A novel targeted approach to delineate a role for estrogen receptor-β in ameliorating murine mammary tumor-associated neuroinflammation

Grant, Corena V.; Russart, Kathryn L.G.; Pyter, Leah M.

doi:10.1007/s12020-021-02931-7

Cited by 4 publications

(11 citation statements)

References 59 publications

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“…In addition to mediators directly implicated in neuroinflammation, we expanded our gene expression analyses to include Icam1 to investigate the contribution of microglia in cell‐cell communication propagating peripheral inflammation to neuroinflammatory signals. Indeed, Icam1 has been reported to be elevated in vivo under different inflammatory conditions 61,62 ; our previous report and the current study indicate that these findings are extended to tumor‐induced neuroinflammation 37 . This study indicates that microglia are implicated in tumor‐induced elevations of Icam1 expression in the amygdala, but not the hippocampus.…”

Section: Discussionsupporting

confidence: 64%

“…Protein analyses of plasma determined that the potential confounding effects of CSF1R inhibition on circulating immunity were minimal in BALB/c mice (Figure S2). Indeed, PLX chow did not attenuate the previously reported tumor‐induced elevations in circulating markers 12,36,37 . Thus, the observed neuroinflammatory results were likely driven by the depletion of microglia and not a dampened peripheral‐to‐brain signal.…”

Section: Resultsmentioning

confidence: 65%

“…To investigate the contribution of microglia in tumor‐induced elevations of inflammatory mediators within the brain, region‐specific RT‐qPCR was performed after microglia depletion. We have previously reported that this mammary tumor increases the gene expression of cytokines and chemokines in the hippocampus 11,12,36,37 . Here, we expanded our regions of interest to include the amygdala as it is also implicated in the regulation of fear/affective‐like behaviors 58 and has been minimally studied in relation to cancer‐associated behavioral side effects.…”

Section: Discussionmentioning

confidence: 99%

“…Plasma inflammatory markers (IL‐1β, IL‐6, TNF‐α, and C‐X‐C motif chemokine ligand 1 [CXCL1, also known as KC/GRO]) were measured using a multiplex immunoassay (U‐PLEX; Meso Scale Diagnostics, Rockville, MD, USA) according to the manufacturer's instructions on a QuickPlex SQ 120 instrument (Meso Scale Diagnostics). We have previously reported that this mammary tumor increases the concentrations of these mediators in circulation 11,36,37 . All samples were run in duplicate; wells that were undetectable for a particular analyte were excluded and the detectable well value for that sample was used.…”

Section: Methodsmentioning

confidence: 99%

“…Gene expression was measured in duplicate using TaqMan Fast Advanced Master Mix and TaqMan predesigned gene expression primers and probes (Thermo Fisher Scientific) and amplified using a QuantStudio 5 Real‐Time PCR System (Thermo Fisher Scientific). The following probes were used based on our previous findings of tumor‐induced effects 37 . Ccl2 (Mm00441242_m1), Gapdh (Mm99999915_g1), Hprt (Mm03024075_m1), Icam1 (Mm00516023_m1), Il1b (Mm00434228_m1), Il6 (Mm00446190_m1), Tbp (Mm01277042_m1), Tnf (Mm00443258_m1).…”

Section: Methodsmentioning

confidence: 99%

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Microglia contribute to mammary tumor‐induced neuroinflammation in a female mouse model

Strehle,

Otto‐Dobos,

Grant

et al. 2024

The FASEB Journal

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Following diagnosis but before treatment, up to 30% of breast cancer patients report behavioral side effects (e.g., anxiety, depression, memory impairment). Our rodent mammary tumor model recapitulates aspects of these behavioral sequelae, as well as elevated circulating and brain inflammatory mediators. Neuroinflammation is a proposed mechanism underlying the etiology of mood disorders and cognitive deficits, and therefore may be contributing to tumor‐associated behavioral side effects. The cellular mechanisms by which tumor‐induced neuroinflammation occurs remain unknown, making targeted treatment approaches inaccessible. Here, we tested the hypotheses that microglia are the primary cells driving tumor‐induced neuroinflammation and behavioral side effects. Young adult female BALB/c mice were induced with a 67NR mammary tumor; tumor‐free controls underwent a sham surgery. Mammary tumors increased IBA1+ and GFAP+ staining in the amygdala and hippocampus relative to tumor‐free controls. However, tumors did not alter gene expression of Percoll‐enriched microglia isolated from the whole brain. While cognitive, social, and anhedonia‐like behaviors were not altered in tumor‐bearing mice, tumors increased central tendency in the open‐field test; microglia depletion did not reverse this effect. Brain region RT‐qPCR data indicated that microglia depletion attenuated tumor‐induced elevations of neuroinflammatory gene expression in a region‐ and mediator‐specific manner. These results indicate a causal role of microglia in tumor‐induced neuroinflammation. This research advances our understanding of the cellular mechanisms underlying tumor‐induced neuroinflammation in order to understand how brain responses (e.g., behavior) may be altered with subsequent cancer‐related immune challenges.

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Section: Discussionsupporting

confidence: 64%

Section: Resultsmentioning

confidence: 65%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Microglia contribute to mammary tumor‐induced neuroinflammation in a female mouse model

Strehle,

Otto‐Dobos,

Grant

et al. 2024

The FASEB Journal

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Synthesis of polyethylene glycol gel-modified gold nanoparticles for targeted tumor therapy and correlation with the physiological environment

Zhang

2023

AIP Advances

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In the field of biomedical research, nanotechnology is a cutting-edge area of study that holds immense promise for the treatment of tumors. In this paper, Sgc8 nucleic acid aptamer-mediated gold nanoparticles of different diameters are used to investigate the treatment methods for leukemia patients. Targeted and polyethylene glycol (PEG) gel functional modifications were employed to achieve the desired binding analysis of both positive and negative human acute lymphatic leukemia cells (CCRF-CEM) and Ramos cells. In addition, the targeting capabilities of Sgc8 nucleic acid aptamer-mediated gold nanoparticles have been tested under physiological conditions, including serum. The results indicate that the addition of PEG gel-modified Sgc8 nucleic acid aptamers significantly reduces the adsorption of nanoparticles to non-specific biomolecules, as compared to the control random sequence. The characterization results using a dynamic light scattering particle size analyzer, UV spectrophotometer, and transmission electron microscope all converge to prove consistent particle size, with gold nanoparticles evenly dispersed without agglomeration. The emergence of new targeted tumor nanomaterials has underscored the ease with which gel functionalization can be realized, along with their exceptional chemical stability, providing a valuable reference for future clinical research.

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Ovarian status modulates endocrine and neuroinflammatory responses to a murine mammary tumor

Strehle

Russart

Burch

et al. 2022

American Journal of Physiology-Regulatory, Integrative and Comp

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Breast cancer patients have increased circulating inflammatory markers and mammary tumors increase neuroinflammation in rodent models. Menopausal status is not only important in the context of breast cancer as circulating estrogen influences tumor progression, but also because estrogen is anti-inflammatory and an essential modulator of endocrine function in the brain and body. Here, we manipulated "menopause" status (ovary-intact and ovariectomized) in an ER+ mouse mammary tumor model to determine the extent to which ovarian status modulates: 1) tumor effects on estrogen concentrations and signaling in the brain, 2) tumor effects on estrogen-associated neurobiology and inflammation, and 3) the ability for tumor resection to resolve the effects of a tumor. We hypothesized that reduced circulating estradiol (E2) following ovariectomy exacerbates tumor-induced peripheral and central inflammation. Notably, we observed ovarian-dependent modulation on tumor-induced peripheral outcomes, including E2-dependent processes and, to a lesser degree, circulating inflammatory markers. In the brain, ovariectomy exacerbated neuroinflammatory markers in select brain regions and modulated E2-related neurobiology due to a tumor and/or resection. Overall, our data suggest that ovarian status has moderate implications for tumor-induced alterations in neuroendocrinology and neuroinflammation and mild effects on peripheral inflammatory outcomes in this murine mammary tumor model.

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A novel targeted approach to delineate a role for estrogen receptor-β in ameliorating murine mammary tumor-associated neuroinflammation

Cited by 4 publications

References 59 publications

Microglia contribute to mammary tumor‐induced neuroinflammation in a female mouse model

Microglia contribute to mammary tumor‐induced neuroinflammation in a female mouse model

Synthesis of polyethylene glycol gel-modified gold nanoparticles for targeted tumor therapy and correlation with the physiological environment

Ovarian status modulates endocrine and neuroinflammatory responses to a murine mammary tumor

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