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Acidity and mesenchymal stem cells as a new liaison in human melanoma malignancy

2014; Frontiers Media; Volume: 5; Linguagem: Inglês

10.3389/conf.fphar.2014.61.00037

1663-9812

Silvia Peppicelli, Francesca Bianchini, Calorini Lido,

Cancer Research and Treatments

Event Abstract Back to Event Acidity and mesenchymal stem cells as a new liaison in human melanoma malignancy Silvia Peppicelli1, Francesca Bianchini1 and Lido Calorini1* 1 University of Florence, Department of Experimental and Clinical Biomedical Sciences, Italy Background and aim. Tumors may be considered as a “wound that never heals”and, as the healing process, tumor cells actively recruit host cells, including bone marrow-derived mesenchymal stem cells (MSC). Large number of MSC are recruited into the stroma of developing tumors and recent evidence suggests that these cells play a role in facilitating cancer progression. It was suggested that interactions between MSC and breast cancer cells greatly increase their metastatic dissemination (1). Following co-culture with MSC, breast cancer cells express epithelial-to-mesenchymal transition (EMT) specific markers up-regulation. These changes were cell contact mediated and appeared to be MSC specific (2). Thus, MSC-tumor cell interactions acquire a particular importance and further understanding of these interactions is required to determine their role in tumor progression. An emerging, but old, hallmark of cancer is the reprogramming energy metabolism (e.g. aerobic glycolysis), that contributes to the “reversed “ pH gradient observed in tumors (3) and proton pump inhibitors (PPI) was proposed as a new antitumor agent (4). MSC/tumor cell interactions are probably influenced by the acidic environment resulting from tumors deregulated pH. The aim of this study is to elucidate whether acidity affects cross-talk between MSC and tumor cells. We used a human melanoma cell line, A375-M6 cells, as prototype of aggressive human tumor cells. Methods. Media conditioned by acidic or non-acidic MSC were used to grow A375-M6 human melanoma cells that were tested in vitro (molecular analysis, motility, invasiveness) and in vivo (xenograft experiments), in esomeprazole (ESO)-treated SCID bg/bg immunodeficient mice. Results. We found that A375-M6 cells grown in MSC-conditioned medium, previously exposed to low pH (pH 6.7) (LowpHMSC-M6c) express a lower level of E-cadherin and increased level of N-cadherin compared to control cells and to cells exposed to MSC-conditioned medium, grown in standard pH (SpHMSC-M6c). These changes came in LowpHMSC-M6c with a mesenchymal morphology. The mesenchymal phenotype of LowpHMSC-M6c is also characterized by an increased mRNA for TGFβ and a switch from TGFβR3 to a TGFβR1 and R2 pattern. LowpHMSC-M6c show enhanced motility through Boyden chamber membrane and increased invasiveness through Matrigel. Using a xenograft model in which A375-M6 cells were mixed with SpHMSC or LowpHMSC and injected subcutaneously into immunodeficient mice, we found that growth kinetics of LowpHMSC-containing tumors was significantly accelerated over that of SpHMSC-containing tumors and tumors made of melanoma cells alone. Growth kinetic of LowpHMSC- as SpHMSC-containing tumors was inhibited in tumor-bearing animals treated intravenously with ESO, a potent PPI. Conclusions / Discussion. We observed that acidity promotes a MSC phenotype compatible with a stronger capacity to elicit in melanoma cells a more aggressive phenotype, probably sustained by an autocrine loop of TGFβ/TGFβR. ESO abrogates LowpHMSC and SpHMSC promotion melanoma xenografts, confirming the growing interest of PPI in tumor therapy. Acknowledgements Grants from Istituto Toscano Tumori, Ente Cassa di Risparmio di Firenze. References 1. Karnoub AE, Dash AB, Vo AP, Sullivan A, Brooks MW, Bell GW, Richardson AL, Polyak K, Tubo R, Weinberg RA. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature (2007) 449:557-63. 2. Martin FT, Dwyer RM, Kelly J, Khan S, Murphy JM, Curran C, Miller N, Hennessy E, Dockery P, Barry FP, O'Brien T, Kerin MJ. Potential role of mesenchymal stem cells (MSCs) in the breast tumour microenvironment: stimulation of epithelial to mesenchymal transition (EMT). Breast Cancer Res Treat (2010) 124:317-26. doi: 10.1007/s10549-010-0734-1. 3. Calorini L, Peppicelli S, Bianchini F. Extracellular acidity as favouring factor of tumor progression and metastatic dissemination. Exp Oncol (2012) 34:79-84. 4. De Milito A, Canese R, Marino ML, Borghi M, Iero M, Villa A, Venturi G, Lozupone F, Iessi E, Logozzi M, Della Mina P, Santinami M, Rodolfo M, Podo F, Rivoltini L, Fais S. pH-dependent antitumor activity of proton pump inhibitors against human melanoma is mediated by inhibition of tumor acidity. Int J Cancer (2010) 127:207-19. doi: 10.1002/ijc.25009. Keywords: low pH microenvironment, Mesenchymal Stem Cells, epithelial-to-mesenchymal transition, stroma-tumor cells interactions, Proton Pump Inhibitors Conference: 4th Annual Meeting of the International Society of Proton Dynamics in Cancer, Garching, Germany, 10 Oct - 12 Oct, 2013. Presentation Type: Abstract Topic: 6. pH control of immune functions and tumor cell plasticity Citation: Peppicelli S, Bianchini F and Calorini L (2014). Acidity and mesenchymal stem cells as a new liaison in human melanoma malignancy. Front. Pharmacol. Conference Abstract: 4th Annual Meeting of the International Society of Proton Dynamics in Cancer. doi: 10.3389/conf.fphar.2014.61.00037 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 15 Jan 2014; Published Online: 07 Feb 2014. * Correspondence: Prof. Lido Calorini, University of Florence, Department of Experimental and Clinical Biomedical Sciences, Florence, 50134, Italy, lido.calorini@unifi.it Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Silvia Peppicelli Francesca Bianchini Lido Calorini Google Silvia Peppicelli Francesca Bianchini Lido Calorini Google Scholar Silvia Peppicelli Francesca Bianchini Lido Calorini PubMed Silvia Peppicelli Francesca Bianchini Lido Calorini Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.