Immunity, Hypoxia, and Metabolism–the Ménage à Trois of Cancer: Implications for Immunotherapy

Physiological Reviews, Journal Year: 2019, Volume and Issue: 100(1), P. 1 - 102

Published: Aug. 15, 2019

It is generally accepted that metabolism able to shape the immune response. Only recently we are gaining awareness metabolic crosstalk between different tumor compartments strongly contributes harsh microenvironment (TME) and ultimately impairs cell fitness effector functions. The major aims of this review provide an overview on system in cancer; position oxygen shortage competition as ground a restrictive TME important players anti-tumor response; define how immunotherapies affect hypoxia/oxygen delivery landscape tumor; vice versa, metabolites within impinge success immunotherapies. By analyzing preclinical clinical endeavors, will discuss characterization can identify novel targets signatures could be exploited combination with standard help predict benefit new traditional immunotherapeutic drugs.

Language: Английский

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Phase Separation as a Missing Mechanism for Interpretation of Disease Mutations

Cell, Journal Year: 2020, Volume and Issue: 183(7), P. 1742 - 1756

Published: Dec. 1, 2020

Language: Английский

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Immune control by amino acid catabolism during tumorigenesis and therapy

Nature reviews. Cancer, Journal Year: 2019, Volume and Issue: 19(3), P. 162 - 175

Published: Jan. 29, 2019

Language: Английский

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Cancer Cells Tune the Signaling Pathways to Empower de Novo Synthesis of Nucleotides

Cancers, Journal Year: 2019, Volume and Issue: 11(5), P. 688 - 688

Published: May 17, 2019

Cancer cells exhibit a dynamic metabolic landscape and require sufficient supply of nucleotides other macromolecules to grow proliferate. To meet the requirements for cell growth, cancer must stimulate de novo nucleotide synthesis obtain adequate pools support nucleic acid protein along with energy preservation, signaling activity, glycosylation mechanisms, cytoskeletal function. Both oncogenes tumor suppressors have recently been identified as key molecular determinants that contribute maintenance homeostasis proliferation cells. Inactivation such TP53 LKB1 hyperactivation mTOR pathway MYC, RAS, AKT shown fuel in The mechanisms by which these hubs influence metabolism, especially pathways synthesis, continue emerge. Here, we focus on current understanding modulate and, based insights, discuss potential strategies target proliferation.

Language: Английский

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CCL5/CCR5 axis in human diseases and related treatments

Genes & Diseases, Journal Year: 2021, Volume and Issue: 9(1), P. 12 - 27

Published: Aug. 26, 2021

To defense harmful stimuli or maintain the immune homeostasis, body produces and recruits a superfamily of cytokines such as interleukins, interferons, chemokines etc. Among them, act crucial regulators in systems. CCL5/CCR5 combination is known for facilitating inflammatory responses, well inducing adhesion migration different T cell subsets responses. In addition, recent studies have shown that interaction between CCL5 CCR5 involved various pathological processes including inflammation, chronic diseases, cancers infection COVID-19. This review focuses on how axis participates diseases their relevant signaling pathways regulation axis. Moreover, we highlighted gene therapy chemotherapy treating CCR5-related ongoing clinical trials. The barriers perspectives future application translational research were also summarized.

Language: Английский

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Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

Cells, Journal Year: 2019, Volume and Issue: 8(12), P. 1584 - 1584

Published: Dec. 6, 2019

Cancer cells support their growth and proliferation by reprogramming metabolism in order to gain access nutrients. Despite the heterogeneity genetic mutations that lead tumorigenesis, a common alteration tumors occurs pathways upregulate nutrient acquisition. A central signaling pathway controls metabolic processes is mTOR pathway. The elucidation of regulation functions can be traced discovery natural compound, rapamycin. Studies using rapamycin have unraveled role control cell metabolism. By sensing intracellular status, orchestrates controlling uptake flux through various pathways. rewiring makes it promising target for cancer therapy. Numerous clinical trials are ongoing evaluate efficacy inhibition treatment. Rapamycin analogs been approved treat specific types cancer. Since does not fully inhibit activity, new compounds engineered catalytic activity more potently block its functions. highly pre-clinical studies, early trial results these second generation inhibitors revealed increased toxicity modest antitumor activity. plasticity seemingly enormous capacity malignant salvage nutrients mechanisms make therapy extremely challenging. Therefore, identifying vulnerabilities different would present opportunities rational therapeutic strategies. Understanding how sources metabolized just growing tumor but also other from microenvironment, particular, immune cells, will facilitate design sophisticated effective regimen. In this review, we discuss illuminated studies. We then review key findings lessons learned both studies could provide insights on innovative strategies, including immunotherapy network

Language: Английский

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Fasting inhibits aerobic glycolysis and proliferation in colorectal cancer via the Fdft1-mediated AKT/mTOR/HIF1α pathway suppression

Nature Communications, Journal Year: 2020, Volume and Issue: 11(1)

Published: April 20, 2020

Evidence suggests that fasting exerts extensive antitumor effects in various cancers, including colorectal cancer (CRC). However, the mechanism behind this response is unclear. We investigate effect of on glucose metabolism and malignancy CRC. find upregulates expression a cholesterogenic gene, Farnesyl-Diphosphate Farnesyltransferase 1 (FDFT1), during inhibition CRC cell aerobic glycolysis proliferation. In addition, downregulation FDFT1 correlated with malignant progression poor prognosis Moreover, acts as critical tumor suppressor Mechanistically, performs its tumor-inhibitory function by negatively regulating AKT/mTOR/HIF1α signaling. Furthermore, mTOR inhibitor can synergize inhibiting proliferation These results indicate key downstream target may be involved metabolism. Our suggest therapeutic implications potential crosstalk between gene glycolysis.

Language: Английский

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Cancer nanotechnology: current status and perspectives

Nano Convergence, Journal Year: 2021, Volume and Issue: 8(1)

Published: Nov. 2, 2021

Modern medicine has been waging a war on cancer for nearly century with no tangible end in sight. Cancer treatments have significantly progressed, but the need to increase specificity and decrease systemic toxicities remains. Early diagnosis holds key improving prognostic outlook patient quality of life, diagnostic tools are cusp technological revolution. Nanotechnology steadily expanded into reaches chemotherapy, radiotherapy, diagnostics, imaging, demonstrating capacity augment each advance care. Nanomaterials provide an abundance versatility, functionality, applications engineer specifically targeted medicine, accurate early-detection devices, robust imaging modalities, enhanced radiotherapy adjuvants. This review provides insights current clinical pre-clinical nanotechnological drug therapy, radiation therapy.

Language: Английский

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mTORC1 as a Regulator of Mitochondrial Functions and a Therapeutic Target in Cancer

Frontiers in Oncology, Journal Year: 2019, Volume and Issue: 9

Published: Dec. 13, 2019

Continuous proliferation of tumor cells require many adjustments energy metabolism to rapidly fuel cell growth and division. This energetic reprogramming often comprises deregulated glucose uptake lactate production in the presence oxygen, a process known as "Warburg effect". For years it was thought that Warburg effect result mitochondrial damage however, unlike this proposal, mitochondria not only retain their functionality, but also instrumental for integrating variety signals adjusting metabolic activity cell. The mammalian/mechanistic target rapamycin complex 1 (mTORC1) is master regulator numerous cellular processes implicated growth. mTORC1 controls mainly by regulating translation transcription genes. Here we present an overview on role regulation functions cancer, considering new evidences showing regulates nucleus-encoded mRNAs increased ATP production. Moreover, discuss relationship between glutaminolysis, well metabolites. In addition, fission regulated its impact cancer are discussed. We finally review therapeutic efficacy inhibitors treatments, use combination with other drugs, particular metabolism, could help improve anti neoplastic eliminate patients.

Language: Английский

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Structural basis for the docking of mTORC1 on the lysosomal surface

Science, Journal Year: 2019, Volume and Issue: 366(6464), P. 468 - 475

Published: Oct. 10, 2019

The mTORC1 (mechanistic target of rapamycin complex 1) protein kinase regulates growth in response to nutrients and factors. Nutrients promote its translocation the lysosomal surface, where Raptor subunit interacts with Rag guanosine triphosphatase (GTPase)-Ragulator complex. switch heterodimeric GTPases among four different nucleotide-binding states, only one which (RagA/B•GTP-RagC/D•GDP) permits association. We used cryo-electron microscopy determine structure supercomplex Rag-Ragulator at a resolution 3.2 angstroms. Our findings indicate that α-solenoid directly detects nucleotide state RagA while "claw" threads between GTPase domains detect RagC. Mutations disrupted Rag-Raptor binding inhibited localization signaling. By comparison bound activator Rheb, we developed model active docked on lysosome.

Language: Английский

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