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BMC Cancer
Published in: BMC Cancer 1/2013

Open Access 01-12-2013 | Research article

Multicellular tumor spheroid models to explore cell cycle checkpoints in 3D

Authors: Jennifer Laurent, Céline Frongia, Martine Cazales, Odile Mondesert, Bernard Ducommun, Valérie Lobjois

Published in: BMC Cancer | Issue 1/2013

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Abstract

Background

MultiCellular Tumor Spheroid (MCTS) mimics the organization of a tumor and is considered as an invaluable model to study cancer cell biology and to evaluate new antiproliferative drugs. Here we report how the characteristics of MCTS in association with new technological developments can be used to explore the regionalization and the activation of cell cycle checkpoints in 3D.

Methods

Cell cycle and proliferation parameters were investigated in Capan-2 spheroids by immunofluorescence staining, EdU incorporation and using cells engineered to express Fucci-red and -green reporters.

Results

We describe in details the changes in proliferation and cell cycle parameters during spheroid growth and regionalization. We report the kinetics and regionalized aspects of cell cycle arrest in response to checkpoint activation induced by EGF starvation, lovastatin treatment and etoposide-induced DNA damage.

Conclusion

Our data present the power and the limitation of spheroids made of genetically modified cells to explore cell cycle checkpoints. This study paves the way for the investigation of molecular aspects and dynamic studies of the response to novel antiproliferative agents in 3D models.
Appendix
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Literature
1.
Dubessy C, Merlin JM, Marchal C, Guillemin F: Spheroids in radiobiology and photodynamic therapy. Crit Rev Oncol Hematol. 2000, 36 (2-3): 179-192. 10.1016/S1040-8428(00)00085-8.CrossRefPubMed
2.
Sutherland RM: Cell and environment interactions in tumor microregions: the multicell spheroid model. Science. 1988, 240 (4849): 177-184. 10.1126/science.2451290.CrossRefPubMed
3.
Friedrich J, Ebner R, Kunz-Schughart LA: Experimental anti-tumor therapy in 3-D: spheroids-old hat or new challenge?. Int J Radiat Biol. 2007, 83 (11-12): 849-871. 10.1080/09553000701727531.CrossRefPubMed
4.
Hirschhaeuser F, Menne H, Dittfeld C, West J, Mueller-Klieser W, Kunz-Schughart LA: Multicellular tumor spheroids: an underestimated tool is catching up again. J Biotechnol. 2010, 148 (1): 3-15. 10.1016/j.jbiotec.2010.01.012.CrossRefPubMed
5.
Desoize B, Jardillier J: Multicellular resistance: a paradigm for clinical resistance?. Crit Rev Oncol Hematol. 2000, 36 (2-3): 193-207. 10.1016/S1040-8428(00)00086-X.CrossRefPubMed
6.
Kunz-Schughart LA, Freyer JP, Hofstaedter F, Ebner R: The use of 3-D cultures for high-throughput screening: the multicellular spheroid model. J Biomol Screen. 2004, 9 (4): 273-285. 10.1177/1087057104265040.CrossRefPubMed
7.
Dai Y, Grant S: New insights into checkpoint kinase 1 in the DNA damage response signaling network. Clin Cancer Res. 2010, 16 (2): 376-383. 10.1158/1078-0432.CCR-09-1029.CrossRefPubMedPubMedCentral
8.
Malumbres M, Barbacid M: Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer. 2009, 9 (3): 153-166.CrossRefPubMed
9.
Degenhardt Y, Lampkin T: Targeting Polo-like kinase in cancer therapy. Clin Cancer Res. 2010, 16 (2): 384-389. 10.1158/1078-0432.CCR-09-1380.CrossRefPubMed
10.
Hanahan D, Weinberg RA: Hallmarks of cancer: the next generation. Cell. 2011, 144 (5): 646-674. 10.1016/j.cell.2011.02.013.CrossRefPubMed
11.
Carpinelli P, Moll J: Aurora kinases and their inhibitors: more than one target and one drug. Adv Exp Med Biol. 2008, 610: 54-73. 10.1007/978-0-387-73898-7_5.CrossRefPubMed
12.
Cicenas J, Valius M: The CDK inhibitors in cancer research and therapy. J Cancer Res Clin Oncol. 2011, 137 (10): 1409-1418. 10.1007/s00432-011-1039-4.CrossRefPubMed
13.
14.
Vassilev LT: Cell cycle synchronization at the G2/M phase border by reversible inhibition of CDK1. Cell Cycle. 2006, 5 (22): 2555-2556. 10.4161/cc.5.22.3463.CrossRefPubMed
15.
Carrassa L, Damia G: Unleashing Chk1 in cancer therapy. Cell Cycle. 2011, 10 (13): 2121-2128. 10.4161/cc.10.13.16398.CrossRefPubMed
16.
Ma CX, Janetka JW, Piwnica-Worms H: Death by releasing the breaks: CHK1 inhibitors as cancer therapeutics. Trends Mol Med. 2011, 17 (2): 88-96. 10.1016/j.molmed.2010.10.009.CrossRefPubMed
17.
Dufau I, Frongia C, Sicard F, Dedieu L, Cordelier P, Ausseil F, Ducommun B, Valette A: Multicellular Tumor Spheroid model to evaluate spatio-temporal dynamics effect of chemotherapeutics. Application to the gemcitabine / CHK1 inhibitor combination in pancreatic cancer. BMC Cancer. 2012, 12 (1): 15-10.1186/1471-2407-12-15.CrossRefPubMedPubMedCentral
18.
Yerushalmi R, Woods R, Ravdin PM, Hayes MM, Gelmon KA: Ki67 in breast cancer: prognostic and predictive potential. Lancet Oncol. 2010, 11 (2): 174-183. 10.1016/S1470-2045(09)70262-1.CrossRefPubMed
19.
Sakaue-Sawano A, Kurokawa H, Morimura T, Hanyu A, Hama H, Osawa H, Kashiwagi S, Fukami K, Miyata T, Miyoshi H: Visualizing spatiotemporal dynamics of multicellular cell-cycle progression. Cell. 2008, 132 (3): 487-498. 10.1016/j.cell.2007.12.033.CrossRefPubMed
20.
Javanmoghadam-Kamrani S, Keyomarsi K: Synchronization of the cell cycle using lovastatin. Cell Cycle. 2008, 7 (15): 2434-2440.CrossRefPubMed
21.
Zhong WB, Hsu SP, Ho PY, Liang YC, Chang TC, Lee WS: Lovastatin inhibits proliferation of anaplastic thyroid cancer cells through up-regulation of p27 by interfering with the Rho/ROCK-mediated pathway. Biochem Pharmacol. 2011, 82 (11): 1663-1672. 10.1016/j.bcp.2011.08.021.CrossRefPubMed
22.
LaRue KE, Khalil M, Freyer JP: Microenvironmental regulation of proliferation in multicellular spheroids is mediated through differential expression of cyclin-dependent kinase inhibitors. Cancer Res. 2004, 64 (5): 1621-1631. 10.1158/0008-5472.CAN-2902-2.CrossRefPubMed
23.
Xouri G, Lygerou Z, Nishitani H, Pachnis V, Nurse P, Taraviras S: Cdt1 and geminin are down-regulated upon cell cycle exit and are over-expressed in cancer-derived cell lines. Eur J Biochem. 2004, 271 (16): 3368-3378. 10.1111/j.1432-1033.2004.04271.x.CrossRefPubMed
24.
Frongia C, Lorenzo C, Gianni F, Prevost GP, Ducommun B, Lobjois V: 3D imaging of the response to CDC25 inhibition in multicellular spheroids. Cancer Biol Ther. 2009, 8 (23): 2230-2236.CrossRefPubMed
25.
Walker F, Zhang HH, Burgess AW: Identification of a novel EGF-sensitive cell cycle checkpoint. Exp Cell Res. 2007, 313 (3): 511-526. 10.1016/j.yexcr.2006.10.026.CrossRefPubMed
Metadata
Title
Multicellular tumor spheroid models to explore cell cycle checkpoints in 3D
Authors
Jennifer Laurent
Céline Frongia
Martine Cazales
Odile Mondesert
Bernard Ducommun
Valérie Lobjois
Publication date
01-12-2013
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2013
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-13-73

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