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Organotypic three-dimensional cancer cell cultures mirror drug responses in vivo: lessons learned from the inhibition of EGFR signaling
Complex three-dimensional (3D) in vitro models that recapitulate human tumor biology are essential to understand the pathophysiology of the disease and to aid in the discovery of novel anti-cancer therapies. 3D organotypic cultures exhibit intercellular communication, nutrient and oxygen gradients,...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5746077/ https://www.ncbi.nlm.nih.gov/pubmed/29296175 http://dx.doi.org/10.18632/oncotarget.22475 |
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author | Jacobi, Nico Seeboeck, Rita Hofmann, Elisabeth Schweiger, Helmut Smolinska, Veronika Mohr, Thomas Boyer, Alexandra Sommergruber, Wolfgang Lechner, Peter Pichler-Huebschmann, Corina Önder, Kamil Hundsberger, Harald Wiesner, Christoph Eger, Andreas |
author_facet | Jacobi, Nico Seeboeck, Rita Hofmann, Elisabeth Schweiger, Helmut Smolinska, Veronika Mohr, Thomas Boyer, Alexandra Sommergruber, Wolfgang Lechner, Peter Pichler-Huebschmann, Corina Önder, Kamil Hundsberger, Harald Wiesner, Christoph Eger, Andreas |
author_sort | Jacobi, Nico |
collection | PubMed |
description | Complex three-dimensional (3D) in vitro models that recapitulate human tumor biology are essential to understand the pathophysiology of the disease and to aid in the discovery of novel anti-cancer therapies. 3D organotypic cultures exhibit intercellular communication, nutrient and oxygen gradients, and cell polarity that is lacking in two-dimensional (2D) monolayer cultures. In the present study, we demonstrate that 2D and 3D cancer models exhibit different drug sensitivities towards both targeted inhibitors of EGFR signaling and broad acting cytotoxic agents. Changes in the kinase activities of ErbB family members and differential expression of apoptosis- and survival-associated genes before and after drug treatment may account for the differential drug sensitivities. Importantly, EGFR oncoprotein addiction was evident only in the 3D cultures mirroring the effect of EGFR inhibition in the clinic. Furthermore, targeted drug efficacy was strongly increased when incorporating cancer-associated fibroblasts into the 3D cultures. Taken together, we provide conclusive evidence that complex 3D cultures are more predictive of the clinical outcome than their 2D counterparts. In the future, 3D cultures will be instrumental for understanding the mode of action of drugs, identifying genotype-drug response relationships and developing patient-specific and personalized cancer treatments. |
format | Online Article Text |
id | pubmed-5746077 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-57460772018-01-02 Organotypic three-dimensional cancer cell cultures mirror drug responses in vivo: lessons learned from the inhibition of EGFR signaling Jacobi, Nico Seeboeck, Rita Hofmann, Elisabeth Schweiger, Helmut Smolinska, Veronika Mohr, Thomas Boyer, Alexandra Sommergruber, Wolfgang Lechner, Peter Pichler-Huebschmann, Corina Önder, Kamil Hundsberger, Harald Wiesner, Christoph Eger, Andreas Oncotarget Research Paper Complex three-dimensional (3D) in vitro models that recapitulate human tumor biology are essential to understand the pathophysiology of the disease and to aid in the discovery of novel anti-cancer therapies. 3D organotypic cultures exhibit intercellular communication, nutrient and oxygen gradients, and cell polarity that is lacking in two-dimensional (2D) monolayer cultures. In the present study, we demonstrate that 2D and 3D cancer models exhibit different drug sensitivities towards both targeted inhibitors of EGFR signaling and broad acting cytotoxic agents. Changes in the kinase activities of ErbB family members and differential expression of apoptosis- and survival-associated genes before and after drug treatment may account for the differential drug sensitivities. Importantly, EGFR oncoprotein addiction was evident only in the 3D cultures mirroring the effect of EGFR inhibition in the clinic. Furthermore, targeted drug efficacy was strongly increased when incorporating cancer-associated fibroblasts into the 3D cultures. Taken together, we provide conclusive evidence that complex 3D cultures are more predictive of the clinical outcome than their 2D counterparts. In the future, 3D cultures will be instrumental for understanding the mode of action of drugs, identifying genotype-drug response relationships and developing patient-specific and personalized cancer treatments. Impact Journals LLC 2017-11-17 /pmc/articles/PMC5746077/ /pubmed/29296175 http://dx.doi.org/10.18632/oncotarget.22475 Text en Copyright: © 2017 Jacobi et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (http://creativecommons.org/licenses/by/3.0/) (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Jacobi, Nico Seeboeck, Rita Hofmann, Elisabeth Schweiger, Helmut Smolinska, Veronika Mohr, Thomas Boyer, Alexandra Sommergruber, Wolfgang Lechner, Peter Pichler-Huebschmann, Corina Önder, Kamil Hundsberger, Harald Wiesner, Christoph Eger, Andreas Organotypic three-dimensional cancer cell cultures mirror drug responses in vivo: lessons learned from the inhibition of EGFR signaling |
title | Organotypic three-dimensional cancer cell cultures mirror drug responses in vivo: lessons learned from the inhibition of EGFR signaling |
title_full | Organotypic three-dimensional cancer cell cultures mirror drug responses in vivo: lessons learned from the inhibition of EGFR signaling |
title_fullStr | Organotypic three-dimensional cancer cell cultures mirror drug responses in vivo: lessons learned from the inhibition of EGFR signaling |
title_full_unstemmed | Organotypic three-dimensional cancer cell cultures mirror drug responses in vivo: lessons learned from the inhibition of EGFR signaling |
title_short | Organotypic three-dimensional cancer cell cultures mirror drug responses in vivo: lessons learned from the inhibition of EGFR signaling |
title_sort | organotypic three-dimensional cancer cell cultures mirror drug responses in vivo: lessons learned from the inhibition of egfr signaling |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5746077/ https://www.ncbi.nlm.nih.gov/pubmed/29296175 http://dx.doi.org/10.18632/oncotarget.22475 |
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