Starvation and antimetabolic therapy promote cytokine release and recruitment of immune cells

Autor: Raffaella Iurlaro, Jaime Redondo-Pedraza, Sandrine Marchetti, Eric Eldering, Ernest Nadal, Jean-Ehrland Ricci, Cristina Muñoz-Pinedo, Franziska Püschel, Blanca Majem, Francesca Favaro, Eric Chevet, Estefanía Lucendo
Přispěvatelé: Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), University of Amsterdam [Amsterdam] (UvA), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Universitat de Barcelona (UB), Graduate School, AII - Cancer immunology, CCA - Cancer biology and immunology, Experimental Immunology, Université Nice Sophia Antipolis (1965 - 2019) (UNS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Chemokine
Angiogenesis
Antimetabolites
medicine.medical_treatment
Glutamine
Cell
cancer metabolism
0302 clinical medicine
Immunology and Inflammation
Neoplasms
Citoquines
glucose
Càncer
Promoter Regions
Genetic
Cancer
0303 health sciences
Multidisciplinary
biology
Cell Death
Chemistry
NF-kappa B
Biological Sciences
Metabolisme
Metformin
3. Good health
Cell biology
Cytokine
medicine.anatomical_structure
030220 oncology & carcinogenesis
Cytokines
medicine.symptom
[SDV.CAN]Life Sciences [q-bio]/Cancer
Inflammation
Deoxyglucose
03 medical and health sciences
Immune system
cancer immunity
Stress
Physiological
medicine
Integrated stress response
Humans
030304 developmental biology
Interleukin-6
Macrophages
Interleukin-8
Chemotaxis
Epithelial Cells
biochemical phenomena
metabolism
and nutrition
Activating Transcription Factor 4
cytokines
Metabolism
Glucose
Gene Expression Regulation
Starvation
Glucosa
biology.protein
bacteria
HeLa Cells
Zdroj: Proceedings of the National Academy of Sciences of the United States of America
Proceedings of the National Academy of Sciences of the United States of America, National Academy of Sciences, 2020, 117 (18), pp.9932-9941. ⟨10.1073/pnas.1913707117⟩
Proceedings of the National Academy of Sciences of the United States of America, 117(18), 9932-9941. National Academy of Sciences
Proceedings of the National Academy of Sciences of the United States of America, 2020, 117 (18), pp.9932-9941. ⟨10.1073/pnas.1913707117⟩
Proceedings of the National Academy of Sciences
Dipòsit Digital de la UB
Universidad de Barcelona
ISSN: 1091-6490
0027-8424
DOI: 10.1073/pnas.1913707117⟩
Popis: Significance Poorly irrigated tumors exhaust nutrients from their environment. On the other hand, innate immune cells, such as neutrophils and macrophages, have been frequently shown to infiltrate tumors and promote an immunosuppressive environment. Our results show that, when nutrients are low, tumor cells secrete factors related to wound healing that stimulate endothelial cells and attract innate immune cells. This suggests that targeting signals elicited by metabolic stress may help the immune system target malignant cells and that metabolites regulate the communication between immune and tumor cells also through modulation of peptidic signals.
Cellular starvation is typically a consequence of tissue injury that disrupts the local blood supply but can also occur where cell populations outgrow the local vasculature, as observed in solid tumors. Cells react to nutrient deprivation by adapting their metabolism, or, if starvation is prolonged, it can result in cell death. Cell starvation also triggers adaptive responses, like angiogenesis, that promote tissue reorganization and repair, but other adaptive responses and their mediators are still poorly characterized. To explore this issue, we analyzed secretomes from glucose-deprived cells, which revealed up-regulation of multiple cytokines and chemokines, including IL-6 and IL-8, in response to starvation stress. Starvation-induced cytokines were cell type-dependent, and they were also released from primary epithelial cells. Most cytokines were up-regulated in a manner dependent on NF-κB and the transcription factor of the integrated stress response ATF4, which bound directly to the IL-8 promoter. Furthermore, glutamine deprivation, as well as the antimetabolic drugs 2-deoxyglucose and metformin, also promoted the release of IL-6 and IL-8. Finally, some of the factors released from starved cells induced chemotaxis of B cells, macrophages, and neutrophils, suggesting that nutrient deprivation in the tumor environment can serve as an initiator of tumor inflammation.
Databáze: OpenAIRE
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