Mast cells are directly activated by contact with cancer cells by a mechanism involving autocrine formation of adenosine and autocrine/paracrine signaling of the adenosine A3 receptor

Yaara Gorzalczany, Eyal Akiva, Ofir Klein, Ofer Merimsky, Ronit Sagi-Eisenberg*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Mast cells (MCs) constitute an important part of the tumor microenvironment (TME). However, their underlying mechanisms of activation within the TME remain poorly understood. Here we show that recapitulating cell-to-cell contact interactions by exposing MCs to membranes derived from a number of cancer cell types, results in MC activation, evident by the increased phosphorylation of the ERK1/2 MAP kinases and Akt, in a phosphatidylinositol 3-kinase dependent fashion. Activation is unidirectional since MC derived membranes do not activate cancer cells. Stimulated ERK1/2 phosphorylation is strictly dependent on the ecto enzyme CD73 that mediates autocrine formation of adenosine, and is inhibited by knockdown of the A3 adenosine receptor (A3R) as well as by an A3R antagonist or by agonist-stimulated down-regulation of the A3R. We also show that cancer cell mediated triggering upregulates expression and stimulates secretion of interleukin 8 from the activated MCs. These findings provide evidence for a novel mode of unidirectional crosstalk between MCs and cancer cells implicating direct activation by cancer cells in MC reprogramming into a pro tumorigenic profile.

Original languageEnglish
Pages (from-to)23-32
Number of pages10
JournalCancer Letters
Volume397
DOIs
StatePublished - 1 Jul 2017

Funding

FundersFunder number
Frida Hamer and Haya Hamer Fund for Medical Research
Israel Hamer
Varda and Boaz Dotan Research Center
Royal Society of Edinburgh
Tel Aviv University

    Keywords

    • Adenosine
    • Adenosine A3 receptor
    • Mast cells
    • Tumor microenvironment

    Fingerprint

    Dive into the research topics of 'Mast cells are directly activated by contact with cancer cells by a mechanism involving autocrine formation of adenosine and autocrine/paracrine signaling of the adenosine A3 receptor'. Together they form a unique fingerprint.

    Cite this