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Molecular Cancer
Published in: Molecular Cancer 1/2015

Open Access 01-12-2015 | Research

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

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

Published in: Molecular Cancer | Issue 1/2015

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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.
Appendix
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Literature
1.
Ratajczak MZ, Jadczyk T, Schneider G, Kakar SS, Kucia M. Induction of a tumor-metastasis-receptive microenvironment as an unwanted and underestimated side effect of treatment by chemotherapy or radiotherapy. J Ovarian Res. 2013;6:95.PubMedCentralCrossRefPubMed
2.
Hodgson DC. Long-term toxicity of chemotherapy and radiotherapy in lymphoma survivors: optimizing treatment for individual patients. Clin Adv Hematol Oncol. 2015;13:103–12.PubMed
3.
Schneider G, Bryndza E, Abdel-Latif A, Ratajczak J, Maj M, Tarnowski M, et al. Bioactive lipids S1P and C1P are prometastatic factors in human rhabdomyosarcoma, and their tissue levels increase in response to radio/chemotherapy. Mol Cancer Res. 2013;11:793–807.PubMedCentralCrossRefPubMed
4.
Schneider G, Sellers ZP, Abdel-Latif A, Morris AJ, Ratajczak MZ. Bioactive lipids, LPC and LPA, are novel prometastatic factors and their tissue levels increase in response to radio/chemotherapy. Mol Cancer Res. 2014;12:1560–73.PubMedCentralCrossRefPubMed
5.
Gunjal PM, Schneider G, Ismail AA, Kakar SS, Kucia M, Ratajczak MZ. Evidence for induction of a tumor metastasis-receptive microenvironment for ovarian cancer cells in bone marrow and other organs as an unwanted and underestimated side effect of chemotherapy/radiotherapy. J Ovarian Res. 2015;8:20.PubMedCentralCrossRefPubMed
6.
Glaser T, Cappellari AR, Pillat MM, Iser IC, Wink MR, Battastini AM, et al. Perspectives of purinergic signaling in stem cell differentiation and tissue regeneration. Purinergic Signal. 2012;8:523–37.PubMedCentralCrossRefPubMed
7.
Guzman-Aranguez A, Santano C, Martin-Gil A, Fonseca B, Pintor J. Nucleotides in the eye: focus on functional aspects and therapeutic perspectives. J Pharmacol Exp Ther. 2011;345:331–41.CrossRef
8.
Burnstock G, Knight GE. Cellular distribution and functions of P2 receptor subtypes in different systems. Int Rev Cytol. 2004;240:31–304.CrossRefPubMed
9.
Kronlage M, Song J, Sorokin L, Isfort K, Schwerdtle T, Leipziger J, et al. Autocrine purinergic receptor signaling is essential for macrophage chemotaxis. Sci Signal. 2010;3:ra55.PubMed
10.
Ulrich H. Purinergic receptors in stem cell biology. M.A. Hayat. (Org.). Stem Cells and Cancer Stem Cells. Dordrecht, Heidelberg: Springer; 2012.
11.
Qian Y, Wang X, Liu Y, Li Y, Colvin RA, Tong L, et al. Extracellular ATP is internalized by macropinocytosis and induces intracellular ATP increase and drug resistance in cancer cells. Cancer Lett. 2014;351:242–51.CrossRefPubMed
12.
Nascimento IC, Glaser T, Nery AA, Pillat MM, Pesquero JB, Ulrich H. Kinin-B1 and B2 receptor activity in proliferation and neural phenotype determination of mouse embryonic stem cells. Cytometry A. 2015;87:989–1000.
13.
Ratajczak M, Tarnowski M, Staniszewska M, Sroczynski T, Banach B. Mechanisms of cancer metastasis: involvement of cancer stem cells? Minerva Med. 2010;101:179–91.PubMed
14.
Kim D, Kim S, Koh H, Yoon SO, Chung AS, Cho KS, et al. Akt/PKB promotes cancer cell invasion via increased motility and metalloproteinase production. Faseb J. 2001;15:1953–62.CrossRefPubMed
15.
Kukreja P, Abdel-Mageed AB, Mondal D, Liu K, Agrawal KC. Up-regulation of CXCR4 expression in PC-3 cells by stromal-derived factor-1alpha (CXCL12) increases endothelial adhesion and transendothelial migration: role of MEK/ERK signaling pathway-dependent NF-kappaB activation. Cancer Res. 2005;65:9891–8.CrossRefPubMed
16.
Zhou JZ, Riquelme MA, Gao X, Ellies LG, Sun LZ, Jiang JX. Differential impact of adenosine nucleotides released by osteocytes on breast cancer growth and bone metastasis. Oncogene. 2015;34:1831–42.PubMedCentralCrossRefPubMed
17.
Takai E, Tsukimoto M, Harada H, Kojima S. Autocrine signaling via release of ATP and activation of P2X7 receptor influences motile activity of human lung cancer cells. Purinergic Signal. 2014;10:487–97.PubMedCentralCrossRefPubMed
18.
19.
Bortolato M, Yardley MM, Khoja S, Godar SC, Asatryan L, Finn DA, et al. Pharmacological insights into the role of P2X4 receptors in behavioural regulation: lessons from ivermectin. Int J Neuropsychopharmacol. 2013;16:1059–70.PubMedCentralCrossRefPubMed
20.
21.
Schafer R, Sedehizade F, Welte T, Reiser G. ATP- and UTP-activated P2Y receptors differently regulate proliferation of human lung epithelial tumor cells. Am J Physiol Lung Cell Mol Physiol. 2003;285:L376–85.CrossRefPubMed
22.
Buzzi N, Bilbao PS, Boland R, de Boland AR. Extracellular ATP activates MAP kinase cascades through a P2Y purinergic receptor in the human intestinal Caco-2 cell line. Biochim Biophys Acta. 1790;2009:1651–9.
23.
24.
Huang SH, Perez-Ordonez B, Weinreb I, Hope A, Massey C, Waldron JN, et al. Natural course of distant metastases following radiotherapy or chemoradiotherapy in HPV-related oropharyngeal cancer. Oral Oncol. 2013;49:79–85.CrossRefPubMed
25.
Dou Y, Wu HJ, Li HQ, Qin S, Wang YE, Li J, et al. Microglial migration mediated by ATP-induced ATP release from lysosomes. Cell Res. 2012;22:1022–33.PubMedCentralCrossRefPubMed
26.
27.
28.
Martins I, Tesniere A, Kepp O, Michaud M, Schlemmer F, Senovilla L, et al. Chemotherapy induces ATP release from tumor cells. Cell Cycle. 2009;8:3723–8.CrossRefPubMed
29.
30.
Al-Rayahi IA, Sanyi RH. The overlapping roles of antimicrobial peptides and complement in recruitment and activation of tumor-associated inflammatory cells. Front Immunol. 2015;6:2.PubMedCentralCrossRefPubMed
31.
Rutkowski MJ, Sughrue ME, Kane AJ, Mills SA, Parsa AT. Cancer and the complement cascade. Mol Cancer Res. 2010;8:1453–65.CrossRefPubMed
32.
Surace L, Lysenko V, Fontana AO, Cecconi V, Janssen H, Bicvic A, et al. Complement is a central mediator of radiotherapy-induced tumor-specific immunity and clinical response. Immunity. 2015;42:767–77.CrossRefPubMed
33.
34.
Burnstock G, Williams M. P2 purinergic receptors: modulation of cell function and therapeutic potential. J Pharmacol Exp Ther. 2000;295:862–9.PubMed
35.
Virtanen SS, Kukkonen-Macchi A, Vainio M, Elima K, Harkonen PL, Jalkanen S, et al. Adenosine inhibits tumor cell invasion via receptor-independent mechanisms. Mol Cancer Res. 2014;12:1863–74.CrossRefPubMed
36.
Buzzi N, Boland R, Russo de Boland A. Signal transduction pathways associated with ATP-induced proliferation of colon adenocarcinoma cells. Biochim Biophys Acta. 2010;1800:946–55.CrossRefPubMed
37.
Hattori F, Ohshima Y, Seki S, Tsukimoto M, Sato M, Takenouchi T, et al. Feasibility study of B16 melanoma therapy using oxidized ATP to target purinergic receptor P2X7. Eur J Pharmacol. 2012;695:20–6.CrossRefPubMed
38.
Yang D, Song J, Wu L, Ma Y, Song C, Dovat S, et al. Induction of senescence by adenosine suppressing the growth of lung cancer cells. Biochem Biophys Res Commun. 2013;440:62–7.CrossRefPubMed
39.
Hatta Y, Takahashi M, Enomoto Y, Takahashi N, Sawada U, Horie T. Adenosine triphosphate (ATP) enhances the antitumor effect of etoposide (VP16) in lung cancer cells. Oncol Rep. 2004;12:1139–42.PubMed
40.
Swennen EL, Ummels V, Buss I, Jaehde U, Bast A, Dagnelie PC. ATP sensitizes H460 lung carcinoma cells to cisplatin-induced apoptosis. Chem Biol Interact. 2010;184:338–45.CrossRefPubMed
41.
Jin H, Eun SY, Lee JS, Park SW, Lee JH, Chang KC, et al. P2Y2 receptor activation by nucleotides released from highly metastatic breast cancer cells increases tumor growth and invasion via crosstalk with endothelial cells. Breast Cancer Res. 2014;16:R77.PubMedCentralCrossRefPubMed
42.
Patel L, Thaker A. The effects of adenosine A2B receptor inhibition on VEGF and nitric oxide axis-mediated renal function in diabetic nephropathy. Ren Fail. 2014;36:916–24.CrossRefPubMed
43.
Ferrari D, Gulinelli S, Salvestrini V, Lucchetti G, Zini R, Manfredini R, et al. Purinergic stimulation of human mesenchymal stem cells potentiates their chemotactic response to CXCL12 and increases the homing capacity and production of proinflammatory cytokines. Exp Hematol. 2011;39:360–74. 74 e1-5.CrossRefPubMed
44.
Gast RE, Konig S, Rose K, Ferenz KB, Krieglstein J. Binding of ATP to vascular endothelial growth factor isoform VEGF-A165 is essential for inducing proliferation of human umbilical vein endothelial cells. BMC Biochem. 2011;12:28.PubMedCentralCrossRefPubMed
45.
Bergamin LS, Braganhol E, Zanin RF, Edelweiss MI, Battastini AM. Ectonucleotidases in tumor cells and tumor-associated immune cells: an overview. J Biomed Biotechnol. 2012;2012:959848.PubMedCentralCrossRefPubMed
46.
47.
Yegutkin GG. Enzymes involved in metabolism of extracellular nucleotides and nucleosides: functional implications and measurement of activities. Crit Rev Biochem Mol Biol. 2014;49:473–97.CrossRefPubMed
48.
Pellegatti P, Raffaghello L, Bianchi G, Piccardi F, Pistoia V, Di Virgilio F. Increased level of extracellular ATP at tumor sites: in vivo imaging with plasma membrane luciferase. PLoS One. 2008;3:e2599.PubMedCentralCrossRefPubMed
49.
Tafani M, Schito L, Pellegrini L, Villanova L, Marfe G, Anwar T, et al. Hypoxia-increased RAGE and P2X7R expression regulates tumor cell invasion through phosphorylation of Erk1/2 and Akt and nuclear translocation of NF-{kappa}B. Carcinogenesis. 2011;32:1167–75.CrossRefPubMed
Metadata
Title
Extracellular nucleotides as novel, underappreciated pro-metastatic factors that stimulate purinergic signaling in human lung cancer cells
Authors
Gabriela Schneider
Talita Glaser
Claudiana Lameu
Ahmed Abdelbaset-Ismail
Zachariah Payne Sellers
Marcin Moniuszko
Henning Ulrich
Mariusz Z. Ratajczak
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2015
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/s12943-015-0469-z

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