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Lung cancer-derived extracellular vesicles: a possible mediator of mast cell activation in the tumor microenvironment

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Abstract

Activated mast cells are often found in the tumor microenvironment. They have both pro- and anti-tumorigenic roles, depending on the tumor type. Several lines of evidence suggest that the tumor microenvironment contains multiple soluble factors that can drive mast cell recruitment and activation. However, it is not yet clear how mast cells are activated by tumor cells. In this study, we explored whether tumor-derived microvesicles (TMV) from non-small cell lung cancer (NSCLC) cells interact with human mast cells, activate them to release cytokines, and affect their migratory ability. PKH67-labelled TMV isolated from NSCLC cell lines were found to be internalized by mast cells. This internalization was first noticed after 4 h and peaked within 24 h of co-incubation. Furthermore, internalization of TMV derived from NSCLC cell lines or from surgical lung tissue specimens resulted in ERK phosphorylation, enhanced mast cell migratory ability and increased release of cytokines and chemokines, such as TNF-α and MCP-1. Our data are thus, consistent with the conclusion that TMV have the potential to influence mast cell activity and thereby, affect tumorigenesis.

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Abbreviations

ATCC:

American type culture collection

CCL2:

Chemokine (C–C motif) ligand 2

ERK:

Extracellular signal-regulated kinase

EVs:

Extracellular vesicles

MC:

Mast cells

MCP-1:

Monocyte chemoattractant protein 1

MV:

Microvesicles

mvT*:

Microvesicles derived from activated T cells

NSCLC:

Non-small cell lung cancer

TMV:

Tumor-derived microvesicles

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Acknowledgements

Faye Schreiber, MSc edited the manuscript. She is an employee of Meir Medical Center.

Funding

This work was supported in part by the Israel Cancer Association (#20190025).

Author information

Authors and Affiliations

  1. The Herbert Mast Cell Disorders Center, Laboratory of Allergy and Clinical Immunology, Meir Medical Center, 59 Tchernichovsky St., 4428164, Kfar Saba, Israel

    Pazit Salamon, Yoseph A. Mekori & Irit Shefler

  2. Sackler School of Medicine, Tel Aviv University, Ramat Aviv, Tel Aviv, Israel

    Yoseph A. Mekori

  3. Tel Hai College, Tel Hai, Israel

    Yoseph A. Mekori

Authors
  1. Pazit Salamon
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  2. Yoseph A. Mekori
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  3. Irit Shefler
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Contributions

IS and YAM designed the study. IS and PS performed the experiments. The first draft of the manuscript was written by IS. All authors reviewed and commented on the different versions of the manuscript and approved its final version.

Corresponding author

Correspondence to Irit Shefler.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval and ethical standards

The study was approved by the Meir Medical Center Institutional Review Board (Helsinki Committee; #0059-14-MMC, July 2015) and complies with the 1964 Helsinki Declaration and its later amendments.

Informed consent

Written informed consent was obtained from all individual participants included in the study. Patients who underwent surgery for newly diagnosed lung cancer agreed, prior to their surgery, to the use of their residual specimens for medical research and publication.

Animal source

This article does not contain any studies with animals performed by any of the authors.

Cell line authentication

For lines A549, H1299 and H1975, cell line authentication was performed at the Genomics Center of Biomedical Core Facility, Technion, Haifa, Israel. The test was performed using the Promega GenePrint 24 System to determine short tandem repeat (STR) profile of 23 loci plus Amelogenin for sex determination (X or XY). In addition, the male-specific DYS391 locus is included to identify null Y allele results for Amelogenin. The results were analyzed using the 3500xl Genetic Analyzer (Life Echnologies NY, USA) and GeneMapper IDX software. For line H1299, the sample profile matches 8 of the 9 available loci of the STR profile from ATCC (American Type Culture Collection). In light of these results, it seems that the tested cell line is indeed NCI-H1299. For line H1975, the sample profile matches 8 of the 9 available loci of the STR profile from ATCC. Locus D13S317 presents a loss of heterozygosity (LOH). In light of these results, it seems that the tested cell line is indeed NCI-H1975. For line A549, the sample profile matches 9 of the 9 available loci of the STR profile from ATCC for line A549 (CCL-185). In light of these results, it seems that the tested cell line is indeed A549. The cell lines H1299, H1975 and A549 were kindly provided from the Lung Cancer Research Laboratory, Meir Medical Center, Kfar Saba, Israel. The LAD2 cell line was established from bone marrow aspirates from a patient with mast cell sarcoma/leukemia. Thus, no STR profile was available for authentication analysis. All experiments were conducted on cell lines at the same passages. The human LAD2 MC were kindly provided by Dr. A.S. Kirshenbaum [31].

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Salamon, P., Mekori, Y.A. & Shefler, I. Lung cancer-derived extracellular vesicles: a possible mediator of mast cell activation in the tumor microenvironment. Cancer Immunol Immunother 69, 373–381 (2020). https://doi.org/10.1007/s00262-019-02459-w

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