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.
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.
Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel.
Yaara
Y
Gorzalczany
Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel.
Eyal
E
Akiva
Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel.
Ofir
O
Klein
Unit of Soft Tissue and Bone Oncology, Division of Oncology, The Tel Aviv Sourasky Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel.
Ofer
O
Merimsky
Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel. Electronic address: histol3@post.tau.ac.il.
Ronit
R
Sagi-Eisenberg
D000072283:A549 Cells; D000241:Adenosine / Q000378:metabolism*; D019898:Autocrine Communication; D002462:Cell Membrane / Q000378:metabolism; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism*; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008407:Mast Cells / Q000378:metabolism* / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019899:Paracrine Communication; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D043684:Receptor, Adenosine A3 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D059016:Tumor Microenvironment
C508606:CXCL8 protein, human; D016209:Interleukin-8; D043684:Receptor, Adenosine A3; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D000241:Adenosine
Adenosine; Adenosine A3 receptor; Mast cells; Tumor microenvironment