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

Molecular Cancer

Research

Talita Glaser¹  Claudiana Lameu¹  Henning Ulrich¹  Marcin Moniuszko²  Zachariah Payne Sellers³  Ahmed Abdelbaset-Ismail³  Gabriela Schneider³  Mariusz Z. Ratajczak⁴ 

[1] Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil;Department of Regenerative Medicine and Immune Regulation, Medical University of Bialystok, Bialystok, Poland;Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, 500 South Floyd Street, 40202, Louisville, KY, USA;Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, 500 South Floyd Street, 40202, Louisville, KY, USA;Department of Regenerative Medicine, Medical University of Warsaw, Warsaw, Poland;

关键词: Extracellular nucleotides;    Purinergic signaling;    ATP;    UTP;    Lung cancer;    Metastasis;   

DOI  :  10.1186/s12943-015-0469-z

 received in 2015-05-31, accepted in 2015-11-10,  发布年份 2015

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY   
© Schneider et al. 2015