title: Extracellular nucleotides as novel, underappreciated pro-metastatic factors that stimulate purinergic signaling in human lung cancer cells.
abstract: BACKGROUND
  One 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.
  
  
  METHODS
  To 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.
  
  
  RESULTS
  We 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.
  
  
  CONCLUSIONS
  Based 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.
authors.affiliation: Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, 500 South Floyd Street, Louisville, KY, 40202, USA.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Schneider
authors.affiliation: Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Talita
authors.initials: T
authors.lastname: Glaser
authors.affiliation: Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Claudiana
authors.initials: C
authors.lastname: Lameu
authors.affiliation: Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, 500 South Floyd Street, Louisville, KY, 40202, USA.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Abdelbaset-Ismail
authors.affiliation: Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, 500 South Floyd Street, Louisville, KY, 40202, USA.
authors.forename: Zachariah Payne
authors.initials: ZP
authors.lastname: Sellers
authors.affiliation: Department of Regenerative Medicine and Immune Regulation, Medical University of Bialystok, Bialystok, Poland.
authors.forename: Marcin
authors.initials: M
authors.lastname: Moniuszko
authors.affiliation: Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Henning
authors.initials: H
authors.lastname: Ulrich
authors.affiliation: Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, 500 South Floyd Street, Louisville, KY, 40202, USA. mzrata01@louisville.edu.|Department of Regenerative Medicine, Medical University of Warsaw, Warsaw, Poland. mzrata01@louisville.edu.
authors.forename: Mariusz Z
authors.initials: MZ
authors.lastname: Ratajczak
mesh_terms: D000255:Adenosine Triphosphate / Q000502:physiology*; D000818:Animals; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D059248:Chemoradiotherapy / Q000009:adverse effects; D002630:Chemotactic Factors / Q000502:physiology*; D002633:Chemotaxis; D045604:Extracellular Fluid / Q000502:physiology; D017228:Hepatocyte Growth Factor / Q000502:physiology; D006801:Humans; D008113:Liver Neoplasms / Q000209:etiology / Q000517:prevention & control / Q000556:secondary*; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D058915:Purinergic P1 Receptor Antagonists / Q000494:pharmacology; D058919:Purinergic P2 Receptor Antagonists / Q000494:pharmacology; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D002630:Chemotactic Factors; C066855:HGF protein, human; D058915:Purinergic P1 Receptor Antagonists; D058919:Purinergic P2 Receptor Antagonists; D018047:Receptors, Purinergic P1; D018048:Receptors, Purinergic P2; D017228:Hepatocyte Growth Factor; D000255:Adenosine Triphosphate