Biomarkers for simplifying HTS 3D cell culture platforms for drug discovery: the case for cytokines
Abstract
In this review, we discuss the microenvironmental cues that modulate the status of cells to yield physiologically more relevant three-dimensional (3D) cell-based high throughput drug screening (HTS) platforms for drug discovery. Evidence is provided to support the view that simplifying 3D cell culture platforms for HTS applications calls for identifying and validating ubiquitous three-dimensionality biomarkers. Published results from avascular tumorigenesis and early stages of inflammatory wound healing, where cells transition from a two-dimensional (2D) to 3D microenvironment, conclusively report regulation by cytokines, providing the physiological basis for focusing on cytokines as potential three-dimensionality biomarkers. We discuss additional support for cytokines that comes from numerous 2D and 3D comparative transcriptomic and proteomic studies, which generally report upregulation of cytokines in 3D compared with 2D culture counterparts.
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Others seek to develop a reproducible 3D cell culture platform for high throughput screening through the identification and validation of ubiquitous three-dimensionality biomarkers, such as the cytokine family.
“Others seek simply to develop a reproducible 3D cell culture platform for high throughput screening through the identification and validation of ubiquitous three-dimensionality biomarkers, such as the cytokine family. 72”
From Three-dimensional cell culture systems and their applications in drug discovery and cell-based biosensors (2014) · cites this paper as [72]
Cites
Coussens, L. M., & Werb, Z. (2002) · Nature · doi:10.1038/nature01322 · Cited by 15,111 · see citing works
Tissue Cells Feel and Respond to the Stiffness of Their Substrate
Discher, D. E., Janmey, P., & Wang, Y.-L. (2005) · Science · doi:10.1126/science.1116995 · Cited by 6,382 · see citing works
Reconstituting organ-level lung functions on a chip
Huh, D., Matthews, B. D., Mammoto, A., Montoya-Zavala, M., Hsin, H. Y., & Ingber, D. E. (2010) · Science · doi:10.1126/science.1188302 · Cited by 4,250 · see citing works
The third dimension bridges the gap between cell culture and live tissue
Pampaloni, F., Reynaud, E. G., & Stelzer, E. H. K. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2236 · Cited by 2,817 · see citing works
Capturing complex 3D tissue physiology in vitro
Griffith, L. G., & Swartz, M. A. (2006) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1858 · Cited by 2,274 · see citing works
Modeling Tissue Morphogenesis and Cancer in 3D
Yamada, K. M., & Cukierman, E. (2007) · Cell · doi:10.1016/j.cell.2007.08.006 · Cited by 1,751 · see citing works
Weaver, V. M., Petersen, O. W., Wang, F., Larabell, C. A., Briand, P., Damsky, C., & Bissell, M. J. (1997) · The Journal of Cell Biology · doi:10.1083/jcb.137.1.231 · Cited by 1,483 · see citing works
Compensation mechanism in tumor cell migration
Wolf, K., Mazo, I. B., Leung, H. C. H., Engelke, K., von Andrian, U. H., Deryugina, E. I., Strongin, A. Y., Bröcker, E., & Friedl, P. (2003) · The Journal of Cell Biology · doi:10.1083/jcb.200209006 · Cited by 1,392 · see citing works
Three-dimensional culture models of normal and malignant breast epithelial cells
Lee, G. Y., Kenny, P. A., Lee, E. H., & Bissell, M. J. (2007) · Nature Methods · doi:10.1038/nmeth1015 · Cited by 1,336 · see citing works
Zaman, M. H., Trapani, L. M., Sieminski, A. L., MacKellar, D. C., Gong, H., Kamm, R. D., Wells, A. H., Lauffenburger, D. A., & Matsudaira, P. T. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0604460103 · Cited by 1,159 · see citing works
Substrate Modulus Directs Neural Stem Cell Behavior
Saha, K., Keung, A. J., Irwin, E. F., Li, Y., Little, L., Schaffer, D. V., & Healy, K. E. (2008) · Biophysical Journal · doi:10.1529/biophysj.108.132217 · Cited by 1,096 · see citing works
Mechanical regulation of cell function with geometrically modulated elastomeric substrates
Fu, J., Wang, Y.-K., Yang, M. T., Desai, R. A., Yu, X., Liu, Z., & Chen, C. S. (2010) · Nature Methods · doi:10.1038/nmeth.1487 · Cited by 1,073 · see citing works
Engineering tumors with 3D scaffolds
Fischbach, C., Chen, R., Matsumoto, T., Schmelzle, T., Brugge, J. S., Polverini, P. J., & Mooney, D. J. (2007) · Nature Methods · doi:10.1038/nmeth1085 · Cited by 823 · see citing works
The use of 3-d cultures for high-throughput screening: the multicellular spheroid model.
Kunz-Schughart, L. A., Freyer, J. P., Hofstaedter, F., & Ebner, R. (2004) · SLAS DISCOVERY · doi:10.1177/1087057104265040 · Cited by 797 · see citing works
Wilkening, S., Stahl, F., & Bader, A. (2003) · Drug Metabolism and Disposition · doi:10.1124/dmd.31.8.1035 · Cited by 794 · see citing works
Probing the role of multicellular organization in three-dimensional microenvironments
Albrecht, D. R., Underhill, G. H., Wassermann, T., Sah, R. L., & Bhatia, S. N. (2006) · Nature Methods · doi:10.1038/nmeth873 · Cited by 553 · see citing works
3D cell culture opens new dimensions in cell-based assays
Justice, B. A., Badr, N. A., & Felder, R. A. (2008) · Drug Discovery Today · doi:10.1016/j.drudis.2008.11.006 · Cited by 340 · see citing works
Ghosh, S., Spagnoli, G. C., Martin, I., Ploegert, S., Demougin, P., Heberer, M., & Reschner, A. (2005) · Journal of Cellular Physiology · doi:10.1002/jcp.20320 · Cited by 326 · see citing works
Cancer cell angiogenic capability is regulated by 3D culture and integrin engagement
Fischbach, C., Kong, H. J., Hsiong, S. X., Evangelista, M. B., Yuen, W. W., & Mooney, D. J. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0808932106 · Cited by 312 · see citing works
Acquired multicellular-mediated resistance to alkylating agents in cancer.
Kobayashi, H., Man, S., Graham, C. H., Kapitain, S. J., Teicher, B. A., & Kerbel, R. S. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.8.3294 · Cited by 277 · see citing works
Liver-Specific Functional Studies in a Microfluidic Array of Primary Mammalian Hepatocytes
Kane, B. J., Zinner, M. J., Yarmush, M. L., & Toner, M. (2006) · Analytical Chemistry · doi:10.1021/ac051856v · Cited by 265 · see citing works
Baker, S. C., Atkin, N. J., Gunning, P. A., et al. (2006) · Biomaterials · doi:10.1016/j.biomaterials.2006.01.026 · Cited by 262 · see citing works
Structural Polarity and Functional Bile Canaliculi in Rat Hepatocyte Spheroids
Abu-Absi, S. F., Friend, J. R., Hansen, L. K., & Hu, W. (2002) · Experimental Cell Research · doi:10.1006/excr.2001.5467 · Cited by 230 · see citing works
Tumor biology and experimental therapeutics
Mueller‐Klieser, W. (2000) · Critical Reviews in Oncology/Hematology · doi:10.1016/s1040-8428(00)00082-2 · Cited by 217 · see citing works
Dimensions and dynamics in integrin function
Yamada, K. M., Pankov, R. G., & Cukierman, E. (2003) · Brazilian Journal of Medical and Biological Research · doi:10.1590/s0100-879x2003000800001 · Cited by 192 · see citing works
Stofega, M. R., Sanders, L. C., Gardiner, E. M. M., et al. (2004) · Molecular Biology of the Cell · doi:10.1091/mbc.e03-08-0604 · Cited by 66 · see citing works
Morsiani, E., Brogli, M., Galavotti, D., Bellini, T., Ricci, D., Pazzi, P., & Puviani, A. C. (2001) · Artificial Organs · doi:10.1046/j.1525-1594.2001.06669.x · Cited by 61 · see citing works
Global gene expression of cells attached to a tissue engineering scaffold
Klapperich, C. M., & Bertozzi, C. R. (2004) · Biomaterials · doi:10.1016/j.biomaterials.2004.01.025 · Cited by 55 · see citing works
Clustering of fibroblasts induces proinflammatory chemokine secretion promoting leukocyte migration
Enzerink, A., Salmenperä, P., Kankuri, E. M., et al. (2009) · Molecular Immunology · doi:10.1016/j.molimm.2009.01.018 · Cited by 52 · see citing works
Accelerated formation of multicellular 3‐D structures by cell‐to‐cell cross‐linking
Bank, P. D., Hou, Q., Warner, R. M., Wood, I. V., Ali, B. E., MacNeil, S., Kendall, D. A., Kellam, B., Shakesheff, K. M., & Buttery, L. D. K. (2007) · Biotechnology and Bioengineering · doi:10.1002/bit.21343 · Cited by 38 · see citing works
SU-8 microstructure for quasi-three-dimensional cell-based biosensing
Wang, L., Wu, Z., Xu, B., et al. (2009) · Sensors and Actuators B Chemical · doi:10.1016/j.snb.2009.05.009 · Cited by 24 · see citing works
Miyashita, T., Enosawa, S., Suzuki, S., et al. (2000) · Transplantation Proceedings · doi:10.1016/s0041-1345(00)01697-3 · Cited by 22 · see citing works
Wang, L., & Kisaalita, W. S. (2010) · Journal of Biomedical Materials Research Part B Applied Biomaterials · doi:10.1002/jbm.b.31646 · Cited by 18 · see citing works
Self-citationKisaalita, W. S. (2010) · Thammasat University Digital Collections · Cited by 11 · see citing works
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Edmondson, R., Broglie, J. J., Adcock, A. F., & Yang, L. (2014) · ASSAY and Drug Development Technologies · doi:10.1089/adt.2014.573 · Cited by 2,515 · see citing works
Lei, K. F., Wu, M.-H., Hsu, C.-W., & Chen, Y.-D. (2014) · Biosensors and Bioelectronics · doi:10.1016/j.bios.2013.07.031 · Cited by 111 · see citing works
- Authors
- Lai, Y., Asthana, A., & Kisaalita, W. S.
- Affiliations
- University of Georgia (US)
- Corresponding author
- Kisaalita, William S.
- Venue
- Drug Discovery Today
- Publisher
- Elsevier BV
- Published
- 2011-04
- Volume
- 16
- Issue
- 7-8
- Pages
- 293-297
- ISSN
- 1359-6446 (ISSN-L)
- OpenAlex
- W2034085946
- Cited by
- 43
- References
- 34
- Citations by year
- 2026: 2 · 2025: 3 · 2023: 1 · 2022: 4 · 2021: 1 · 2020: 3 · 2019: 3 · 2018: 3 · 2017: 5 · 2016: 2 · 2015: 2 · 2014: 3 · 2013: 5 · 2012: 5
- FWCI
- 0.36
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Drug Discovery Today (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- 3D cell culture, high-throughput screening, cytokines, tumor microenvironment, wound healing, transcriptomics, proteomics
- MeSH terms
- Drug Evaluation, Preclinical, Humans, Biomarkers, Cytokines, Cell Culture Techniques, Drug Discovery, High-Throughput Screening Assays
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