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3D Models of Mesothelioma in the Study of Mechanisms of Cell Survival

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Asbestos and Mesothelioma

Part of the book series: Current Cancer Research ((CUCR))

Abstract

Three-dimensional models can provide another experimental system for investigating many aspects of tumor biology, particularly of cell death and survival. These models, both in vitro and ex vivo, may be ideally suited for studying mesothelioma. Here we discuss the reports that are currently available on this subject and highlight areas in which 3D biology may provide insights into the mechanisms of cell death and survival in mesothelioma. It has long been known that single cells or monolayers are more sensitive to cell death than 3D aggregates or spheroids, which acquire resistance called “multicellular resistance.” Possible survival mechanisms that have been studied using multicellular spheroids (in vitro) and tumor fragment spheroids (ex vivo) include growth factor pathways, calcium-dependent cell-cell adhesion, resistance to drug penetrance, gene expression, epigenetics, Bcl-2 anti-apoptotic family expression, and autophagy. In general, cells in a 3D setting show many differences compared to the same cells in a 2D monolayer. Many of these differences appear to contribute to cell survival. In many cases, these features can be shown to be more similar to those in the actual tumor. Thus, whereas 3D studies offer more challenges for study, they offer the opportunity for new insights not possible in 2D studies. They may thus offer an intermediate model between the monolayer and in vivo studies and hopefully lead to discoveries that can be tested in clinical trials to benefit patients.

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References

  • Aceto N, Bardia A, Miyamoto DT et al (2014) Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis. Cell 158:1110–1122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Barbone D, Cheung P, Battula S et al (2012) Vorinostat eliminates multicellular resistance of mesothelioma 3D spheroids via restoration of Noxa expression. PLoS One 7:e52753

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Barbone D, Follo C, Echeverry N et al (2015) Autophagy correlates with the therapeutic responsiveness of malignant pleural mesothelioma in 3D models. PLoS One 10:e0134825

    Article  PubMed  PubMed Central  Google Scholar 

  • Barbone D, Ryan JA, Kolhatkar N et al (2011) The Bcl-2 repertoire of mesothelioma spheroids underlies acquired apoptotic multicellular resistance. Cell Death Dis 2:e174

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Barbone D, Van Dam L, Follo C et al (2016) Analysis of gene expression in 3D spheroids highlights a survival role for ASS1 in mesothelioma. PLoS One 11:e0150044

    Article  PubMed  PubMed Central  Google Scholar 

  • Barbone D, Yang TM, Morgan JR et al (2008) Mammalian target of rapamycin contributes to the acquired apoptotic resistance of human mesothelioma multicellular spheroids. J Biol Chem 283:13021–13030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bidlingmaier S, He J, Wang Y et al (2009) Identification of MCAM/CD146 as the target antigen of a human monoclonal antibody that recognizes both epithelioid and sarcomatoid types of mesothelioma. Cancer Res 69:1570–1577

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Birgersdotter A, Baumforth KR, Porwit A et al (2007) Three-dimensional culturing of the Hodgkin lymphoma cell-line L1236 induces a HL tissue-like gene expression pattern. Leuk Lymphoma 48:2042–2053

    Article  CAS  PubMed  Google Scholar 

  • Birgersdotter A, Sandberg R, Ernberg I (2005) Gene expression perturbation in vitro--a growing case for three-dimensional (3D) culture systems. Semin Cancer Biol 15:405–412

    Article  PubMed  Google Scholar 

  • Bobek V, Kacprzak G, Rzechonek A et al (2014) Detection and cultivation of circulating tumor cells in malignant pleural mesothelioma. Anticancer Res 34:2565–2569

    PubMed  Google Scholar 

  • Broaddus VC, Dansen TB, Abayasiriwardana KS et al (2005) Bid mediates apoptotic synergy between TRAIL and DNA damage. J Biol Chem 280:12486–12493

    Article  CAS  PubMed  Google Scholar 

  • Cang S, Iragavarapu C, Savooji J et al (2015) ABT-199 (venetoclax) and BCL-2 inhibitors in clinical development. J Hematol Oncol 8:129

    Article  PubMed  PubMed Central  Google Scholar 

  • Cheung KJ, Ewald AJ (2016) A collective route to metastasis: seeding by tumor cell clusters. Science 352:167–169

    Article  CAS  PubMed  Google Scholar 

  • Cortes-Dericks L, Froment L, Boesch R et al (2014) Cisplatin-resistant cells in malignant pleural mesothelioma cell lines show ALDH(high)CD44(+) phenotype and sphere-forming capacity. BMC Cancer 14:304

    Article  PubMed  PubMed Central  Google Scholar 

  • Cortes-Dericks L, Froment L, Kocher G et al (2016) Human lung-derived mesenchymal stem cell-conditioned medium exerts in vitro antitumor effects in malignant pleural mesothelioma cell lines. Stem Cell Res Ther 7:25

    Article  PubMed  PubMed Central  Google Scholar 

  • Craighead JE, Akley NJ, Gould LB et al (1987) Characteristics of tumors and tumor cells cultured from experimental asbestos-induced mesotheliomas in rats. Am J Pathol 129:448–462

    CAS  PubMed  PubMed Central  Google Scholar 

  • Daubriac J, Fleury-Feith J, Kheuang L et al (2009) Malignant pleural mesothelioma cells resist anoikis as quiescent pluricellular aggregates. Cell Death Differ 16:1146–1155

    Article  CAS  PubMed  Google Scholar 

  • Delage B, Fennell DA, Nicholson L et al (2010) Arginine deprivation and argininosuccinate synthetase expression in the treatment of cancer. Int J Cancer 126:2762–2772

    CAS  PubMed  Google Scholar 

  • Deng XB, Xiao L, Wu Y et al (2015) Inhibition of mesothelioma cancer stem-like cells with adenovirus-mediated NK4 gene therapy. Int J Cancer 137:481–490

    Article  CAS  PubMed  Google Scholar 

  • Desoize B, Jardillier J (2000) Multicellular resistance: a paradigm for clinical resistance? Crit Rev Oncol Hematol 36:193–207

    Article  CAS  PubMed  Google Scholar 

  • Dubessy C, Merlin JM, Marchal C et al (2000) Spheroids in radiobiology and photodynamic therapy. Crit Rev Oncol Hematol 36:179–192

    Article  CAS  PubMed  Google Scholar 

  • Echeverry N, Ziltener G, Barbone D et al (2015) Inhibition of autophagy sensitizes malignant pleural mesothelioma cells to dual PI3K/mTOR inhibitors. Cell Death Dis 6:e1757

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Eguchi R, Fujita Y, Tabata C et al (2015) Inhibition of Src family kinases overcomes anoikis resistance induced by spheroid formation and facilitates cisplatin-induced apoptosis in human mesothelioma cells. Oncol Rep 34:2305–2310

    CAS  PubMed  Google Scholar 

  • Ernst A, Hofmann S, Ahmadi R et al (2009) Genomic and expression profiling of glioblastoma stem cell-like spheroid cultures identifies novel tumor-relevant genes associated with survival. Clin Cancer Res 15:6541–6550

    Article  CAS  PubMed  Google Scholar 

  • Fjellbirkeland L, Bjerkvig R, Laerum OD (1995) Tumour fragment spheroids from human non-small-cell lung cancer maintained in organ culture. Virchows Arch 426:169–178

    Article  CAS  PubMed  Google Scholar 

  • Follo C, Barbone D, Richards WG et al (2016) Autophagy initiation correlates with the autophagic flux in 3D models of mesothelioma and with patient outcome. Autophagy 12:1180–1194

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Friedrich J, Seidel C, Ebner R et al (2009) Spheroid-based drug screen: considerations and practical approach. Nat Protoc 4:309–324

    Article  CAS  PubMed  Google Scholar 

  • Ghani FI, Yamazaki H, Iwata S et al (2011) Identification of cancer stem cell markers in human malignant mesothelioma cells. Biochem Biophys Res Commun 404:735–742

    Article  CAS  PubMed  Google Scholar 

  • Gordon DJ, Milner AE, Beaney RP et al (1990) The increase in radioresistance of Chinese hamster cells cultured as spheroids is correlated to changes in nuclear morphology. Radiat Res 121:175–179

    Article  CAS  PubMed  Google Scholar 

  • Hoda MA, Mohamed A, Ghanim B et al (2011) Temsirolimus inhibits malignant pleural mesothelioma growth in vitro and in vivo: synergism with chemotherapy. J Thorac Oncol 6:852–863

    Article  PubMed  Google Scholar 

  • Jagirdar RM, Apostolidou E, Molyvdas PA et al (2016) Influence of AQP1 on cell adhesion, migration, and tumor sphere formation in malignant pleural mesothelioma is substratum- and histological-type dependent. Am J Phys Lung Cell Mol Phys 310:L489–L495

    Google Scholar 

  • Katt ME, Placone AL, Wong AD et al (2016) In vitro tumor models: advantages, disadvantages, variables, and selecting the right platform. Front Bioeng Biotechnol 4:12

    Article  PubMed  PubMed Central  Google Scholar 

  • Kim H, Phung Y, Ho M (2012) Changes in global gene expression associated with 3D structure of tumors: an ex vivo matrix-free mesothelioma spheroid model. PLoS One 7:e39556

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim KU, Wilson AD, Abayasiriwardana KS et al (2005) A novel in vitro model of human mesothelioma for studying tumor biology and apoptotic resistance. Am J Respir Cell Mol Biol 33:541–548

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kindler HL (2008) Systemic treatments for mesothelioma: standard and novel. Curr Treat Options in Oncol 9:171–179

    Article  Google Scholar 

  • Kobayashi H, Man S, Graham CH et al (1993) Acquired multicellular-mediated resistance to alkylating agents in cancer. Proc Natl Acad Sci U S A 90:3294–3298

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kunz-Schughart LA, Freyer JP, Hofstaedter F et al (2004) The use of 3-D cultures for high-throughput screening: the multicellular spheroid model. J Biomol Screen 9:273–285

    Article  CAS  PubMed  Google Scholar 

  • Lao Z, Kelly CJ, Yang XY et al (2015) Improved methods to generate spheroid cultures from tumor cells, tumor cells & fibroblasts or tumor-fragments: microenvironment, microvesicles and miRNA. PLoS One 10:e0133895

    Article  PubMed  PubMed Central  Google Scholar 

  • Leek R, Grimes DR, Harris AL et al (2016) Methods: using three-dimensional culture (spheroids) as an in vitro model of tumour hypoxia. Adv Exp Med Biol 899:167–196

    Article  PubMed  Google Scholar 

  • Lei H, Hofferberth SC, Liu R et al (2015) Paclitaxel-loaded expansile nanoparticles enhance chemotherapeutic drug delivery in mesothelioma 3-dimensional multicellular spheroids. J Thorac Cardiovasc Surg 149:1417–1424. discussion 1424-1425

    Article  CAS  PubMed  Google Scholar 

  • Liu S, Cheng H, Kwan W et al (2008) Histone deacetylase inhibitors induce growth arrest, apoptosis, and differentiation in clear cell sarcoma models. Mol Cancer Ther 7:11751–11761

    Google Scholar 

  • Lobjois V, Frongia C, Jozan S et al (2009) Cell cycle and apoptotic effects of SAHA are regulated by the cellular microenvironment in HCT116 multicellular tumour spheroids. Eur J Cancer 45:2402–2411

    Article  CAS  PubMed  Google Scholar 

  • Manente AG, Pinton G, Zonca S et al (2015) Intracellular lactate-mediated induction of estrogen receptor beta (ERbeta) in biphasic malignant pleural mesothelioma cells. Oncotarget 6:25121–25134

    Article  PubMed  PubMed Central  Google Scholar 

  • Melaiu O, Stebbing J, Lombardo Y et al (2014) MSLN gene silencing has an anti-malignant effect on cell lines overexpressing mesothelin deriving from malignant pleural mesothelioma. PLoS One 9:e85935

    Article  PubMed  PubMed Central  Google Scholar 

  • Menges CW, Kadariya Y, Altomare D et al (2014) Tumor suppressor alterations cooperate to drive aggressive mesotheliomas with enriched cancer stem cells via a p53-miR-34a-c-Met axis. Cancer Res 74:1261–1271

    Article  CAS  PubMed  Google Scholar 

  • Minchinton AI, Tannock IF (2006) Drug penetration in solid tumours. Nat Rev Cancer 6:583–592

    Article  CAS  PubMed  Google Scholar 

  • Miselis NR, Wu ZJ, Van Rooijen N et al (2008) Targeting tumor-associated macrophages in an orthotopic murine model of diffuse malignant mesothelioma. Mol Cancer Ther 7:788–799

    Article  CAS  PubMed  Google Scholar 

  • Miselis NR, Lau BW, Wu Z et al (2011) Kinetics of host cell recruitment during dissemination of diffuse malignant peritoneal mesothelioma. Cancer Microenviron 4:39–50

    Article  CAS  Google Scholar 

  • Napolitano AP, Chai P, Dean DM et al (2007) Dynamics of the self-assembly of complex cellular aggregates on micromolded nonadhesive hydrogels. Tissue Eng 13:2087–2094

    Article  CAS  PubMed  Google Scholar 

  • Nath S, Devi GR (2016) Three-dimensional culture systems in cancer research: Focus on tumor spheroid model. Pharmacol Ther 163:94–108

    Article  CAS  PubMed  Google Scholar 

  • Nishikawa S, Tanaka A, Matsuda A et al (2014) A molecular targeting against nuclear factor-kappaB, as a chemotherapeutic approach for human malignant mesothelioma. Cancer Med 3:416–425

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pasdar EA, Smits M, Stapelberg M et al (2015) Characterisation of mesothelioma-initiating cells and their susceptibility to anti-cancer agents. PLoS One 10:e0119549

    Article  PubMed  PubMed Central  Google Scholar 

  • Pastrana E, Silva-Vargas V, Doetsch F (2011) Eyes wide open: a critical review of sphere-formation as an assay for stem cells. Cell Stem Cell 8:486–498

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pease JC, Brewer M, Tirnauer JS (2012) Spontaneous spheroid budding from monolayers: a potential contribution to ovarian cancer dissemination. Biol Open 1:622–628

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Raphael J, Massard C, Gong IY et al (2015) Detection of circulating tumour cells in peripheral blood of patients with malignant pleural mesothelioma. Cancer Biomark 15:151–156

    Article  PubMed  Google Scholar 

  • Ruppen J, Cortes-Dericks L, Marconi E et al (2014) A microfluidic platform for chemoresistive testing of multicellular pleural cancer spheroids. Lab Chip 14:1198–1205

    Article  CAS  PubMed  Google Scholar 

  • Schelch K, Hoda MA, Klikovits T et al (2014) Fibroblast growth factor receptor inhibition is active against mesothelioma and synergizes with radio- and chemotherapy. Am J Respir Crit Care Med 190:763–772

    Article  CAS  PubMed  Google Scholar 

  • Shield K, Ackland ML, Ahmed N et al (2009) Multicellular spheroids in ovarian cancer metastases: biology and pathology. Gynecol Oncol 113:143–148

    Article  PubMed  Google Scholar 

  • Stapelberg M, Gellert N, Swettenham E et al (2005) Alpha-tocopheryl succinate inhibits malignant mesothelioma by disrupting the fibroblast growth factor autocrine loop: mechanism and the role of oxidative stress. J Biol Chem 280:25369–25376

    Article  CAS  PubMed  Google Scholar 

  • Steadman K, Stein WD, Litman T et al (2008) PolyHEMA spheroids are an inadequate model for the drug resistance of the intractable solid tumors. Cell Cycle 7:818–829

    Article  CAS  PubMed  Google Scholar 

  • Sutherland RM, McCredie JA, Inch WR (1971) Growth of multicell spheroids in tissue culture as a model of nodular carcinomas. J Natl Cancer Inst 46:113–120

    CAS  PubMed  Google Scholar 

  • Varghese S, Whipple R, Martin SS et al (2012) Multipotent cancer stem cells derived from human malignant peritoneal mesothelioma promote tumorigenesis. PLoS One 7:e52825

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vogelzang NJ, Rusthoven JJ, Symanowski J et al (2003) Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 21:2636–2644

    Article  CAS  PubMed  Google Scholar 

  • Wangpaichitr M, Wu C, Bigford G et al (2014) Combination of arginine deprivation with TRAIL treatment as a targeted-therapy for mesothelioma. Anticancer Res 34:6991–6999

    CAS  PubMed  Google Scholar 

  • Weiswald LB, Bellet D, Dangles-Marie V (2015) Spherical cancer models in tumor biology. Neoplasia 17:1–15

    Article  PubMed  PubMed Central  Google Scholar 

  • West CM, Sutherland RM (1987) The radiation response of a human colon adenocarcinoma grown in monolayer, as spheroids, and in nude mice. Radiat Res 112:105–115

    Article  CAS  PubMed  Google Scholar 

  • Whitaker D (1977) Cell aggregates in malignant mesothelioma. Acta Cytol 21:236–239

    CAS  PubMed  Google Scholar 

  • Wilson SM, Barbone D, Yang TM et al (2008) mTOR mediates survival signals in malignant mesothelioma grown as tumor fragment spheroids. Am J Respir Cell Mol Biol 39:576–583

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xiang X, Phung Y, Feng M et al (2011) The development and characterization of a human mesothelioma in vitro 3D model to investigate immunotoxin therapy. PLoS One 6:e14640

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang TM, Barbone D, Fennell DA et al (2009) Bcl-2 family proteins contribute to apoptotic resistance in lung cancer multicellular spheroids. Am J Respir Cell Mol Biol 41:14–23

    Article  CAS  PubMed  Google Scholar 

  • Yoneda K, Tanaka F, Kondo N et al (2014) Circulating tumor cells (CTCs) in malignant pleural mesothelioma (MPM). Ann Surg Oncol 21(Suppl 4):S472–S480

    Article  PubMed  Google Scholar 

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Acknowledgments

We wish to acknowledge the funding sources that made this work possible, including the Department of Defense, the Mesothelioma Foundation (MARF), and the Simmons Foundation (a private, nonprofit organization founded by the Simmons Law Firm).

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Authors and Affiliations

  1. Division of Pulmonary and Critical Care Medicine, Zuckerberg San Francisco General Hospital and Trauma Center, San Francisco, CA, 94110-3518, USA

    V. Courtney Broaddus, Carlo Follo & Dario Barbone

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  1. V. Courtney Broaddus
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  2. Carlo Follo
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  3. Dario Barbone
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Correspondence to V. Courtney Broaddus .

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Editors and Affiliations

  1. Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA

    Joseph R. Testa

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Broaddus, V.C., Follo, C., Barbone, D. (2017). 3D Models of Mesothelioma in the Study of Mechanisms of Cell Survival. In: Testa, J. (eds) Asbestos and Mesothelioma. Current Cancer Research. Springer, Cham. https://doi.org/10.1007/978-3-319-53560-9_11

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  • DOI: https://doi.org/10.1007/978-3-319-53560-9_11

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