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Published in: Journal of Cancer Research and Clinical Oncology 5/2015

01-05-2015 | Rapid Communication

Evaluation of chemotherapeutics in a three-dimensional breast cancer model

Authors: Carrie J. Lovitt, Todd B. Shelper, Vicky M. Avery

Published in: Journal of Cancer Research and Clinical Oncology | Issue 5/2015

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Abstract

Purpose

Utilization of miniaturized three-dimensional (3D) cell culture-based assays enables investigation into the anticancer activity of drug candidates and further elucidation of the anticancer profile of standard-of-care chemotherapeutic agents against tumor cells. Drug discovery assays established using 3D cell culture, which better recapitulate the tumor microenvironment, may more accurately reflect the antitumor activity of compounds.

Methods

Several standard-of-care anticancer drugs, epirubicin, paclitaxel and vinorelbine, were evaluated against a panel of breast cancer cell lines grown in a 3D cell culture microenvironment in the presence of extracellular matrix. A comparison of this antitumor activity in 3D conditions was made with that observed in traditional two-dimensional (2D) monolayer conditions.

Results

Examination of the above mentioned drugs against breast tumor cells cultured in 3D conditions demonstrated significantly altered potency and efficacy in comparison with cells propagated in a 2D monolayer system. The differences observed were cell line-dependent and drug-specific; the triple-negative cell line MDA-MB-231 and the endocrine receptor-positive cell line MCF-7 consistently displayed resistance to therapeutics with distinct modes of action (i.e., topoisomerase II and microtubules) in 3D cell culture in comparison with ErbB2 receptor-positive BT-474 cells.

Conclusion

The data presented herein demonstrates the cellular viability and physical changes observed within the 3D spheroid following exposure to drug, which is not always reflected in 2D cell culture models.
Literature
go back to reference Barbone D, Yang TM, Morgan JR, Gaudino G, Broaddus VC (2008) Mammalian target of rapamycin contributes to the acquired apoptotic resistance of human mesothelioma multicellular spheroids. J Biol Chem 283(19):13021–13030CrossRefPubMedCentralPubMed Barbone D, Yang TM, Morgan JR, Gaudino G, Broaddus VC (2008) Mammalian target of rapamycin contributes to the acquired apoptotic resistance of human mesothelioma multicellular spheroids. J Biol Chem 283(19):13021–13030CrossRefPubMedCentralPubMed
go back to reference Benton G, Kleinman HK, George J, Arnaoutova I (2011) Multiple uses of basement membrane-like matrix (BME/Matrigel) in vitro and in vivo with cancer cells. Int J Cancer 128(8):1751–1757CrossRefPubMed Benton G, Kleinman HK, George J, Arnaoutova I (2011) Multiple uses of basement membrane-like matrix (BME/Matrigel) in vitro and in vivo with cancer cells. Int J Cancer 128(8):1751–1757CrossRefPubMed
go back to reference Breslin S, O’Driscoll L (2013) Three-dimensional cell culture: the missing link in drug discovery. Drug Discov Today 18(5–6):240–249CrossRefPubMed Breslin S, O’Driscoll L (2013) Three-dimensional cell culture: the missing link in drug discovery. Drug Discov Today 18(5–6):240–249CrossRefPubMed
go back to reference Burdett E, Kasper FK, Mikos AG, Ludwig JA (2010) Engineering tumors: a tissue engineering perspective in cancer biology. Tissue Eng Part B Rev 16(3):351–359CrossRefPubMed Burdett E, Kasper FK, Mikos AG, Ludwig JA (2010) Engineering tumors: a tissue engineering perspective in cancer biology. Tissue Eng Part B Rev 16(3):351–359CrossRefPubMed
go back to reference Fallahi-Sichani M, Honarnejad S, Heiser LM, Gray JW, Sorger PK (2013) Metrics other than potency reveal systematic variation in responses to cancer drugs. Nat Chem Biol 9(11):708–714CrossRefPubMedCentralPubMed Fallahi-Sichani M, Honarnejad S, Heiser LM, Gray JW, Sorger PK (2013) Metrics other than potency reveal systematic variation in responses to cancer drugs. Nat Chem Biol 9(11):708–714CrossRefPubMedCentralPubMed
go back to reference Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin D, Forman D, Bray F (2013) GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Accessed 16 December 2013 Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin D, Forman D, Bray F (2013) GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Accessed 16 December 2013
go back to reference Hickman JA, Graeser R, de Hoogt R, Vidic S, Brito C, Gutekunst M, van der Kuip H (2014) Three-dimensional models of cancer for pharmacology and cancer cell biology: capturing tumor complexity in vitro/ex vivo. Biotechnol J 9(9):1115–1128CrossRefPubMed Hickman JA, Graeser R, de Hoogt R, Vidic S, Brito C, Gutekunst M, van der Kuip H (2014) Three-dimensional models of cancer for pharmacology and cancer cell biology: capturing tumor complexity in vitro/ex vivo. Biotechnol J 9(9):1115–1128CrossRefPubMed
go back to reference Huang S, Pang L (2012) Comparing statistical methods for quantifying drug sensitivity based on in vitro dose-response assays. Assay Drug Dev Technol 10(1):88–96CrossRefPubMed Huang S, Pang L (2012) Comparing statistical methods for quantifying drug sensitivity based on in vitro dose-response assays. Assay Drug Dev Technol 10(1):88–96CrossRefPubMed
go back to reference Huang C, Park CC, Hilsenbeck SG, Ward R, Rimawi MF, Wang YC, Shou J, Bissell MJ, Osborne CK, Schiff R (2011) beta1 integrin mediates an alternative survival pathway in breast cancer cells resistant to lapatinib. Breast Cancer Res 13(4):R84CrossRefPubMedCentralPubMed Huang C, Park CC, Hilsenbeck SG, Ward R, Rimawi MF, Wang YC, Shou J, Bissell MJ, Osborne CK, Schiff R (2011) beta1 integrin mediates an alternative survival pathway in breast cancer cells resistant to lapatinib. Breast Cancer Res 13(4):R84CrossRefPubMedCentralPubMed
go back to reference Kenny PA, Lee GY, Myers CA, Neve RM, Semeiks JR, Spellman PT, Lorenz K, Lee EH, Barcellos-Hoff MH, Petersen OW, Gray JW, Bissell MJ (2007) The morphologies of breast cancer cell lines in three-dimensional assays correlate with their profiles of gene expression. Mol Oncol 1(1):84–96CrossRefPubMedCentralPubMed Kenny PA, Lee GY, Myers CA, Neve RM, Semeiks JR, Spellman PT, Lorenz K, Lee EH, Barcellos-Hoff MH, Petersen OW, Gray JW, Bissell MJ (2007) The morphologies of breast cancer cell lines in three-dimensional assays correlate with their profiles of gene expression. Mol Oncol 1(1):84–96CrossRefPubMedCentralPubMed
go back to reference Kim JB (2005) Three-dimensional tissue culture models in cancer biology. Semin Cancer Biol 15(5):365–377CrossRefPubMed Kim JB (2005) Three-dimensional tissue culture models in cancer biology. Semin Cancer Biol 15(5):365–377CrossRefPubMed
go back to reference Lovitt CJ, Shelper TB, Avery VM (2013) Miniaturized three-dimensional cancer model for drug evaluation. Assay Drug Dev Technol 11(7):435–448CrossRefPubMed Lovitt CJ, Shelper TB, Avery VM (2013) Miniaturized three-dimensional cancer model for drug evaluation. Assay Drug Dev Technol 11(7):435–448CrossRefPubMed
go back to reference Marlow R, Honeth G, Lombardi S, Cariati M, Hessey S, Pipili A, Mariotti V, Buchupalli B, Foster K, Bonnet D, Grigoriadis A, Rameshwar P, Purushotham A, Tutt A, Dontu G (2013) A novel model of dormancy for bone metastatic breast cancer cells. Cancer Res 73(23):6886–6899CrossRefPubMed Marlow R, Honeth G, Lombardi S, Cariati M, Hessey S, Pipili A, Mariotti V, Buchupalli B, Foster K, Bonnet D, Grigoriadis A, Rameshwar P, Purushotham A, Tutt A, Dontu G (2013) A novel model of dormancy for bone metastatic breast cancer cells. Cancer Res 73(23):6886–6899CrossRefPubMed
go back to reference Meads MB, Gatenby RA, Dalton WS (2009) Environment-mediated drug resistance: a major contributor to minimal residual disease. Nat Rev Cancer 9(9):665–674CrossRefPubMed Meads MB, Gatenby RA, Dalton WS (2009) Environment-mediated drug resistance: a major contributor to minimal residual disease. Nat Rev Cancer 9(9):665–674CrossRefPubMed
go back to reference Muranen T, Selfors LM, Worster DT, Iwanicki MP, Song L, Morales FC, Gao S, Mills GB, Brugge JS (2012) Inhibition of PI3 K/mTOR leads to adaptive resistance in matrix-attached cancer cells. Cancer Cell 21(2):227–239CrossRefPubMedCentralPubMed Muranen T, Selfors LM, Worster DT, Iwanicki MP, Song L, Morales FC, Gao S, Mills GB, Brugge JS (2012) Inhibition of PI3 K/mTOR leads to adaptive resistance in matrix-attached cancer cells. Cancer Cell 21(2):227–239CrossRefPubMedCentralPubMed
go back to reference Nicolini A, Giardino R, Carpi A, Ferrari P, Anselmi L, Colosimo S, Conte M, Fini M, Giavaresi G, Berti P, Miccoli P (2006) Metastatic breast cancer: an updating. Biomed Pharmacother 60(9):548–556CrossRefPubMed Nicolini A, Giardino R, Carpi A, Ferrari P, Anselmi L, Colosimo S, Conte M, Fini M, Giavaresi G, Berti P, Miccoli P (2006) Metastatic breast cancer: an updating. Biomed Pharmacother 60(9):548–556CrossRefPubMed
go back to reference Nirmalanandhan VS, Duren A, Hendricks P, Vielhauer G, Sittampalam GS (2010) Activity of anticancer agents in a three-dimensional cell culture model. Assay Drug Dev Technol 27:27 Nirmalanandhan VS, Duren A, Hendricks P, Vielhauer G, Sittampalam GS (2010) Activity of anticancer agents in a three-dimensional cell culture model. Assay Drug Dev Technol 27:27
go back to reference Sethi T, Rintoul RC, Moore SM, MacKinnon AC, Salter D, Choo C, Chilvers ER, Dransfield I, Donnelly SC, Strieter R, Haslett C (1999) Extracellular matrix proteins protect small cell lung cancer cells against apoptosis: a mechanism for small cell lung cancer growth and drug resistance in vivo. Nat Med 5(6):662–668CrossRefPubMed Sethi T, Rintoul RC, Moore SM, MacKinnon AC, Salter D, Choo C, Chilvers ER, Dransfield I, Donnelly SC, Strieter R, Haslett C (1999) Extracellular matrix proteins protect small cell lung cancer cells against apoptosis: a mechanism for small cell lung cancer growth and drug resistance in vivo. Nat Med 5(6):662–668CrossRefPubMed
go back to reference Sodunke TR, Turner KK, Caldwell SA, McBride KW, Reginato MJ, Noh HM (2007) Micropatterns of Matrigel for three-dimensional epithelial cultures. Biomaterials 28(27):4006–4016CrossRefPubMed Sodunke TR, Turner KK, Caldwell SA, McBride KW, Reginato MJ, Noh HM (2007) Micropatterns of Matrigel for three-dimensional epithelial cultures. Biomaterials 28(27):4006–4016CrossRefPubMed
go back to reference Vinci M, Gowan S, Boxall F, Patterson L, Zimmermann M, Court W, Lomas C, Mendiola M, Hardisson D, Eccles SA (2012) Advances in establishment and analysis of 3D tumour spheroid-based functional assays for target validation and drug evaluation. BMC Biol 10(1):29CrossRefPubMedCentralPubMed Vinci M, Gowan S, Boxall F, Patterson L, Zimmermann M, Court W, Lomas C, Mendiola M, Hardisson D, Eccles SA (2012) Advances in establishment and analysis of 3D tumour spheroid-based functional assays for target validation and drug evaluation. BMC Biol 10(1):29CrossRefPubMedCentralPubMed
go back to reference Weigelt B, Lo AT, Park CC, Gray JW, Bissell MJ (2009) HER2 signaling pathway activation and response of breast cancer cells to HER2-targeting agents is dependent strongly on the 3D microenvironment. Breast Cancer Res Treat 122:35–43CrossRefPubMedCentralPubMed Weigelt B, Lo AT, Park CC, Gray JW, Bissell MJ (2009) HER2 signaling pathway activation and response of breast cancer cells to HER2-targeting agents is dependent strongly on the 3D microenvironment. Breast Cancer Res Treat 122:35–43CrossRefPubMedCentralPubMed
go back to reference Weigelt B, Ghajar CM, Bissell MJ (2014) The need for complex 3D culture models to unravel novel pathways and identify accurate biomarkers in breast cancer. Adv Drug Deliv Rev 69–70C:42–51CrossRef Weigelt B, Ghajar CM, Bissell MJ (2014) The need for complex 3D culture models to unravel novel pathways and identify accurate biomarkers in breast cancer. Adv Drug Deliv Rev 69–70C:42–51CrossRef
Metadata
Title
Evaluation of chemotherapeutics in a three-dimensional breast cancer model
Authors
Carrie J. Lovitt
Todd B. Shelper
Vicky M. Avery
Publication date
01-05-2015
Publisher
Springer Berlin Heidelberg
Published in
Journal of Cancer Research and Clinical Oncology / Issue 5/2015
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI
https://doi.org/10.1007/s00432-015-1950-1

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