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NK1R antagonist decreases inflammation and metastasis of breast carcinoma cells metastasized to liver but not to brain; phenotype-dependent therapeutic and toxic consequences

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Abstract

Substance P a neuro-immune mediator acts on Neurokinin-1 and -2 receptors (NK1R and NK2R). Inhibitors of NK1R are considered to be safe and effective approaches for cancer treatment since Aprepitant, a non-peptide antagonist of NK1R is widely used for chemotherapy-induced emesis and has cytotoxic and antitumor effects in various models for cancer. On the other hand, our previous findings demonstrated that systemic inhibition of NK1R may decrease cytotoxic anti-tumoral immune response. Hence, actual consequences of inhibition of neurokinin receptors under in vivo conditions in a syngeneic model of carcinoma should be determined. The effects of highly potent and selective non-peptide mouse NK1R and NK2R antagonists RP 67580 and GR 159897, respectively, on metastatic breast carcinoma were evaluated. Specifically, 4T1 breast cancer cells metastasized to brain (denoted as 4TBM) and liver (denoted as 4TLM) were used to induce tumors in Balb-c mice. Changes in tumor growth, metastasis and immune response to cancer cells were determined. We here observed differential effects of NK1R antagonist depended on the subset of metastatic cells. Specifically, inhibition of NK1R markedly increased liver metastasis of tumors formed by 4TBM but not 4TLM cells. On the contrary, NK1R antagonist decreased inflammatory response and liver metastasis in 4TLM-injected mice. 4TLM tumors act more aggressively inducing more inflammatory response compared to 4TBM tumors. Hence, differential effects of NK1R antagonist are at least partly due to extend and type of the inflammatory response evoked by specific subset metastatic cells. These findings demonstrate the necessity for understanding the immunological consequences of tumor-microenvironment interactions.

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Abbreviations

NK1R:

Neurokinin-1 receptors

NK2R:

Neurokinin-2 receptors

SP:

Substance P

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Funding

This work was supported by funds from TÜBITAK 1002 project no: 214S389.

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Authors and Affiliations

  1. Department of Medical Pharmacology, School of Medicine, Akdeniz University, B-blok kat 1 Immunoloji, 07070, Antalya, Turkey

    Esra Nizam & Nuray Erin

  2. Medical Microbiology, School of Medicine, Akdeniz University, Antalya, Turkey

    Sadi Köksoy

Authors
  1. Esra Nizam
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  2. Sadi Köksoy
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  3. Nuray Erin
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Contributions

EN and NE carried out the experiments and performed the analysis. SK supervised and involved in analysis of the immunological experiments. NE conceived and planned the experiments as well as wrote the manuscript with support from EN and SK.

Corresponding author

Correspondence to Nuray Erin.

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Conflict of interest

The author declares that she has no conflict of interest.

Ethical approval and ethical standards for animal work

All animal experimentation was performed following the guidelines of an accredited animal care committee. Ethical approval from Akdeniz University ethics committee supervising studies involving animals was given to NE (no: 10.02.2014) and performed following guidelines of an accredited animal care committee.

Animal source

Wild-type (WT) female BALB/c mice were purchased from Kobay Research Animal Laboratory, Ankara Turkey.

Cell line authentication

4T1 cells were gift from Dr. Danny Welch. The cell lines used were derived from 4T1 cells metastasized to different organs by. Dr. Erin. Hence authentication was not possible.

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Research does not involve human so ‘Informed consent’ is not required.

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Nizam, E., Köksoy, S. & Erin, N. NK1R antagonist decreases inflammation and metastasis of breast carcinoma cells metastasized to liver but not to brain; phenotype-dependent therapeutic and toxic consequences. Cancer Immunol Immunother 69, 1639–1650 (2020). https://doi.org/10.1007/s00262-020-02574-z

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