A Novel Standardized Inflammatory Cell-Modulated 3D Tumor Tissue Model for Analysis of Tumor-Stroma Interaction and Drug Discovery

Sabine Hensler; Claudia Kuehlbach; Bianka Kotkamp; Dario Frey; Margareta Maria Mueller

doi:doi:10.11648/j.bio.20210904.13

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A Novel Standardized Inflammatory Cell-Modulated 3D Tumor Tissue Model for Analysis of Tumor-Stroma Interaction and Drug Discovery

Sabine Hensler, Claudia Kuehlbach, Bianka Kotkamp, Dario Frey, Margareta Maria Mueller

Published in American Journal of Bioscience and Bioengineering (Volume 9, Issue 4)

Received: 29 June 2021 Accepted: 21 July 2021 Published: 11 August 2021

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Abstract

The last decades were marked by substantial progress in understanding the role of tumor-supporting inflammatory reactions in tumor growth and progression. While in vivo data substantiate the contribution of the inflammatory infiltrate and of tumor associated fibroblasts in promoting tumor growth and progression, little is known about the dynamic interaction of these two stromal cell types and their reciprocal influence on each other and on the tumor cells. Mechanistical analyses of these crucial interactions require a standardized and easy to manipulate environment. We therefore established a 3D organotypic in vitro model for epithelial tumors to analyze the interaction of macrophages, neutrophils and fibroblasts in the tumor microenvironment of malignant tumors. In the 3D model, epithelial tumor cells are grown on a collagen type I gel containing fibroblasts, macrophages and neutrophils. Comparable to the in vivo setting, the cytokine driven interaction between macrophages and fibroblasts markedly influences invasion and enhances M2 differentiation in the presence of tumor cells. Addition of neutrophils further leads to a strikingly enhanced tumor invasion associated with an increased expression of MMP-9 and a N2 differentiation of neutrophils. Thus, this novel 3D model provides an in vivo like tissue context to analyze tumor stroma interactions and presents an excellent tool for targeted interference. As such, the model is highly suitable for pharmaceutical screening of novel therapeutics. However, the use of collagen type 1 with its known batch to batch variability as ECM equivalent prohibits the model-standardization that is needed for pharmaceutical testing. Therefore, the 3D in vitro tumor-stroma model was adapted to the use of a bioinert dextran-hydrogel providing a highly standardized and easily modifiable scaffold material that allows the recovery of cells after pharmaceutical experiments. Comparable to the collagen-based model, cells maintained their physiological proliferation, migration and differentiation. Utilizing this standardized model, the efficacy and the tissue impact of novel pharmaceuticals can be investigated in detail with respect to cell morphology, behavior, viability as well as gene expression profiles thereby providing a 3D hydrogel tumor stroma a model that is of great interest for the pharmaceutical industry.

Published in	American Journal of Bioscience and Bioengineering (Volume 9, Issue 4)
DOI	10.11648/j.bio.20210904.13
Page(s)	110-122
Creative Commons	This is an Open Access article, distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium or format, provided the original work is properly cited.
Copyright	Copyright © The Author(s), 2021. Published by Science Publishing Group

Keywords

Standardized 3D Model, Tumor Stroma Interaction, Inflammatory Cells, Dextran Hydrogel

References

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APA Style

Sabine Hensler, Claudia Kuehlbach, Bianka Kotkamp, Dario Frey, Margareta Maria Mueller. (2021). A Novel Standardized Inflammatory Cell-Modulated 3D Tumor Tissue Model for Analysis of Tumor-Stroma Interaction and Drug Discovery. American Journal of Bioscience and Bioengineering, 9(4), 110-122. https://doi.org/10.11648/j.bio.20210904.13

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ACS Style

Sabine Hensler; Claudia Kuehlbach; Bianka Kotkamp; Dario Frey; Margareta Maria Mueller. A Novel Standardized Inflammatory Cell-Modulated 3D Tumor Tissue Model for Analysis of Tumor-Stroma Interaction and Drug Discovery. Am. J. BioSci. Bioeng. 2021, 9(4), 110-122. doi: 10.11648/j.bio.20210904.13

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AMA Style

Sabine Hensler, Claudia Kuehlbach, Bianka Kotkamp, Dario Frey, Margareta Maria Mueller. A Novel Standardized Inflammatory Cell-Modulated 3D Tumor Tissue Model for Analysis of Tumor-Stroma Interaction and Drug Discovery. Am J BioSci Bioeng. 2021;9(4):110-122. doi: 10.11648/j.bio.20210904.13

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@article{10.11648/j.bio.20210904.13,
  author = {Sabine Hensler and Claudia Kuehlbach and Bianka Kotkamp and Dario Frey and Margareta Maria Mueller},
  title = {A Novel Standardized Inflammatory Cell-Modulated 3D Tumor Tissue Model for Analysis of Tumor-Stroma Interaction and Drug Discovery},
  journal = {American Journal of Bioscience and Bioengineering},
  volume = {9},
  number = {4},
  pages = {110-122},
  doi = {10.11648/j.bio.20210904.13},
  url = {https://doi.org/10.11648/j.bio.20210904.13},
  eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.bio.20210904.13},
  abstract = {The last decades were marked by substantial progress in understanding the role of tumor-supporting inflammatory reactions in tumor growth and progression. While in vivo data substantiate the contribution of the inflammatory infiltrate and of tumor associated fibroblasts in promoting tumor growth and progression, little is known about the dynamic interaction of these two stromal cell types and their reciprocal influence on each other and on the tumor cells. Mechanistical analyses of these crucial interactions require a standardized and easy to manipulate environment. We therefore established a 3D organotypic in vitro model for epithelial tumors to analyze the interaction of macrophages, neutrophils and fibroblasts in the tumor microenvironment of malignant tumors. In the 3D model, epithelial tumor cells are grown on a collagen type I gel containing fibroblasts, macrophages and neutrophils. Comparable to the in vivo setting, the cytokine driven interaction between macrophages and fibroblasts markedly influences invasion and enhances M2 differentiation in the presence of tumor cells. Addition of neutrophils further leads to a strikingly enhanced tumor invasion associated with an increased expression of MMP-9 and a N2 differentiation of neutrophils. Thus, this novel 3D model provides an in vivo like tissue context to analyze tumor stroma interactions and presents an excellent tool for targeted interference. As such, the model is highly suitable for pharmaceutical screening of novel therapeutics. However, the use of collagen type 1 with its known batch to batch variability as ECM equivalent prohibits the model-standardization that is needed for pharmaceutical testing. Therefore, the 3D in vitro tumor-stroma model was adapted to the use of a bioinert dextran-hydrogel providing a highly standardized and easily modifiable scaffold material that allows the recovery of cells after pharmaceutical experiments. Comparable to the collagen-based model, cells maintained their physiological proliferation, migration and differentiation. Utilizing this standardized model, the efficacy and the tissue impact of novel pharmaceuticals can be investigated in detail with respect to cell morphology, behavior, viability as well as gene expression profiles thereby providing a 3D hydrogel tumor stroma a model that is of great interest for the pharmaceutical industry.},
 year = {2021}
}

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TY  - JOUR
T1  - A Novel Standardized Inflammatory Cell-Modulated 3D Tumor Tissue Model for Analysis of Tumor-Stroma Interaction and Drug Discovery
AU  - Sabine Hensler
AU  - Claudia Kuehlbach
AU  - Bianka Kotkamp
AU  - Dario Frey
AU  - Margareta Maria Mueller
Y1  - 2021/08/11
PY  - 2021
N1  - https://doi.org/10.11648/j.bio.20210904.13
DO  - 10.11648/j.bio.20210904.13
T2  - American Journal of Bioscience and Bioengineering
JF  - American Journal of Bioscience and Bioengineering
JO  - American Journal of Bioscience and Bioengineering
SP  - 110
EP  - 122
PB  - Science Publishing Group
SN  - 2328-5893
UR  - https://doi.org/10.11648/j.bio.20210904.13
AB  - The last decades were marked by substantial progress in understanding the role of tumor-supporting inflammatory reactions in tumor growth and progression. While in vivo data substantiate the contribution of the inflammatory infiltrate and of tumor associated fibroblasts in promoting tumor growth and progression, little is known about the dynamic interaction of these two stromal cell types and their reciprocal influence on each other and on the tumor cells. Mechanistical analyses of these crucial interactions require a standardized and easy to manipulate environment. We therefore established a 3D organotypic in vitro model for epithelial tumors to analyze the interaction of macrophages, neutrophils and fibroblasts in the tumor microenvironment of malignant tumors. In the 3D model, epithelial tumor cells are grown on a collagen type I gel containing fibroblasts, macrophages and neutrophils. Comparable to the in vivo setting, the cytokine driven interaction between macrophages and fibroblasts markedly influences invasion and enhances M2 differentiation in the presence of tumor cells. Addition of neutrophils further leads to a strikingly enhanced tumor invasion associated with an increased expression of MMP-9 and a N2 differentiation of neutrophils. Thus, this novel 3D model provides an in vivo like tissue context to analyze tumor stroma interactions and presents an excellent tool for targeted interference. As such, the model is highly suitable for pharmaceutical screening of novel therapeutics. However, the use of collagen type 1 with its known batch to batch variability as ECM equivalent prohibits the model-standardization that is needed for pharmaceutical testing. Therefore, the 3D in vitro tumor-stroma model was adapted to the use of a bioinert dextran-hydrogel providing a highly standardized and easily modifiable scaffold material that allows the recovery of cells after pharmaceutical experiments. Comparable to the collagen-based model, cells maintained their physiological proliferation, migration and differentiation. Utilizing this standardized model, the efficacy and the tissue impact of novel pharmaceuticals can be investigated in detail with respect to cell morphology, behavior, viability as well as gene expression profiles thereby providing a 3D hydrogel tumor stroma a model that is of great interest for the pharmaceutical industry.
VL  - 9
IS  - 4
ER  -

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Author Information

Sabine Hensler

Molecular Cell Biology Laboratory and Institute of Technical Medicine, Furtwangen University, Villingen-Schwenningen, Germany
Claudia Kuehlbach

Molecular Cell Biology Laboratory and Institute of Technical Medicine, Furtwangen University, Villingen-Schwenningen, Germany
Bianka Kotkamp

Molecular Cell Biology Laboratory and Institute of Technical Medicine, Furtwangen University, Villingen-Schwenningen, Germany
Dario Frey

Molecular Cell Biology Laboratory and Institute of Technical Medicine, Furtwangen University, Villingen-Schwenningen, Germany
Margareta Maria Mueller

Molecular Cell Biology Laboratory and Institute of Technical Medicine, Furtwangen University, Villingen-Schwenningen, Germany

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APA Style

Sabine Hensler, Claudia Kuehlbach, Bianka Kotkamp, Dario Frey, Margareta Maria Mueller. (2021). A Novel Standardized Inflammatory Cell-Modulated 3D Tumor Tissue Model for Analysis of Tumor-Stroma Interaction and Drug Discovery. American Journal of Bioscience and Bioengineering, 9(4), 110-122. https://doi.org/10.11648/j.bio.20210904.13

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ACS Style

Sabine Hensler; Claudia Kuehlbach; Bianka Kotkamp; Dario Frey; Margareta Maria Mueller. A Novel Standardized Inflammatory Cell-Modulated 3D Tumor Tissue Model for Analysis of Tumor-Stroma Interaction and Drug Discovery. Am. J. BioSci. Bioeng. 2021, 9(4), 110-122. doi: 10.11648/j.bio.20210904.13

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AMA Style

Sabine Hensler, Claudia Kuehlbach, Bianka Kotkamp, Dario Frey, Margareta Maria Mueller. A Novel Standardized Inflammatory Cell-Modulated 3D Tumor Tissue Model for Analysis of Tumor-Stroma Interaction and Drug Discovery. Am J BioSci Bioeng. 2021;9(4):110-122. doi: 10.11648/j.bio.20210904.13

Copy | Download

@article{10.11648/j.bio.20210904.13,
  author = {Sabine Hensler and Claudia Kuehlbach and Bianka Kotkamp and Dario Frey and Margareta Maria Mueller},
  title = {A Novel Standardized Inflammatory Cell-Modulated 3D Tumor Tissue Model for Analysis of Tumor-Stroma Interaction and Drug Discovery},
  journal = {American Journal of Bioscience and Bioengineering},
  volume = {9},
  number = {4},
  pages = {110-122},
  doi = {10.11648/j.bio.20210904.13},
  url = {https://doi.org/10.11648/j.bio.20210904.13},
  eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.bio.20210904.13},
  abstract = {The last decades were marked by substantial progress in understanding the role of tumor-supporting inflammatory reactions in tumor growth and progression. While in vivo data substantiate the contribution of the inflammatory infiltrate and of tumor associated fibroblasts in promoting tumor growth and progression, little is known about the dynamic interaction of these two stromal cell types and their reciprocal influence on each other and on the tumor cells. Mechanistical analyses of these crucial interactions require a standardized and easy to manipulate environment. We therefore established a 3D organotypic in vitro model for epithelial tumors to analyze the interaction of macrophages, neutrophils and fibroblasts in the tumor microenvironment of malignant tumors. In the 3D model, epithelial tumor cells are grown on a collagen type I gel containing fibroblasts, macrophages and neutrophils. Comparable to the in vivo setting, the cytokine driven interaction between macrophages and fibroblasts markedly influences invasion and enhances M2 differentiation in the presence of tumor cells. Addition of neutrophils further leads to a strikingly enhanced tumor invasion associated with an increased expression of MMP-9 and a N2 differentiation of neutrophils. Thus, this novel 3D model provides an in vivo like tissue context to analyze tumor stroma interactions and presents an excellent tool for targeted interference. As such, the model is highly suitable for pharmaceutical screening of novel therapeutics. However, the use of collagen type 1 with its known batch to batch variability as ECM equivalent prohibits the model-standardization that is needed for pharmaceutical testing. Therefore, the 3D in vitro tumor-stroma model was adapted to the use of a bioinert dextran-hydrogel providing a highly standardized and easily modifiable scaffold material that allows the recovery of cells after pharmaceutical experiments. Comparable to the collagen-based model, cells maintained their physiological proliferation, migration and differentiation. Utilizing this standardized model, the efficacy and the tissue impact of novel pharmaceuticals can be investigated in detail with respect to cell morphology, behavior, viability as well as gene expression profiles thereby providing a 3D hydrogel tumor stroma a model that is of great interest for the pharmaceutical industry.},
 year = {2021}
}

Copy | Download

TY  - JOUR
T1  - A Novel Standardized Inflammatory Cell-Modulated 3D Tumor Tissue Model for Analysis of Tumor-Stroma Interaction and Drug Discovery
AU  - Sabine Hensler
AU  - Claudia Kuehlbach
AU  - Bianka Kotkamp
AU  - Dario Frey
AU  - Margareta Maria Mueller
Y1  - 2021/08/11
PY  - 2021
N1  - https://doi.org/10.11648/j.bio.20210904.13
DO  - 10.11648/j.bio.20210904.13
T2  - American Journal of Bioscience and Bioengineering
JF  - American Journal of Bioscience and Bioengineering
JO  - American Journal of Bioscience and Bioengineering
SP  - 110
EP  - 122
PB  - Science Publishing Group
SN  - 2328-5893
UR  - https://doi.org/10.11648/j.bio.20210904.13
AB  - The last decades were marked by substantial progress in understanding the role of tumor-supporting inflammatory reactions in tumor growth and progression. While in vivo data substantiate the contribution of the inflammatory infiltrate and of tumor associated fibroblasts in promoting tumor growth and progression, little is known about the dynamic interaction of these two stromal cell types and their reciprocal influence on each other and on the tumor cells. Mechanistical analyses of these crucial interactions require a standardized and easy to manipulate environment. We therefore established a 3D organotypic in vitro model for epithelial tumors to analyze the interaction of macrophages, neutrophils and fibroblasts in the tumor microenvironment of malignant tumors. In the 3D model, epithelial tumor cells are grown on a collagen type I gel containing fibroblasts, macrophages and neutrophils. Comparable to the in vivo setting, the cytokine driven interaction between macrophages and fibroblasts markedly influences invasion and enhances M2 differentiation in the presence of tumor cells. Addition of neutrophils further leads to a strikingly enhanced tumor invasion associated with an increased expression of MMP-9 and a N2 differentiation of neutrophils. Thus, this novel 3D model provides an in vivo like tissue context to analyze tumor stroma interactions and presents an excellent tool for targeted interference. As such, the model is highly suitable for pharmaceutical screening of novel therapeutics. However, the use of collagen type 1 with its known batch to batch variability as ECM equivalent prohibits the model-standardization that is needed for pharmaceutical testing. Therefore, the 3D in vitro tumor-stroma model was adapted to the use of a bioinert dextran-hydrogel providing a highly standardized and easily modifiable scaffold material that allows the recovery of cells after pharmaceutical experiments. Comparable to the collagen-based model, cells maintained their physiological proliferation, migration and differentiation. Utilizing this standardized model, the efficacy and the tissue impact of novel pharmaceuticals can be investigated in detail with respect to cell morphology, behavior, viability as well as gene expression profiles thereby providing a 3D hydrogel tumor stroma a model that is of great interest for the pharmaceutical industry.
VL  - 9
IS  - 4
ER  -

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