Stress-induced Norepinephrine Downregulates CCL2 in Macrophages to Suppress Tumor Growth in a Model of Malignant Melanoma

Steinberger, Kayla J.; Bailey, Michael T.; Gross, Amy C.; Sumner, Laura A.; Voorhees, Jeffrey L.; Crouser, Nisha; Curry, Jennifer M.; Wang, Yijie; DeVries, A. Courtney; Marsh, Clay B.; Glaser, Ronald; Yang, Eric V.; Eubank, Timothy D.

doi:10.1158/1940-6207.capr-19-0370

Cited by 12 publications

(6 citation statements)

References 51 publications

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“…CCL2 expressed in circulating fibrous cells is involved in the recruitment of Ly6C monocytes and metastasizes B16F10 cells to the lung [119]. In a mouse model, stress-loaded norepinephrine suppresses blood CCL2 levels and macrophage infiltration into cancer tissues, and β-epinephrine receptors may be targets for melanoma treatment [120]. CCR2 inhibitors enhanced the therapeutic effect of anti-PD-1 antibodies in several mouse tumor models [121].…”

Section: Other Cancersmentioning

confidence: 99%

Roles of CCL2-CCR2 Axis in the Tumor Microenvironment

Kadomoto

Izumi

Mizokami

2021

IJMS

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Chemokines are a small family of cytokines that were first discovered as chemotactic factors in leukocytes during inflammation, and reports on the relationship between chemokines and cancer progression have recently been increasing. The CCL2-CCR2 axis is one of the major chemokine signaling pathways, and has various functions in tumor progression, such as increasing tumor cell proliferation and invasiveness, and creating a tumor microenvironment through increased angiogenesis and recruitment of immunosuppressive cells. This review discusses the roles of the CCL2-CCR2 axis and the tumor microenvironment in cancer progression and their future roles in cancer therapy.

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Section: Other Cancersmentioning

confidence: 99%

Roles of CCL2-CCR2 Axis in the Tumor Microenvironment

Kadomoto

Izumi

Mizokami

2021

IJMS

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“…CCL2 is a major chemoattractant implicated in the infiltration of myeloid cells, especially monocytes and neutrophils, into the brain during inflammation 89,90 . A relationship between NE and CCL2 has not been extensively examined in microglia, but a recent report demonstrated that NE reduces CCL2 production in mouse and human macrophages in a β-adrenergic receptor-dependent manner 91 . Additionally, recent work in astrocytes has revealed a complicated relationship between NE and CCL2 that may provide insight for the data in this study and others.…”

Section: Discussionmentioning

confidence: 99%

Locus coeruleus injury modulates ventral midbrain neuroinflammation during DSS-induced colitis

Boles,

Holt,

Cole

et al. 2024

Preprint

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Parkinson's disease (PD) is characterized by a decades-long prodrome, consisting of a collection of non-motor symptoms that emerges prior to the motor manifestation of the disease. Of these non-motor symptoms, gastrointestinal dysfunction and deficits attributed to central norepinephrine (NE) loss, including mood changes and sleep disturbances, are frequent in the PD population and emerge early in the disease. Evidence is mounting that injury and inflammation in the gut and locus coeruleus (LC), respectively, underlie these symptoms, and the injury of these systems is central to the progression of PD. In this study, we generate a novel two-hit mouse model that captures both features, using dextran sulfate sodium (DSS) to induce gut inflammation and N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) to lesion the LC. We first confirmed the specificity of DSP-4 for central NE using neurochemical methods and fluorescence light-sheet microscopy of cleared tissue, and established that DSS-induced outcomes in the periphery, including weight loss, gross indices of gut injury and systemic inflammation, the loss of tight junction proteins in the colonic epithelium, and markers of colonic inflammation, were unaffected with DSP-4 pre-administration. We then measured alterations in neuroimmune gene expression in the ventral midbrain in response to DSS treatment alone as well as the extent to which prior LC injury modified this response. In this two-hit model we observed that DSS-induced colitis activates the expression of key cytokines and chemokines in the ventral midbrain only in the presence of LC injury and the typical DSS-associated neuroimmune is blunted by pre-LC lesioning with DSP-4. In all, this study supports the growing appreciation for the LC as neuroprotective against inflammation-induced brain injury and draws attention to the potential for NEergic interventions to exert disease-modifying effects under conditions where peripheral inflammation may compromise ventral midbrain dopaminergic neurons and increase the risk for development of PD.

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“…Therefore, we also screened for the drug candidates of melanoma, and identified corticosterone as a novel therapeutic drug. A recent study showed that stress-induced increase in corticosterone levels suppressed tumor growth in a model of malignant melanoma ( 41 ). It was worth mentioning that the antitumor effect is mainly through reducing recruitment of TAMs ( 41 ).…”

Section: Discussionmentioning

confidence: 99%

“…A recent study showed that stress-induced increase in corticosterone levels suppressed tumor growth in a model of malignant melanoma ( 41 ). It was worth mentioning that the antitumor effect is mainly through reducing recruitment of TAMs ( 41 ). As mentioned above, the infiltration of TAMs is an adverse prognostic factor for melanoma.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive transcriptomic analysis of immune-related eRNAs associated with prognosis and immune microenvironment in melanoma

Gan

Yang

et al. 2022

Front. Surg.

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BackgroundRecent evidence suggests that enhancer RNAs (eRNAs) play key roles in cancers. Identification of immune-related eRNAs (ireRNAs) in melanoma can provide novel insights into the mechanisms underlying its genesis and progression, along with potential therapeutic targets.AimTo establish an ireRNA-related prognostic signature for melanoma and identify potential drug candidates.MethodsThe ireRNAs associated with the overall survival (OS-ireRNAs) of melanoma patients were screened using data from The Cancer Genome Atlas (TCGA) via WGCNA and univariate Cox analysis. A prognostic signature based on these OS-ireRNAs was then constructed by performing the least absolute shrinkage and selection operator (LASSO) Cox regression analysis. The immune landscape associated with the prognostic model was evaluated by the ESTIMATE algorithm and CIBERSORT method. Finally, the potential drug candidates for melanoma were screened through the cMap database.ResultsA total of 24 OS-ireRNAs were obtained, of which 7 ireRNAs were used to construct a prognostic signature. The ireRNAs-related signature performed well in predicting the overall survival (OS) of melanoma patients. The risk score of the established signature was further verified as an independent risk factor, and was associated with the unique tumor microenvironment in melanoma. We also identified several potential anti-cancer drugs for melanoma, of which corticosterone ranked first.ConclusionsThe ireRNA-related signature is an effective prognostic predictor and provides reliable information to better understand the mechanism of ireRNAs in the progression of melanoma.

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Stress-induced Norepinephrine Downregulates CCL2 in Macrophages to Suppress Tumor Growth in a Model of Malignant Melanoma

Cited by 12 publications

References 51 publications

Roles of CCL2-CCR2 Axis in the Tumor Microenvironment

Roles of CCL2-CCR2 Axis in the Tumor Microenvironment

Locus coeruleus injury modulates ventral midbrain neuroinflammation during DSS-induced colitis

Comprehensive transcriptomic analysis of immune-related eRNAs associated with prognosis and immune microenvironment in melanoma

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