Extracellular nucleotides as novel, underappreciated pro-metastatic factors that stimulate purinergic signaling in human lung cancer cells.

Gabriela Schneider,Henning Ulrich,Mariusz Z Ratajczak,Marcin Moniuszko,Ahmed Abdelbaset-Ismail,Talita Glaser,Zachariah Payne Sellers,Claudiana Lameu

doi:10.1186/s12943-015-0469-z

Abstract

BackgroundOne of the challenging problems of current radio-chemotherapy is recurrence and metastasis of cancer cells that survive initial treatment. We propose that one of the unwanted effects of radiochemotherapy is the release from damaged (“leaky”) cells of nucleotides such as ATP and UTP that exert pro-metastatic functions and can directly stimulate chemotaxis of cancer cells.MethodsTo address this problem in a model of human lung cancer (LC), we employed several complementary in vitro and in vivo approaches to demonstrate the role of extracellular nucleotides (EXNs) in LC cell line metastasis and tumor progression. We measured concentrations of EXNs in several organs before and after radiochemotherapy. The purinergic receptor agonists and antagonists, inhibiting all or selected subtypes of receptors, were employed in in vitro and in vivo pro-metastatic assays.ResultsWe found that EXNs accumulate in several organs in response to radiochemotherapy, and RT-PCR analysis revealed that most of the P1 and P2 receptor subtypes are expressed in human LC cells. EXNs were found to induce chemotaxis and adhesion of LC cells, and an autocrine loop was identified that promotes the proliferation of LC cells. Most importantly, metastasis of these cells could be inhibited in immunodeficient mice in the presence of specific small molecule inhibitors of purinergic receptors.ConclusionsBased on this result, EXNs are novel pro-metastatic factors released particularly during radiochemotherapy, and inhibition of their pro-metastatic effects via purinergic signaling could become an important part of anti-metastatic treatment.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-015-0469-z) contains supplementary material, which is available to authorized users.

Highlights

One of the challenging problems of current radio-chemotherapy is recurrence and metastasis of cancer cells that survive initial treatment
We propose the novel concept that toxic damage in various organs leads to an upregulation of the expression and activity of several factors in “bystander” tissues, including extracellular nucleotides (EXNs), which provide chemotactic signals to cancer cells that survived the initial treatment
It is clear that EXNs are novel pro-metastatic factors and that inhibition of their pro-metastatic effects via purinergic signaling could become an important part of anti-metastatic treatment

Summary

Introduction

One of the challenging problems of current radio-chemotherapy is recurrence and metastasis of cancer cells that survive initial treatment. We propose the novel concept that toxic damage in various organs leads to an upregulation of the expression and activity of several factors in “bystander” tissues, including extracellular nucleotides (EXNs), which provide chemotactic signals to cancer cells that survived the initial treatment. We propose that this mechanism plays an important role in the metastasis of cancer cells and indicates the need to develop efficient anti-metastatic drugs that work in combination with, or follow, standard. The mammalian metabotropic P2 receptor family contains eight different subtypes, denoted P2Y1, 2, 4, 6, 11, 12, 13, and 14 [7, 8]

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Results

Conclusion