Cancer activates microglia to the same extent as chronic stress throughout stress neurocircuitry in a mouse model of breast cancer

McCaffrey, Delyse; Lawther, Adam J.; Weickert, Cynthia Shannon; Walker, Adam K.

doi:10.1016/j.psyneuen.2022.105938

Cited by 5 publications

(9 citation statements)

References 53 publications

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“…While other brain regions were not investigated by immunostaining in this study, GFAP protein concentrations of the whole cerebrum were elevated in tumor‐bearing mice relative to controls, suggesting that tumor‐induced astrocyte activation occurs in additional brain regions 64 . In contrast to our findings, a more aggressive mammary tumor cell line, 4T1.2, reduces GFAP immunoreactivity in cortical structures without affecting GFAP immunostaining in the amygdala or hippocampus 45 . The present data warrant additional studies to elucidate the functional contribution of astrocytes to tumor‐induced neuroinflammation and behavioral side effects (e.g., inhibit astrocytes, brain region‐specific isolation, and quantification of astrocyte‐released mediators).…”

Section: Discussioncontrasting

confidence: 88%

“…Similar to our findings, non‐orthoptic bone cancer in rats results in increased IBA1 + immunoreactivity across the hippocampus 46 . In contrast, neither a non‐orthotopic colon adenocarcinoma nor a different orthotopic mammary tumor affects IBA1 + immunoreactivity in the hippocampus 44,45 . Thus, tumor type and location, and therefore microenvironment, may modulate the extent to which brain microglial morphology is altered.…”

Section: Discussionsupporting

confidence: 86%

“…Thus, these analyses suggested that hippocampal microglia, particularly those in the DG, may be activated in response to an orthotopic mammary tumor 22 . A study using the 4T1.2 orthotopic mammary tumor model observed similar hippocampal subregion‐specific IBA1 + cell body enlargement 45 . Collectively, these findings indicate that different types of tumors located outside the brain impact neurobiology and have region‐specific effects on microglia.…”

Section: Discussionmentioning

confidence: 83%

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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: Discussioncontrasting

confidence: 88%

Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 83%

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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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“…Thus, cancer may cause neuroinflammation and affect stress responses by altering different aspects of neural function, such as circadian rhythm dysfunction, sleep disturbances, aberrant glucocorticoid production, and dysregulation of neural network activity ( Pyter, 2016 ). In accordance, McCaffrey et al (2022) have most recently demonstrated that, analogously to chronic stress, cancer itself activates microglia through stress neurocircuitry.…”

Section: Chronic Stress and Cancer—a Bidirectional Relationshipmentioning

confidence: 67%

“…In particular, glucocorticoid-induced increase in ROS production triggers NF-κB-mediated NOD-like receptor protein 3 (NLRP3) inflammasome activation and subsequent IL-1β secretion ( Feng et al, 2019 ), and the activation of this pathway in hippocampal microglia has been suggested to mediate chronic stress-induced neuroinflammation. Most importantly, McCaffrey et al (2022) have revealed that cancer and chronic stress activates microglia to the same extent in the same brain regions. Therefore, both chronic stress- and cancer-activated microglia can contribute to the dysfunctional neuroendocrine-immune response by reinforcing stress-related neurocircuitry.…”

Section: Low-grade Inflammation As a Common Feature Underlying The Cr...mentioning

confidence: 99%

Interplay between stress and cancer—A focus on inflammation

Petrinović

Milošević²,

Marković³

et al. 2023

Front. Physiol.

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Stress is an integral part of life. While acute responses to stress are generally regarded as beneficial in dealing with immediate threats, chronic exposure to threatening stimuli exerts deleterious effects and can be either a contributing or an aggravating factor for many chronic diseases including cancer. Chronic psychological stress has been identified as a significant factor contributing to the development and progression of cancer, but the mechanisms that link chronic stress to cancer remain incompletely understood. Psychological stressors initiate multiple physiological responses that result in the activation of the hypothalamic-pituitary-adrenal (HPA) axis, sympathetic nervous system, and the subsequent changes in immune function. Chronic stress exposure disrupts the homeostatic communication between the neuroendocrine and immune systems, shifting immune signaling toward a proinflammatory state. Stress-induced chronic low-grade inflammation and a decline in immune surveillance are both implicated in cancer development and progression. Conversely, tumor-induced inflammatory cytokines, apart from driving a tumor-supportive inflammatory microenvironment, can also exert their biological actions distantly via circulation and therefore adversely affect the stress response. In this minireview, we summarize the current findings on the relationship between stress and cancer, focusing on the role of inflammation in stress-induced neuroendocrine-immune crosstalk. We also discuss the underlying mechanisms and their potential for cancer treatment and prevention.

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Mechanisms Mediating the Effect of Stress on the Tumor Process

Mravec

2024

Neurobiology of Cancer

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Cancer activates microglia to the same extent as chronic stress throughout stress neurocircuitry in a mouse model of breast cancer

Cited by 5 publications

References 53 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

Interplay between stress and cancer—A focus on inflammation

Mechanisms Mediating the Effect of Stress on the Tumor Process

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