild the anti-tumor function of CD8+ T cells has proved effective in some cancer models. Thus, mitochondria in CD8+ T cells may be a potential and powerful target for cancer treatment in the future.


Assuntos
Mitocôndrias , Neoplasias , Apoptose , Linfócitos T CD8-Positivos , Humanos , Mitocôndrias/metabolismo , Neoplasias/metabolismo , Neoplasias/terapia , Espécies Reativas de Oxigênio/metabolismo
20.
Front Biosci (Landmark Ed) ; 27(7): 203, 2022 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-35866391

RESUMO

Ferroptosis is an emerging form of non-apoptotic, regulated cell death that is mechanistically dependent on aberrant iron accumulation and excessive lipid peroxidation. Further evidence indicates that ferroptosis plays a crucial role in the efficacy of tumor immunotherapy. Ferroptosis is often constrained by tumor-associated macrophages (TAMs), and this poses a challenge to clinicians aiming to exploit the potency of immunotherapy to treat various forms of cancer. Current advances revealed a dual character to TAMs in regulating tumor ferroptosis. Specifically, some signaling molecules released from cells undergoing ferroptosis can exert effects on TAM polarization. In this review, we summarize the currently characterized mechanisms of macrophage-ferroptosis crosstalk, discuss how macrophage-ferroptosis crosstalk affects the outcome of tumor immunotherapy, and provide an overview of current advances that seek to leverage this crosstalk to improve cancer immunotherapy efficacy. Despite the fact that further efforts are still required to achieve a more comprehensive understanding of the mechanisms that control this signaling, targeting macrophage-ferroptosis crosstalk has clear potential for reversing immunotherapeutic resistance and may shed light on new therapeutic strategies to overcome some advanced and metastatic malignancies.


Assuntos
Ferroptose , Neoplasias , Humanos , Imunoterapia , Peroxidação de Lipídeos , Macrófagos/metabolismo , Neoplasias/metabolismo , Neoplasias/terapia
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