an-vivo-mouse-model-total-intravenous-anesthesia-during-cancer

An <em>In Vivo</em> Mouse Model of Total Intravenous Anesthesia During Cancer Resection Surgery

Anesthesia is a routine component of cancer care that is used for diagnostic and therapeutic procedures. The anesthetic technique has recently been ...

Monash University

Type 1 diabetes is characterised by early peri-islet insulitis and insulin autoantibodies, followed by invasive insulitis and beta cell destruction. The immunological events that precipitate invasive insulitis are not well understood. We tested the hypothesis that B cells in diabetes-prone NOD mice drive invasive insulitis through elevated expression of CD19 and consequent enhanced uptake and presentation of beta cell membrane-bound antigens to islet invasive T cells.

The CD19 signalling molecule is elevated in NOD mice and controls type 1 diabetes development.

The therapeutic action of a drug depends on its ability to engage with its molecular target in vivo. However, current drug discovery strategies quantify drug levels within organs rather than determining the binding of drugs directly to their specific molecular targets in vivo. This is a particular problem for assessing the therapeutic potential of drugs that target malignant tumors where access and binding may be impaired by disrupted vasculature and local hypoxia. Here we have used triple-negative human breast cancer cells expressing β-adrenoceptors tagged with the bioluminescence protein NanoLuc to provide a bioluminescence resonance energy transfer approach to directly quantify ligand binding to a G protein-coupled receptor in vivo using a mouse model of breast cancer.

Visualizing Ligand Binding to a GPCR In Vivo Using NanoBRET.

Signaling through β-adrenergic receptors drives cancer progression and β-blockers are being evaluated as a novel therapeutic strategy to prevent metastasis. Orthotopic mouse models of breast cancer show that β-adrenergic signaling induced by chronic stress accelerates metastasis, and that β-adrenergic receptors on tumor cells are critical for this. Endogenous catecholamines are released during chronic stress: norepinephrine from the adrenal medulla and sympathetic nerves, and epinephrine from the adrenal medulla. β-adrenergic receptors are much more sensitive to epinephrine than to norepinephrine. To determine if epinephrine is necessary in the effects of stress on cancer progression, we used a denervation strategy to eliminate circulating epinephrine, and quantified the effect on metastasis. Using both human xenograft and immune-intact murine models of breast cancer, we show that circulating epinephrine is dispensable for the effects of chronic stress on cancer progression. Measured levels of circulating norepinephrine were sufficiently low that they were unlikely to influence β-adrenergic signaling, suggesting a possible role for norepinephrine release from sympathetic nerve terminals.

Circulating epinephrine is not required for chronic stress to enhance metastasis.

Cancer patients with non-central nervous system tumors often suffer from cognitive impairment. While chemotherapy has long been attributed as the cause of these memory, learning and concentration difficulties, we recently observed cognitive impairment in cancer patients prior to treatment. This suggests the cancer alone may be sufficient to induce cognitive impairment, however the mechanisms are unknown. Here, we show that we can experimentally replicate the clinical phenomenon of cancer-associated cognitive impairment and we identify inflammation as a causal mechanism. We demonstrate that a peripheral tumor is sufficient to induce memory loss. Using an othotopic mouse model of breast cancer, we found that mice with 4T1.2 or EO771 mammary tumors had significantly poorer memory than mice without tumors. Memory impairment was independent of cancer-induced sickness behavior, which was only observed during the later stage of cancer progression in mice with high metastatic burden. Tumor-secreted factors were sufficient to induce memory impairment and pro-inflammatory cytokines were elevated in the plasma of tumor-bearing mice. Oral treatment with low-dose aspirin completely blocked tumor-induced memory impairment without affecting tumor-induced sickness or tumor growth, demonstrating a causal role for inflammation in cognitive impairment. These findings suggest that anti-inflammatories may be a safe and readily translatable strategy that could be used to prevent cancer-associated cognitive impairment in patients.

Low dose aspirin blocks breast cancer-induced cognitive impairment in mice.

Type 1 Diabetes (T1D) is an autoimmune disease in which insulin producing beta cells of the pancreas are selectively destroyed. Glial Fibrillary Acidic Protein (GFAP) expressed in peri-islet Schwann cells (pSCs) and in the ductal cells of the pancreas is one of the candidate autoantigens for T1D. Immune responses to GFAP expressing cell types precede the islet autoimmunity in Non-Obese Diabetic (NOD) mice. By removing MHC class I from GFAP expressing cell types, we tested the role of autoantigens presented by these cell types in the development of invasive insulitis. Our findings indicate that antigens expressed by pancreatic ductal cells are important in the development of invasive insulitis in NOD mice.

Pancreatic ductal cell antigens are important in the development of invasive insulitis in Non-Obese Diabetic mice.

Inflammation has been proposed to play a causal role in chemobrain which-if true-would represent an opportunity to repurpose existing anti-inflammatory drugs for the prevention and treatment of chemobrain. Here, we show that the chemoagent paclitaxel induces memory impairment and anhedonia in mice within 24 h of treatment cessation, but inflammation is not present until 2 weeks after treatment. We find no evidence of brain inflammation as measured by cytokine analysis at any time point. Furthermore, treating with aspirin to block inflammation did not affect paclitaxel-induced memory impairment. These findings suggest that inflammation may not be responsible for memory impairment induced by paclitaxel. These results contrast with recent findings of a causal role for inflammation in cancer-induced memory deficits in mice that were prevented by treatment with oral aspirin, suggesting that cognitive impairment in cancer patients undergoing treatment may arise from multiple convergent mechanisms.

The Anti-Inflammatory Drug Aspirin Does Not Protect Against Chemotherapy-Induced Memory Impairment by Paclitaxel in Mice.

The sympathetic nervous system drives breast cancer progression through β-adrenergic receptor signalling. This discovery has led to the consideration of cardiac β-blocker drugs as novel strategies for anticancer therapies. Carvedilol is a β-blocker used in the management of cardiovascular disorders, anxiety, migraine and chemotherapy-induced cardiotoxicity. However, little is known about how carvedilol affects cancer-related outcomes.

Article	Year
The CD19 signalling molecule is elevated in NOD mice and controls type 1 diabetes development. Diabetologia\| PubMed ID: 24013782	2013
Visualizing Ligand Binding to a GPCR In Vivo Using NanoBRET. iScience\| PubMed ID: 30240618	2018
Circulating epinephrine is not required for chronic stress to enhance metastasis. Psychoneuroendocrinology\| PubMed ID: 30253326	2019
Low dose aspirin blocks breast cancer-induced cognitive impairment in mice. PloS one\| PubMed ID: 30532184	2018
Pancreatic ductal cell antigens are important in the development of invasive insulitis in Non-Obese Diabetic mice. Journal of neuroimmunology\| PubMed ID: 30685070	2019
The Anti-Inflammatory Drug Aspirin Does Not Protect Against Chemotherapy-Induced Memory Impairment by Paclitaxel in Mice. Frontiers in oncology\| PubMed ID: 33381448	2020
Carvedilol blocks neural regulation of breast cancer progression in vivo and is associated with reduced breast cancer mortality in patients. European journal of cancer (Oxford, England : 1990)\| PubMed ID: 33639323	2021

Alexandra I. Ziegler

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