Chronic neural activity recorded within breast tumors

McCallum, Grant A.; Shiralkar, Jay; Suciu, Diana; Covarrubias, Gil; Yu, Jennifer; Karathanasis, Efstathios; Durand, Dominique M.

doi:10.1038/s41598-020-71670-y

Cited by 36 publications

(36 citation statements)

References 55 publications

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“…NGF has a neuroprotective effect on lidocaine-induced neurotoxicity (Zhao et al, 2017). In breast cancer, lidocaine may directly inhibit neural activity (McCallum et al, 2020). In this study, we observed that continuous intervention with lidocaine can significantly reduce the density of nerve fibers in mice bearing MBA-MB-231 or 4T1 tumors and down-regulate the expression levels of nerve-related proteins such as PGP9.5, NF, NGF, and Nnat.…”

Section: Discussionmentioning

confidence: 61%

“…Studies have shown that there are abundant nerve fibers and electrical activity in breast cancer tissues (McCallum et al, 2020), which are associated with the progression and metastasis of breast cancer (Huang et al, 2014). This may be associated with the ability of breast cancer cells to produce neurotrophic growth factors (Hondermarck, 2012).…”

Section: Introductionmentioning

confidence: 99%

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Lidocaine prevents breast cancer growth by targeting neuronatin to inhibit nerve fibers formation

et al. 2021

J. Toxicol. Sci.

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Lidocaine has been shown to inhibit the invasion and metastasis of breast cancer, but the mechanism still remains unclear. This study explored the relationship between lidocaine and circulating seeding of breast cancer cells from the perspective of nerve fiber formation. The cell lines MDA-MB-231 and 4T1 were subcutaneously inoculated in mice to simulate the tumor self-seeding by circulating cancer cells. Lidocaine was used to treat these mice and tumor growth was observed. Silver staining was performed to observe the distribution of nerve fibers in tumor-bearing tissues, and immunohistochemical analysis was performed to observe the expression levels of nerve-related proteins. The results showed that lidocaine treatment effectively inhibited tumor growth and nerve fiber formation, and down-regulated the expression levels of protein gene product 9.5, neurofilament, nerve growth factor (NGF), and neuronatin (Nnat). Overexpression NGF and Nnat both could reverse the therapeutic effects of lidocaine. These results suggest that the effect of lidocaine on inhibiting breast cancer invasion and metastasis may be achieved by targeting Nnat, regulating the production of NGFs in cancer cells, and subsequently inhibiting the formation of nerve fibers.

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Section: Discussionmentioning

confidence: 61%

Section: Introductionmentioning

confidence: 99%

Lidocaine prevents breast cancer growth by targeting neuronatin to inhibit nerve fibers formation

et al. 2021

J. Toxicol. Sci.

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“…Indeed, denervation causes regression of established breast cancer in ex vivo models [12], providing direct evidence that nerve supply is necessary for breast cancer growth. Consistently, chronic neural activity can be recorded within the tumour mass of mouse breast cancer models [13]. Of interest, sympathetic and parasympathetic nerves appear to have opposite effects on breast cancer growth [14]: sympathetic neurostimulation accelerates, whereas parasympathetic neurostimulation decelerates the progression of both human breast cancer xenografts and spontaneous breast cancer models in mice [14].…”

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confidence: 88%

High nerve density in breast cancer is associated with poor patient outcome

et al. 2021

Preprint

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Background: Active crosstalk between the nervous system and breast cancer cells as well as other cell types within the tumour microenvironment has been experimentally demonstrated in vitro and in animal models. However, low frequencies of peripheral nerve presence in human breast cancers reported in previous studies (~30% of cases) potentially negate a major role of the nervous system in breast cancer development and progression. This study aimed to better define the incidence of nerves within human breast cancers and to delineate associations with clinicopathological features.Methods: Immunohistochemical staining was conducted in formalin-fixed paraffin-embedded breast cancer tissue sections using antibodies against the pan-neuronal markers protein gene product 9.5 (PGP9.5) and growth-associated protein 43 (GAP-43), and the sympathetic nerve-specific marker tyrosine hydroxylase (TH). Nerve trunks (comprised of many nerve fibres/axons) and isolated nerve fibres (positively stained cells with or without typical morphology of axons outside definable nerve trunks) were quantitated. The chi-squared test was used to determine the associations between nerve trunk or isolated nerve fibre counts and clinicopathological parameters. The Log-rank test was used to compare differences in patient progression-free survival (PFS) and overall survival (OS). A multivariate analysis was performed according to the Cox Proportional Hazards Model to assess independent prognostic factors.Results: Nerve trunks and isolated nerve fibres were detected in 75% and 77% of breast cancers, respectively. The overall frequency of peripheral nerves in breast cancers was 85%, a markedly higher proportion than reported previously. Of note, most nerves present in breast cancers were of the sympathetic origin (positive for TH). While high density of nerve trunks or isolated nerve fibres was associated with poor PFS and OS of patients, high nerve trunk density appeared also to predict poor patient PFS independently of lymph node metastasis. Conclusions: Innervation of breast cancers is a common event correlated with poor patient outcomes. These findings support the notion that the nervous system plays an active role in breast cancer pathogenesis.

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“…However, it has also been observed that lidocaine (in clinically relevant doses) is able to block cancer-associated and prognostic relevant variants of voltage-activated sodium channels like Nav1.5 [ 111 ]. Interestingly, a recent animal study detected chronic electric activity in solid breast tumor masses in mice [ 112 ]. This activity is supposedly of neuronal origin, as it has a connection to the parasympathetic nervous system, which disrupts on injection of lidocaine and chemical sympathectomy [ 112 ].…”

Section: Recent and Current Datamentioning

confidence: 99%

“…Interestingly, a recent animal study detected chronic electric activity in solid breast tumor masses in mice [ 112 ]. This activity is supposedly of neuronal origin, as it has a connection to the parasympathetic nervous system, which disrupts on injection of lidocaine and chemical sympathectomy [ 112 ]. With these neuronal networks, systemically administered lidocaine could, therefore, have a new target in its first described mechanism of action, thus disrupting the neuronal membrane potential and neural activity during tumor growth and metastasis.…”

Section: Recent and Current Datamentioning

confidence: 99%

Local Anesthetics and Recurrence after Cancer Surgery-What’s New? A Narrative Review

Müller

Ziegler

Piegeler

2021

JCM

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The perioperative use of regional anesthesia and local anesthetics is part of almost every anesthesiologist’s daily clinical practice. Retrospective analyses and results from experimental studies pointed towards a potential beneficial effect of the local anesthetics regarding outcome—i.e., overall and/or recurrence-free survival—in patients undergoing cancer surgery. The perioperative period, where the anesthesiologist is responsible for the patients, might be crucial for the further course of the disease, as circulating tumor cells (shed from the primary tumor into the patient’s bloodstream) might form new micro-metastases independent of complete tumor removal. Due to their strong anti-inflammatory properties, local anesthetics might have a certain impact on these circulating tumor cells, either via direct or indirect measures, for example via blunting the inflammatory stress response as induced by the surgical stimulus. This narrative review highlights the foundation of these principles, features recent experimental and clinical data and provides an outlook regarding current and potential future research activities.

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Chronic neural activity recorded within breast tumors

Cited by 36 publications

References 55 publications

Lidocaine prevents breast cancer growth by targeting neuronatin to inhibit nerve fibers formation

Lidocaine prevents breast cancer growth by targeting neuronatin to inhibit nerve fibers formation

High nerve density in breast cancer is associated with poor patient outcome

Local Anesthetics and Recurrence after Cancer Surgery-What’s New? A Narrative Review

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