Impact of the 3D Microenvironment on Phenotype, Gene Expression, and EGFR Inhibition of Colorectal Cancer Cell Lines
Open accessAbstract
Three-dimensional (3D) tumor cell cultures grown in laminin-rich-extracellular matrix (lrECM) are considered to reflect human tumors more realistic as compared to cells grown as monolayer on plastic. Here, we systematically investigated the impact of ECM on phenotype, gene expression, EGFR signaling pathway, and on EGFR inhibition in commonly used colorectal cancer (CRC) cell lines. LrECM on-top (3D) culture assays were performed with the CRC cell lines SW-480, HT-29, DLD-1, LOVO, CACO-2, COLO-205 and COLO-206F. Morphology of lrECM cultivated CRC cell lines was determined by phase contrast and confocal laser scanning fluorescence microscopy. Proliferation of cells was examined by MTT assay, invasive capacity of the cell lines was assayed using Matrigel-coated Boyden chambers, and migratory activity was determined employing the Fence assay. Differential gene expression was analyzed at the transcriptional level by the Agilent array platform. EGFR was inhibited by using the specific small molecule inhibitor AG1478. A specific spheroid growth pattern was observed for all investigated CRC cell lines. DLD-1, HT-29 and SW-480 and CACO-2 exhibited a clear solid tumor cell formation, while LOVO, COLO-205 and COLO-206F were characterized by forming grape-like structures. Although the occurrence of a spheroid morphology did not correlate with an altered migratory, invasive, or proliferative capacity of CRC cell lines, gene expression was clearly altered in cells grown on lrECM as compared to 2D cultures. Interestingly, in KRAS wild-type cell lines, inhibition of EGFR was less effective in lrECM (3D) cultures as compared to 2D cell cultures. Thus, comparing both 2D and 3D cell culture models, our data support the influence of the ECM on cancer growth. Compared to conventional 2D cell culture, the lrECM (3D) cell culture model offers the opportunity to investigate permanent CRC cell lines under more physiological conditions, i.e. in the context of molecular therapeutic targets and their pharmacological inhibition.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Proliferation rates of cells cultured in 3D and 2D are usually different and are cell line and matrix dependent.
“The proliferation rates of cells cultured in 3D and 2D are usually different, and are cell line and matrix dependent.”
From Three-dimensional cell culture systems and their applications in drug discovery and cell-based biosensors (2014) · cites this paper as [29]
The Results section (page unavailable) reports significantly lower proliferation in 3D lrECM culture than in 2D culture, and the Discussion says this occurred in all CRC cell lines tested. The paper compares one 3D matrix with plastic; it does not establish that the difference is usually present across cell types or depends on the cell line or matrix used. (LLM, conf=0.85)
Experimental — accuracy not yet measuredOverall, the morphological appearance of 3D spheroids is primarily cell line dependent.
“Overall, the morphological appearance of 3D spheroids is primarily cell line dependent. 29,35,37”
From Three-dimensional cell culture systems and their applications in drug discovery and cell-based biosensors (2014) · cites this paper as [29]
A variety of cell lines showed reduced proliferation rate in 3D cultures compared to those cultured in 2D.
“A variety of cell lines showed reduced proliferation rate in 3D cultures compared to those cultured in 2D. 17,27-31”
From Three-dimensional cell culture systems and their applications in drug discovery and cell-based biosensors (2014) · cites this paper as [29]
In hepatocellular carcinoma models, monolayers showed enrichment in structural gene expression, whereas spheroids upregulated genes related to metabolism and biosynthesis.
“A similar trend was observed in hepatocellular carcinoma models, where monolayers showed enrichment in structural gene expression, whereas spheroids upregulated genes related to metabolism and biosynthesis [196,197,198].”
From Modeling Tumor Microenvironment Complexity In Vitro: Spheroids as Physiologically Relevant Tumor Models and Strategies for Their Analysis (2025) · cites this paper as [197]
The Results section, “Gene Expression is Altered in lrECM 3D ‘On-top’ Cultivated CRC Cells” (page unavailable), compares 2D and 3D colorectal cancer cultures and reports differential gene expression, including genes in a metabolic pathway. It does not address hepatocellular carcinoma models or establish the claimed direction of structural-gene enrichment and metabolism/biosynthesis upregulation. Searches for hepatocellular carcinoma and those gene categories found no passage supporting the specific claim. (LLM, conf=0.75)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT Method
Livak, K. J., & Schmittgen, T. D. (2001) · Methods · doi:10.1006/meth.2001.1262 · Cited by 180,860 · see citing works
Integrins: Versatility, modulation, and signaling in cell adhesion
Hynes, R. O. (1992) · Cell · doi:10.1016/0092-8674(92)90115-s · Cited by 9,857 · see citing works
Di Nicolantonio, F., Martini, M., Molinari, F., Sartore-Bianchi, A., Arena, S., Saletti, P., De Dosso, S., Mazzucchelli, L., Frattini, M., Siena, S., et al. (2008) · Journal of Clinical Oncology · doi:10.1200/jco.2008.18.0786 · Cited by 1,591 · cited 1× · see citing works
“KRAS and BRAF mutational status of patients is usually assessed before EGFR treatment on the basis that only patients exhibiting BRAF and KRAS wild type profit from treatments with anti-EGFR therapies [29,30].”
BackgroundThree-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
Kleinman, H. K., McGarvey, M. L., Liotta, L. A., Robey, P. G., Tryggvason, K., & Martin, G. R. (1982) · Biochemistry · doi:10.1021/bi00267a025 · Cited by 1,231 · see citing works
Basement membrane complexes with biological activity
Kleinman, H. K., McGarvey, M. L., Hassell, J. R., Star, V. L., Cannon, F. B., Laurie, G. W., & Martin, G. R. (1986) · Biochemistry · doi:10.1021/bi00350a005 · Cited by 1,164 · see citing works
PETERSEN, O. W., Rønnov‐Jessen, L., Howlett, A. R., & Bissell, M. J. (1992) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.89.19.9064 · Cited by 1,096 · see citing works
Kenny, P. A., Lee, G. Y., Myers, C. A., Neve, R. M., Semeiks, J. R., Spellman, P. T., Lorenz, K., Lee, E. H., Barcellos‐Hoff, M. H., PETERSEN, O. W., et al. (2008) · eScholarship (California Digital Library) · Cited by 1,039 · see citing works
Benvenuti, S., Sartore-Bianchi, A., Di Nicolantonio, F., Zanon, C., Moroni, M., Veronese, S., Siena, S., & Bardelli, A. (2007) · Cancer Research · doi:10.1158/0008-5472.can-06-4158 · Cited by 830 · see citing works
Weaver, V. M., Lelièvre, S. A., Lakins, J. N., Chrenek, M. A., Jones, J., Giancotti, F. G., Werb, Z., & Bissell, M. J. (2002) · Cancer Cell · doi:10.1016/s1535-6108(02)00125-3 · Cited by 794 · see citing works
The organizing principle: microenvironmental influences in the normal and malignant breast
Bissell, M. J., Radisky, D. C., Rizki, A., Weaver, V. M., & PETERSEN, O. W. (2002) · Differentiation · doi:10.1046/j.1432-0436.2002.700907.x · Cited by 602 · see citing works
Cell line-based platforms to evaluate the therapeutic efficacy of candidate anticancer agents
Sharma, S. V., Haber, D. A., & Settleman, J. (2010) · Nature reviews. Cancer · doi:10.1038/nrc2820 · Cited by 585 · see citing works
Modeling tissue-specific signaling and organ function in three dimensions
Schmeichel, K. L., & Bissell, M. J. (2003) · Journal of Cell Science · doi:10.1242/jcs.00503 · Cited by 583 · see citing works
Baldus, S. E., Schaefer, K.-L., Engers, R., Hartleb, D., Stoecklein, N. H., & Gabbert, H. E. (2010) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-09-2446 · Cited by 432 · see citing works
Self-citationPickl, M., & Ries, C. H. (2008) · Oncogene · doi:10.1038/onc.2008.394 · Cited by 403 · see citing works
Human cancer cell lines: fact and fantasy
Masters, J. R. W. (2000) · Nature Reviews Molecular Cell Biology · doi:10.1038/35043102 · Cited by 352 · see citing works
Weigelt, B., Lo, A. T., Park, C. C., Gray, J. W., & Bissell, M. J. (2009) · Breast Cancer Research and Treatment · doi:10.1007/s10549-009-0502-2 · Cited by 336 · see citing works
Yurchenco, P. D., & O’Rear, J. J. (1994) · Current Opinion in Cell Biology · doi:10.1016/0955-0674(94)90093-0 · Cited by 319 · see citing works
Bissell, M. J., Kenny, P. A., & Radisky, D. C. (2005) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2005.70.013 · Cited by 297 · see citing works
The extracellular matrix: At the center of it all
Bowers, S., Banerjee, I., & Baudino, T. A. (2009) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2009.08.024 · Cited by 277 · see citing works
Yurchenco, P. D. (1992) · The Journal of Cell Biology · doi:10.1083/jcb.117.5.1119 · Cited by 268 · see citing works
The Wnt/β-catenin pathway regulates growth and maintenance of colonospheres
Kanwar, S. S., Yu, Y., Nautiyal, J., Patel, B. B., & Majumdar, A. P. N. (2010) · Molecular Cancer · doi:10.1186/1476-4598-9-212 · Cited by 253 · see citing works
Nidogen mediates the formation of ternary complexes of basement membrane components
Aumailley, M., Battaglia, C., Mayer, U., Reinhardt, D. P., Nischt, R., Timpl, R., & Fox, J. W. (1993) · Kidney International · doi:10.1038/ki.1993.3 · Cited by 178 · see citing works
Hayashi, K., Madri, J. A., & Yurchenco, P. D. (1992) · The Journal of Cell Biology · doi:10.1083/jcb.119.4.945 · Cited by 178 · see citing works
Ottaviano, L., Schaefer, K., Gajewski, M., Huckenbeck, W., Baldus, S. E., Rogel, U., Mackintosh, C., de Álava, E., Myklebost, O., Kresse, S. H., et al. (2009) · Genes Chromosomes and Cancer · doi:10.1002/gcc.20717 · Cited by 173 · see citing works
Self-citationExtracellular matrix control of mammary gland morphogenesis and tumorigenesis: insights from imaging
Ghajar, C. M., & Bissell, M. J. (2008) · Histochemistry and Cell Biology · doi:10.1007/s00418-008-0537-1 · Cited by 161 · see citing works
Advancing science and technology via 3D culture on basement membrane matrix
Benton, G., George, J., Kleinman, H. K., & Arnaoutova, I. (2009) · Journal of Cellular Physiology · doi:10.1002/jcp.21832 · Cited by 151 · see citing works
Variant glycosylation: an underappreciated regulatory mechanism for β1 integrins
Bellis, S. L. (2004) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2004.03.012 · Cited by 150 · see citing works
Li, Q., Chow, A. B., & Mattingly, R. R. (2009) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.109.160390 · Cited by 77 · see citing works
Glycosylation is crucial for stability of tumour and cancer stem cell antigen EpCAM
Münz, M. (2008) · Frontiers in bioscience · doi:10.2741/3075 · Cited by 73 · see citing works
Three-dimensional extracellular matrix culture models of EGFR signalling and drug response
Kenny, P. A. (2007) · Biochemical Society Transactions · doi:10.1042/bst0350665 · Cited by 30 · see citing works
Kenny, P. A., Lee, G. Y., Myers, C. A., Neve, R. M., Semeiks, J. R., Spellman, P. T., Lorenz, K., Lee, E. H., Barcellos-Hoff, M. H., Petersen, O. W., et al. (2007) · Molecular Oncology · doi:10.1016/j.molonc.2007.02.004 · Cited by 2 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
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
3D Cell Culture Systems: Advantages and Applications
Ravi, M., Paramesh, V., Kaviya, S. R., Anuradha, E., & Solomon, F. D. P. (2015) · Journal of Cellular Physiology · doi:10.1002/jcp.24683 · Cited by 1,206 · see citing works
3D tumor spheroids: an overview on the tools and techniques used for their analysis
Costa, E. C., Moreira, A. F., de Melo-Diogo, D., Gaspar, V. M., Carvalho, M. P., & Correia, I. J. (2016) · Biotechnology Advances · doi:10.1016/j.biotechadv.2016.11.002 · Cited by 929 · see citing works
In Vitro Tumor Models: Advantages, Disadvantages, Variables, and Selecting the Right Platform
Katt, M. E., Placone, A. L., Wong, A. D., Xu, Z. S., & Searson, P. C. (2016) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2016.00012 · Cited by 754 · see citing works
3D In Vitro Model (R)evolution: Unveiling Tumor–Stroma Interactions
Rodrigues, J., Heinrich, M. A., Teixeira, L. M., & Prakash, J. (2021) · Trends in Cancer · doi:10.1016/j.trecan.2020.10.009 · Cited by 405 · see citing works
“Gene expression Cell adhesion-, proliferation-, and survival-related genes are usually modified Accurate representation of gene expression patterns [16,85,86]”
BackgroundRiedl, A., Schlederer, M., Pudelko, K., Stadler, M., Walter, S., Unterleuthner, D., Unger, C., Kramer, N., Hengstschläger, M., Kenner, L., et al. (2016) · Journal of Cell Science · doi:10.1242/jcs.188102 · Cited by 389 · see citing works
Białkowska, K., Komorowski, P., Bryszewska, M., & Miłowska, K. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21176225 · Cited by 341 · see citing works
Hickman, J. A., Graeser, R., Hoogt, R. D., Vidic, S., Brito, C., Gutekunst, M., & van der Kuip, H. (2014) · Biotechnology Journal · doi:10.1002/biot.201300492 · Cited by 379 · see citing works
Liao, J., Qian, F., Tchabo, N. E., Mhawech-Fauceglia, P. Y., Beck, A. F., Zikun, Q., Wang, X., Huss, W. J., Lele, S., Morrison, C. D., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0084941 · Cited by 365 · see citing works
Doxorubicin resistance in breast cancer cells is mediated by extracellular matrix proteins
Lovitt, C. J., Shelper, T., & Avery, V. M. (2018) · BMC Cancer · doi:10.1186/s12885-017-3953-6 · Cited by 339 · see citing works
Scaffold-based 3D cell culture models in cancer research
Abuwatfa, W. H., Pitt, W. G., & Husseini, G. A. (2024) · Journal of Biomedical Science · doi:10.1186/s12929-024-00994-y · Cited by 347 · see citing works
Focal adhesion signaling and therapy resistance in cancer
Eke, I., & Cordes, N. (2014) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2014.07.009 · Cited by 331 · see citing works
Engineering cancer microenvironments for in vitro 3-D tumor models
Asghar, W., El Assal, R., Shafiee, H., Pitteri, S., Paulmurugan, R., & Demirci, U. (2015) · Materials Today · doi:10.1016/j.mattod.2015.05.002 · Cited by 316 · see citing works
Breslin, S., & O’Driscoll, L. (2016) · Oncotarget · doi:10.18632/oncotarget.9935 · Cited by 312 · see citing works
Däster, S., Amatruda, N., Calabrese, D., Ivanek, R., Turrini, E., Droeser, R. A., Zajac, P., Fimognari, C., Spagnoli, G. C., Iezzi, G., et al. (2017) · Oncotarget · doi:10.18632/oncotarget.13857 · Cited by 281 · see citing works
Melissaridou, S., Wiechec, E., Magan, M., Jain, M. V., Chung, M. K., Farnebo, L., & Roberg, K. (2019) · Cancer Cell International · doi:10.1186/s12935-019-0733-1 · Cited by 262 · see citing works
do Amaral, R. L. F., Miranda, M. A., Marcato, P. D., & Swiech, K. (2017) · Frontiers in Physiology · doi:10.3389/fphys.2017.00605 · Cited by 222 · see citing works
Piperine inhibits the growth and motility of triple-negative breast cancer cells
Greenshields, A. L., Doucette, C. D., Sutton, K. M., Madera, L., Annan, H. G., Yaffe, P. B., Knickle, A. F., Dong, Z., & Hoskin, D. W. (2014) · Cancer Letters · doi:10.1016/j.canlet.2014.11.017 · Cited by 219 · see citing works
Three‐dimensional cell culture models for anticancer drug screening: Worth the effort?
Verjans, E., Doijen, J., Luyten, W., Landuyt, B., & Schoofs, L. (2018) · Journal of Cellular Physiology · doi:10.1002/jcp.26052 · Cited by 212 · see citing works
Breast cancer models: Engineering the tumor microenvironment
Bahcecioglu, G., Basara, G., Ellis, B. W., Ren, X., & Zorlutuna, P. (2020) · Acta Biomaterialia · doi:10.1016/j.actbio.2020.02.006 · Cited by 213 · see citing works
3D tumor models: History, advances and future perspectives
Benien, P., & Swami, A. (2014) · Future Oncology · doi:10.2217/fon.13.274 · Cited by 208 · see citing works
Yaffe, P. B., Coombs, M. R. P., Doucette, C. D., Walsh, M. J., & Hoskin, D. W. (2014) · Molecular Carcinogenesis · doi:10.1002/mc.22176 · Cited by 188 · see citing works
Advances in Engineering Human Tissue Models
Moysidou, C., Barberio, C., & Owens, R. M. (2021) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2020.620962 · Cited by 182 · see citing works
Ware, M. J., Colbert, K. L., Keshishian, V., Ho, J., Corr, S. J., Curley, S. A., & Godin, B. (2016) · Tissue Engineering Part C Methods · doi:10.1089/ten.tec.2015.0280 · Cited by 171 · see citing works
Mazzocchi, A. R., Söker, S., & Skardal, A. (2019) · Applied Physics Reviews · doi:10.1063/1.5056188 · Cited by 174 · see citing works
Mouse models of colorectal cancer: Past, present and future perspectives
Bürtin, F., Mullins, C. S., & Linnebacher, M. (2020) · World Journal of Gastroenterology · doi:10.3748/wjg.v26.i13.1394 · Cited by 169 · see citing works
Hydrogels for 3D mammalian cell culture: a starting guide for laboratory practice
Rüdinger, F., Lavrentieva, A. V., Blume, C. A., Pepelanova, I., & Scheper, T. H. (2014) · Applied Microbiology and Biotechnology · doi:10.1007/s00253-014-6253-y · Cited by 167 · see citing works
Ekert, J. E., Johnson, K., Strake, B., Pardinas, J. R., Jarantow, S. W., Perkinson, R. A., & Colter, D. C. (2014) · PLoS ONE · doi:10.1371/journal.pone.0092248 · Cited by 165 · see citing works
Liquid-like Solids Support Cells in 3D
Bhattacharjee, T., Gil, C. J., Marshall, S. L., Urueña, J. M., O’Bryan, C. S., Carstens, M. R., Keselowsky, B. G., Palmer, G. D., Ghivizzani, S. C., Gibbs, C. P., et al. (2016) · ACS Biomaterials Science & Engineering · doi:10.1021/acsbiomaterials.6b00218 · Cited by 165 · see citing works
Sánchez‐Martínez, R., Cruz-Gil, S., de Cedrón, M. G., Álvarez‐Fernández, M., Vargas, T., Molina, S., García, B., Herránz, J., Moreno‐Rubio, J., Reglero, G., et al. (2015) · Oncotarget · doi:10.18632/oncotarget.5340 · Cited by 159 · see citing works
Abbas, Z. N., Al‐Saffar, A. Z., Jasim, S. M., & Sulaiman, G. M. (2023) · Scientific Reports · doi:10.1038/s41598-023-45144-w · Cited by 160 · see citing works
A novel 3D human glioblastoma cell culture system for modeling drug and radiation responses
Gomez-Roman, N., Stevenson, K. H., Gilmour, L., Hamilton, G. M., & Chalmers, A. J. (2016) · Neuro-Oncology · doi:10.1093/neuonc/now164 · Cited by 141 · see citing works
Biomaterials‐Based Approaches to Tumor Spheroid and Organoid Modeling
Thakuri, P. S., Liu, C., Luker, G. D., & Tavana, H. (2017) · Advanced Healthcare Materials · doi:10.1002/adhm.201700980 · Cited by 138 · see citing works
The multiple facets of drug resistance: one history, different approaches
Niero, E. L. D. O., Rocha-Sales, B., Lauand, C., Cortez, B. A., de Souza, M. M., Teixeira, P. R., Urabayashi, M. S., Martens, A. A., Neves, J. H., & Machado‐Santelli, G. M. (2014) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/1756-9966-33-37 · Cited by 135 · see citing works
Organic Bioelectronics for In Vitro Systems
Pitsalidis, C., Pappa, A., Boys, A. J., Fu, Y., Moysidou, C., van Niekerk, D. C., Sáez, J., Savva, A., Iandolo, D., & Owens, R. M. (2021) · Chemical Reviews · doi:10.1021/acs.chemrev.1c00539 · Cited by 137 · see citing works
Ruppen, J., Wildhaber, F. D., Strub, C., Hall, S. R. R., Schmid, R. A., Geiser, T., & Guenat, O. T. (2015) · Lab on a Chip · doi:10.1039/c5lc00454c · Cited by 127 · see citing works
Gwon, K., Kim, E., & Tae, G. (2016) · Acta Biomaterialia · doi:10.1016/j.actbio.2016.12.001 · Cited by 126 · see citing works
Impact of the spheroid model complexity on drug response
Hoffmann, O. I., Ilmberger, C., Magosch, S., Joka, M., Jauch, K.-W., & Mayer, B. (2015) · Journal of Biotechnology · doi:10.1016/j.jbiotec.2015.02.029 · Cited by 125 · see citing works
Howes, A. L., Richardson, R. D., Finlay, D., & Vuori, K. (2014) · PLoS ONE · doi:10.1371/journal.pone.0108283 · Cited by 121 · see citing works
Park, Y., Huh, K. M., & Kang, S. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22052491 · Cited by 115 · see citing works
Expansion and Cell-Cycle Arrest: Common Denominators of Cellular Senescence
Ogrodnik, M., Salmonowicz, H., Jurk, D., & Passos, J. F. (2019) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2019.06.011 · Cited by 104 · see citing works
Advancements in 3D Cell Culture Systems for Personalizing Anti-Cancer Therapies
Law, A. M. K., de la Fuente, L. R., Grundy, T. J., Fang, G., Valdés‐Mora, F., & Gallego‐Ortega, D. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.782766 · Cited by 106 · see citing works
Drug screening in 3D in vitro tumor models: overcoming current pitfalls of efficacy read‐outs
Santo, V. E., Rebelo, S. P., Estrada, M. F., Alves, P. M., Boghaert, E. R., & Brito, C. (2016) · Biotechnology Journal · doi:10.1002/biot.201600505 · Cited by 103 · see citing works
Two-Dimensional (2D) and Three-Dimensional (3D) Cell Culturing in Drug Discovery
Joseph, J. S., Malindisa, S. T., & Ntwasa, M. M. (2019) · IntechOpen eBooks · doi:10.5772/intechopen.81552 · Cited by 101 · see citing works
Natural and Synthetic Biomaterials for Engineering Multicellular Tumor Spheroids
Kamatar, A., Gunay, G., & Acar, H. (2020) · Polymers · doi:10.3390/polym12112506 · Cited by 100 · see citing works
Three dimensional spheroid cell culture for nanoparticle safety testing
Sambale, F., Lavrentieva, A. V., Stahl, F., Blume, C. A., Stiesch, M., Kasper, C., Bahnemann, D. W., & Scheper, T. H. (2015) · Journal of Biotechnology · doi:10.1016/j.jbiotec.2015.01.001 · Cited by 98 · see citing works
Routine Optical Clearing of 3D-Cell Cultures: Simplicity Forward
Nürnberg, E., Vitacolonna, M., Klicks, J., von Molitor, E., Cesetti, T., Keller, F., Bruch, R., Ertongur-Fauth, T., Riedel, K., Scholz, P., et al. (2020) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2020.00020 · Cited by 93 · see citing works
Chwalek, K., Bray, L. J., & Werner, C. (2014) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2014.05.006 · Cited by 91 · see citing works
Galassi, C., Musella, M., Manduca, N., Maccafeo, E., & Sistigu, A. (2021) · Cells · doi:10.3390/cells10092361 · Cited by 92 · see citing works
Fan, T. M., Roberts, R. D., & Lizardo, M. M. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.00013 · Cited by 90 · see citing works
Contributions of 3D Cell Cultures for Cancer Research
Ravi, M., Ramesh, A., & Pattabhi, A. (2017) · Journal of Cellular Physiology · doi:10.1002/jcp.25664 · Cited by 88 · see citing works
Polymeric Biomaterials for In Vitro Cancer Tissue Engineering and Drug Testing Applications
Pradhan, S., Hassani, I., Clary, J. M., & Lipke, E. A. (2016) · Tissue Engineering Part B Reviews · doi:10.1089/ten.teb.2015.0567 · Cited by 85 · see citing works
Resveratrol Regulates Colorectal Cancer Cell Invasion by Modulation of Focal Adhesion Molecules
Buhrmann, C., Shayan, P., Goel, A., & Shakibaei, M. (2017) · Nutrients · doi:10.3390/nu9101073 · Cited by 84 · see citing works
In Vitro Modeling of Mechanics in Cancer Metastasis
Malandrino, A., Kamm, R. D., & Moeendarbary, E. (2017) · ACS Biomaterials Science & Engineering · doi:10.1021/acsbiomaterials.7b00041 · Cited by 78 · see citing works
Glioblastoma’s Next Top Model: Novel Culture Systems for Brain Cancer Radiotherapy Research
Caragher, S. P., Chalmers, A. J., & Gomez-Roman, N. (2019) · Cancers · doi:10.3390/cancers11010044 · Cited by 76 · see citing works
Implications of Three-Dimensional Cell Culture in Cancer Therapeutic Research
Poornima, K. N., Francis, A. P., Hoda, M., Eladl, M. A., Subramanian, S., Veeraraghavan, V. P., El‐Sherbiny, M., Asseri, S. M., Hussamuldin, A. B. A., Surapaneni, K. M., et al. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.891673 · Cited by 77 · see citing works
Devarasetty, M., Mazzocchi, A. R., & Skardal, A. (2018) · BioDrugs · doi:10.1007/s40259-017-0258-x · Cited by 76 · see citing works
Ruiz-Garcia, H. J., Alvarado-Estrada, K., Schiapparelli, P. V., Quiñones‐Hinojosa, A., & Trifiletti, D. M. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.558381 · Cited by 75 · see citing works
Engineered Tools to Study Intercellular Communication
Yang, B. A., Westerhof, T. M., Sabin, K., Merajver, S. D., & Aguilar, C. A. (2020) · Advanced Science · doi:10.1002/advs.202002825 · Cited by 73 · see citing works
Bagher, Z., Azami, M., Ebrahimi‐Barough, S., Mirzadeh, H., Solouk, A., Soleimani, M., Ai, J., Nourani, M. R., & Joghataei, M. T. (2015) · Molecular Neurobiology · doi:10.1007/s12035-015-9199-x · Cited by 71 · see citing works
Edmondson, R., Adcock, A. F., & Yang, L. (2016) · PLoS ONE · doi:10.1371/journal.pone.0158116 · Cited by 69 · see citing works
Shah, S., & D’Souza, G. G. M. (2025) · Cells · doi:10.3390/cells14100732 · Cited by 66 · see citing works
Ritter, A., Kreis, N., Hoock, S. C., Solbach, C., Louwen, F., & Yuan, J. (2022) · Cancers · doi:10.3390/cancers14163908 · Cited by 67 · see citing works
A morphospace for synthetic organs and organoids: the possible and the actual
Ollé-Vila, A., Duran‐Nebreda, S., Pueyo, N. C., Montañez, R., & Solé, R. V. (2016) · Integrative Biology · doi:10.1039/c5ib00324e · Cited by 65 · see citing works
Adipocytes in the Tumour Microenvironment
Pallegar, N. K., & Christian, S. L. (2020) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-37184-5_1 · Cited by 63 · see citing works
The role of the microenvironment in the biophysics of cancer
Rianna, C., Kumar, P., & Radmacher, M. (2017) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2017.07.022 · Cited by 62 · see citing works
Matrix Stiffness and Colorectal Cancer
Liu, C., Pei, H., & Tan, F. (2020) · OncoTargets and Therapy · doi:10.2147/ott.s231010 · Cited by 63 · see citing works
Three-dimensional bioactive hydrogel-based scaffolds for bone regeneration in implant dentistry
Sordi, M. B., da Cruz, A. C. C., Fredel, M. C., Magini, R. D. S., & Sharpe, P. T. (2021) · Materials Science and Engineering C · doi:10.1016/j.msec.2021.112055 · Cited by 60 · see citing works
Grunewald, L., Lam, T., Andersch, L., Klaus, A., Schwiebert, S., Winkler, A., Gauert, A., Hagemann, A. I. H., Astrahantseff, K., Klironomos, F., et al. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.689697 · Cited by 60 · see citing works
Akasov, R., Zaytseva‐Zotova, D., Burov, S. V., Leko, M. V., Dontenwill, M., Chiper, M., Vandamme, T., & Арнольдовна, М. Е. (2016) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2016.04.005 · Cited by 59 · see citing works
Castro, F., Pereira, C. L., Macedo, M. H., Almeida, A., Silveira, M. J., Dias, S., Cardoso, A. P., Oliveira, M. J., & Sarmento, B. F. C. C. (2021) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2021.06.001 · Cited by 61 · see citing works
April-Monn, S., Wiedmer, T., Skowronska, M., Maire, R., Lena, M. S., Trippel, M. A., Domenico, A. D., Muffatti, F., Andreasi, V., Capurso, G., et al. (2020) · Neuroendocrinology · doi:10.1159/000507669 · Cited by 58 · see citing works
Monteiro, C. F., Custódio, C. A., & Mano, J. F. (2021) · Acta Biomaterialia · doi:10.1016/j.actbio.2021.07.034 · Cited by 57 · see citing works
3D Cancer Models: Depicting Cellular Crosstalk within the Tumour Microenvironment
Franchi-Mendes, T., Eduardo, R., Domenici, G., & Brito, C. (2021) · Cancers · doi:10.3390/cancers13184610 · Cited by 57 · see citing works
Cucurbitacins from the Leaves of Citrullus colocynthis (L.) Schrad
Chawech, R., Jarraya, R. M., Girardi, C., Vansteelandt, M., Marti, G., Nasri, I., Racaud‐Sultan, C., & Fabre, N. (2015) · Molecules · doi:10.3390/molecules201018001 · Cited by 56 · see citing works
Yoshida, T., Sopko, N. A., Kates, M. R., Liu, X., Joice, G. A., McConkey, D. J., & Bivalacqua, T. J. (2018) · Oncotarget · doi:10.18632/oncotarget.24308 · Cited by 55 · see citing works
Park, S.-R., Kim, S., Lee, J. W., Park, C. H., Yu, W., Lee, S., Chon, S. J., Lee, D. H., & Hong, I. (2020) · Biofabrication · doi:10.1088/1758-5090/abbd29 · Cited by 56 · see citing works
Shamloo, A., Mohammadaliha, N., & Mohseni, M. (2015) · Journal of Biotechnology · doi:10.1016/j.jbiotec.2015.08.005 · Cited by 55 · see citing works
Lou, Y.-F., Zou, Z., Chen, P., Huang, G., Li, B., Zheng, D.-Q., Yu, X., & Luo, X. (2014) · PLoS ONE · doi:10.1371/journal.pone.0097719 · Cited by 55 · see citing works
Roy, V., Magne, B., Vaillancourt-Audet, M., Blais, M., Chabaud, S., Grammond, E., Piquet, L., Fradette, J., Laverdière, I., Moulin, V. J., et al. (2020) · BioMed Research International · doi:10.1155/2020/6051210 · Cited by 53 · see citing works
Kim, H. N., Habbit, N. L., Su, C., Choi, N., Ahn, E. H., Lipke, E. A., & Kim, D. (2019) · Advanced Functional Materials · doi:10.1002/adfm.201807553 · Cited by 55 · see citing works
Bioink: a 3D-bioprinting tool for anticancer drug discovery and cancer management
Pandey-Tiwari, A., Thorat, N. D., Pricl, S., Patil, R. M., Rohiwal, S. S., & Townley, H. E. (2021) · Drug Discovery Today · doi:10.1016/j.drudis.2021.03.010 · Cited by 56 · see citing works
Al‐Lamki, R. S., Bradley, J. R., & Pober, J. S. (2017) · Frontiers in Medicine · doi:10.3389/fmed.2017.00148 · Cited by 53 · see citing works
Faber, S. C., & McCullough, S. D. (2018) · Applied In Vitro Toxicology · doi:10.1089/aivt.2018.0002 · Cited by 50 · see citing works
Oliveira, R. C., Abrantes, A. M., Tralhão, J. G., & Botelho, M. F. (2020) · Animal Models and Experimental Medicine · doi:10.1002/ame2.12102 · Cited by 50 · see citing works
Torras, N., Zabalo, J., Abril, E., Carré, A., García-Díaz, M., & Martínez, E. (2023) · Biomaterials Advances · doi:10.1016/j.bioadv.2023.213534 · Cited by 57 · see citing works
In-depth phenotypic characterization of multicellular tumor spheroids: Effects of 5-Fluorouracil
Virgone‐Carlotta, A., Lemasson, M., Mertani, H. C., Diaz, J., Monnier, S., Dehoux, T., Delanoë‐Ayari, H., Rivière, C., & Rieu, J.-P. (2017) · PLoS ONE · doi:10.1371/journal.pone.0188100 · Cited by 48 · see citing works
Paper as a scaffold for cell cultures: Teaching an old material new tricks
Wu, X., Suvarnapathaki, S., Walsh, K., & Camci‐Unal, G. (2018) · MRS Communications · doi:10.1557/mrc.2018.8 · Cited by 48 · see citing works
3D matrix-based cell cultures: Automated analysis of tumor cell survival and proliferation
Eke, I., Hehlgans, S., Sandfort, V., & Cordes, N. (2015) · International Journal of Oncology · doi:10.3892/ijo.2015.3230 · Cited by 47 · see citing works
Fridman, I. B., Kostas, J. C., Greguš, M., Ray, S., Sullivan, M. R., Ivanov, A. R., Cohen, S., & Konry, T. (2021) · Acta Biomaterialia · doi:10.1016/j.actbio.2021.06.025 · Cited by 46 · see citing works
Bisphenol S and Bisphenol A disrupt morphogenesis of MCF-12A human mammary epithelial cells
Atlas, E., & Dimitrova, V. (2019) · Scientific Reports · doi:10.1038/s41598-019-52505-x · Cited by 45 · see citing works
Al-Kabani, A., Huda, B., Haddad, J., Yousuf, M., Bhurka, F., Ajaz, F., Patnaik, R., Jannati, S., & Banerjee, Y. (2025) · Cancers · doi:10.3390/cancers17132163 · Cited by 44 · see citing works
Funayama, R., Taniguchi, H., Mizuma, M., Fujishima, F., Kobayashi, M., Ohnuma, S., Unno, M., & Nakayama, K. (2017) · Cancer Science · doi:10.1111/cas.13179 · Cited by 45 · see citing works
Anti-Cancer Drug Validation: the Contribution of Tissue Engineered Models
Carvalho, M. R., Lima, D., Reis, R. L., Oliveira, J. M., & Correlo, V. M. (2017) · Stem Cell Reviews and Reports · doi:10.1007/s12015-017-9720-x · Cited by 44 · see citing works
Living Cell Microarrays: An Overview of Concepts
Jonczyk, R., Kurth, T., Lavrentieva, A. V., Walter, J., Scheper, T. H., & Stahl, F. (2016) · Microarrays · doi:10.3390/microarrays5020011 · Cited by 42 · see citing works
Jacobi, N., Seeboeck, R., Hofmann, E., Schweiger, H., Smolinska, V., Mohr, T., Boyer, A., Sommergruber, W., Lechner, P., Pichler-Huebschmann, C., et al. (2017) · Oncotarget · doi:10.18632/oncotarget.22475 · Cited by 43 · see citing works
Kleine‐Brüggeney, H., van Vliet, L., Mulas, C., Gielen, F., Agley, C. C., Silva, J., Smith, A. G., Chalut, K. J., & Hollfelder, F. (2018) · Small · doi:10.1002/smll.201804576 · Cited by 40 · see citing works
Forsythe, S. D., Mehta, N. U., Devarasetty, M., Sivakumar, H., Gmeiner, W. H., Söker, S., Votanopoulos, K. I., & Skardal, A. (2019) · Annals of Biomedical Engineering · doi:10.1007/s10439-019-02269-2 · Cited by 42 · see citing works
Bioengineered Submucosal Organoids for <i>In Vitro</i> Modeling of Colorectal Cancer
Devarasetty, M., Skardal, A., Cowdrick, K., Marini, F., & Soker, S. (2017) · Tissue Engineering Part A · doi:10.1089/ten.tea.2017.0397 · Cited by 41 · see citing works
Arpin, C. C., Mac, S., Jiang, Y., Cheng, H., Grimard, M., Page, B. D. G., Kamocka, M. M., Haftchenary, S., Su, H., Ball, D. P., et al. (2016) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-15-0003 · Cited by 41 · see citing works
- Authors
- Luca, A. C., Mersch, S., Deenen, R., Schmidt, S., Messner, I., Schäfer, K.-L., Baldus, S. E., Huckenbeck, W., Piekorz, R. P., Knoefel, W. T., Krieg, A., & Stoecklein, N. H.
- Affiliations
- Düsseldorf University Hospital (DE)
- Heinrich Heine University Düsseldorf (DE)
- Corresponding author
- Krieg, Andreas
- Stoecklein, Nikolas H.
- ORCID
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2013-03-26
- Volume
- 8
- Issue
- 3
- Pages
- e59689
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3608563
- OpenAlex
- W1983051794
- Cited by
- 341
- References
- 31
- Citations by year
- 2026: 11 · 2025: 14 · 2024: 18 · 2023: 29 · 2022: 27 · 2021: 39 · 2020: 40 · 2019: 29 · 2018: 25 · 2017: 33 · 2016: 29 · 2015: 18 · 2014: 25 · 2013: 4
- FWCI
- 13.56
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Univ. Duesseldorf: Duesseldorfer Dokumenten- und Publikationsserver (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- Deutsche Forschungsgemeinschaft (SFB728)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
- Keywords
- colorectal cancer, 3D cell culture, tumor microenvironment, EGFR signaling, EGFR inhibition, AG1478, gene expression, cell morphology, spheroid formation, cell invasion, cell migration, KRAS wild-type, 2D vs 3D culture comparison, colorectal cancer cell lines
- MeSH terms
- Extracellular Matrix, Humans, Laminin, Phenotype, Colorectal Neoplasms, Gene Expression Regulation, Neoplastic, Spheroids, Cellular, Cell Culture Techniques, Cell Line, Tumor, Protein Kinase Inhibitors, Cell Proliferation, Tumor Microenvironment, ErbB Receptors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
