Proton irradiation orchestrates macrophage reprogramming through NFκB signaling

Genard, Géraldine; Wera, Anne Catherine; Huart, Camille; Calvé, Benjamin Le; Penninckx, Sébastien; Fattaccioli, Antoine; Tabarrant, Tijani; Demazy, Catherine; Ninane, Noëlle; Heuskin, Anne-Catherine; Lucas, Stéphane; Michiels, Carine

doi:10.1038/s41419-018-0757-9

Cited by 59 publications

(69 citation statements)

References 43 publications

(53 reference statements)

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“…The NF-κB-pathway inhibitor (Bay11-7082; S2913, Selleckchem) or JNK inhibitor (SP600125; Sigma Aldrich) were added to the THP-1 macrophages at 10 μM or 30 μM 1 h or Immunofluorescence labeling. Immunofluorescence labeling was performed as described before 21,22 .…”

Section: Methodsmentioning

confidence: 99%

Cycling hypoxia promotes a pro-inflammatory phenotype in macrophages via JNK/p65 signaling pathway

Delprat

Tellier

Demazy

et al. 2020

Sci Rep

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Cycling hypoxia (cyH), also called intermittent hypoxia, occurs in solid tumors and affects different cell types in the tumor microenvironment and in particular the tumor-associated macrophages (TAMs). As cyH and TAMs both favor tumor progression, we investigated whether cyH could drive the pro-tumoral phenotype of macrophages. Here, the effects of cyH on human THP-1 macrophages and murine bone marrow-derived macrophages (BMDM), either unpolarized M0, or polarized in M1 or M2 phenotype were studied. In M0 macrophages, cyH induced a pro-inflammatory phenotype characterized by an increase in tnfα and IL-8/MIP-2 secretion. CyH amplified the pro-inflammatory phenotype of M1 macrophages evidenced by an increased pro-inflammatory cytokine secretion and pro-inflammatory gene expression. Furthermore, cyH increased c-jun activation in human M0 macrophages and highly increased c-jun and NF-κB activation in M1 macrophages. C-jun and p65 are implicated in the effects of cyH on M0 and M1 macrophages since inhibition of their activation prevented the cyH pro-inflammatory effects. In conclusion, we demonstrated that cyH induces or amplifies a pro-inflammatory phenotype in M0 and M1 macrophages by activating JNK/p65 signaling pathway. These results highlight a specific role of cyH in the amplification of tumor-related inflammation by modulating the inflammatory phenotype of macrophages. Tumors are complex tissues composed of multiple cell types interacting and influencing each other, namely malignant cells and stromal cells like endothelial cells, immune cells and fibroblasts 1. The intricate combination of tumor microenvironment composition and environmental factors strongly determines tumor outcome 2. A major factor altering the tumor microenvironment is the presence of low oxygen tension called hypoxia, that is a common feature of malignant tumors 3. Two types of hypoxia can be distinguished: chronic and cycling hypoxia (cyH). Chronic hypoxia (chH) is associated to the limited oxygen distribution in a tissue; it is mainly the result of uncontrolled proliferation of O 2-consuming cancer cells and the O 2 diffusion gradient from blood capillaries 4,5. In contrast, cyH, also called intermittent hypoxia, is related to the irregular erythrocyte flux circulating in the anarchical tumor blood network characterized by the presence of temporary occlusions 6-8. The instability of blood flow leads to periods of hypoxia followed by periods of reoxygenation, occurring over hours through a clear pattern of periodicity 9. We previously demonstrated that cyH amplifies the endothelial inflammatory response induced by TNFα notably through an overactivation of NF-κB. Moreover, we showed that cyH enhances the overall tumor inflammation characterized by a global increase in inflammatory gene expression and by an increase in intratumor leukocyte infiltration in tumor-bearing mice 10. Inflammation is indeed described to be mutagenic and to favor proliferation and survival of malignant cells, angiogenesis, metastasis, corruption of the adaptive immu...

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Section: Methodsmentioning

confidence: 99%

Cycling hypoxia promotes a pro-inflammatory phenotype in macrophages via JNK/p65 signaling pathway

Delprat

Tellier

Demazy

et al. 2020

Sci Rep

Self Cite

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“…A type of CAFs could activate a signal that exerts both protumorigenic or antitumorigenic roles . For example, NF‐kB signaling activated by CAFs take the two opposite functions by promoting antitumor M1 polarity and also by inducing markers related to stemness in CSCs . IL‐8 released by CAFs also takes roles for polarity toward M1 phenotype along with its functioning as a protumorigenic cytokine …”

Section: Caf Targeting As a Promising Therapeutic Approachmentioning

confidence: 99%

Cancer‐associated fibroblasts: Secretions, interactions, and therapy

Farhood

Najafi

Mortezaee

2018

J of Cellular Biochemistry

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Tumor microenvironment (TME) could impose a great challenge for cancer targeted therapies. Immunosuppression within the TME creates a barrier between cancer cells and therapeutic approaches. A number of cells are hosted within this milieu, among them cancer-associated fibroblasts (CAFs) are the most abundant cell populations playing major roles in mediating an immunosuppressive TME. CAFs have cross-talks with almost all cells within the TME for reprogramming them into being tumorigenic. This reprogramming reduces the pre-existing tumor immunity and dampens the efficacy of chemotherapeutic approaches. CAFs would do this through releasing a myriad of factors to the TME making it an appropriate nest for tumor growth. The cells degrade and deposit extracellular matrix components, both of which are tumorigenic. Therefore, disruption of cross-talks between CAFs with other cells within the TME would be a promising approach in cancer targeted therapies.This approach is applicable through dampening dominant signals mediated by CAFs. Another interesting approach would be reprogramming of CAFs toward their normal counterpart. This would need identification of different subtypes for these cells and their functions. More knowledge is also required about selective markers for each CAF subtype. K E Y W O R D Scancer, cancer-associated fibroblasts, extracellular matrix, therapy, transforming growth factor-β, tumor microenvironment J Cell Biochem. 2019;120:2791-2800.wileyonlinelibrary.com/journal/jcb

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“…There is a great deal of evidence suggesting that an increased number of M2 macrophages is associated tumor growth, angiogenesis, invasion and metastasis (34,35). M2 cells promote tumor and local immunosuppression (36). Th2 cells release IL4 and IL13 and induce M2 cell polarization (37,38).…”

Section: Correlation Between Itga5 Expression Levels and Immune Markersmentioning

confidence: 99%

“…TAMs, derived from mononuclear cells, are induced to differentiate into M2 cells by cytokines such as IL-4, IL-10 and IL-13, which are secreted by Th2 cells(42). Moreover, M2 cells exhibit pro-tumoral activity by promoting genetic instability, angiogenesis, stem cell nurturing and local immunosuppression(36,43). Subsequently, IHC was performed on adjacent normal and tumor tissues extracted from gastric cancer patients to nd that Th2 cell markers such as STAT6, GATA3 and the M2 cell polarization marker CD163 were signi cantly increased in patients with high ITGA5 expression levels.…”

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confidence: 99%

ITGA5 Is a Prognostic Biomarker and Correlated with Immune Infiltration In Gastrointestinal Cancers

Zhu

Wang

Zhu

et al. 2020

Preprint

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Background: Integrin Subunit Alpha 5 (ITGA5) belongs to the integrin alpha chain family, is vital for promoting cancer cell invasion, metastasis. However, the correlation between ITGA5 expression and immune infiltration in gastrointestinal (GI) tumors remain unclear.Methods: The expression levels of ITGA5 were detected by Oncomine and Tumor Immune Estimation Resource (TIMER). The association between ITGA5 and prognosis of patients was identified by Kaplan–Meier plotter, Gene Expression Profiling Interactive Analysis 2(GEPIA2) and PrognoScan. We evaluated the correlation between ITGA5 expression and immune infiltrating level via TIMER. Besides, TIMER and immunohistochemistry (IHC) staining were used to explore correlations between ITGA5 expression and markers of immune infiltrates cells. Furthermore, we constructed protein-protein interaction (PPI) network and performed functional enrichment by GeneMANIA and Metascape.Results: ITGA5 was generally overexpressed and correlated with worse prognosis in multiple types of GI tumors. In addition, ITGA5 expression levels was significantly associated with tumor purity and immune infiltration levels of different immune cells in GI tumors. Interestingly, Immune markers for monocytes, tumor - associated macrophages (TAMs), macrophages 2 (M2) cells and T-helper 2 (Th2) cells were found to be significantly and positively correlated with ITGA5 expression levels in colon and gastric cancer. Results from IHC staining further proved that markers of Th2 and M2 cell were significantly increased in gastric cancer patients with high ITGA5 expression levels. Lastly, interaction network and function enrichment analysis revealed ITGA5 were mainly involved in “integrin mediated signaling pathway”, “leukocyte migration”, “cell-substrate adhesion”.Conclutions: our study demonstrated that ITGA5 may act as an essential regulator of tumor immune cell infiltration and a valuable prognostic biomarker in GI tumors. Additional work is needed to fully elucidate the underlying mechanisms behind these observations.

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Proton irradiation orchestrates macrophage reprogramming through NFκB signaling

Cited by 59 publications

References 43 publications

Cycling hypoxia promotes a pro-inflammatory phenotype in macrophages via JNK/p65 signaling pathway

Cycling hypoxia promotes a pro-inflammatory phenotype in macrophages via JNK/p65 signaling pathway

Cancer‐associated fibroblasts: Secretions, interactions, and therapy

ITGA5 Is a Prognostic Biomarker and Correlated with Immune Infiltration In Gastrointestinal Cancers

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