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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 <i>in vivo</i> 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 <i>in vitro</i> 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 <i>in vivo </i>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 <i>in vivo</i> 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 <i>in vitro</i> 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.
Highlights
Enormous progress in the prevention, early detection and treatment of cancer has contributed to a steep decline in age-standardized cancer mortality for years
Reproducible and simple in vivo like models are essential for a better understanding of the molecular interactions between the tumor and its stroma and for the development of new therapeutic strategies. For this purpose a basic 3D organotypic model containing epithelial tumor cells cultivated on top of a collagen type I gel with human dermal fibroblast and macrophages is available [20,21,22]
M2 differentiation of macrophages that occurred in the presence of fibroblasts was accompanied by enhanced tumor cell invasion into the collagen gel [23]
Summary
Enormous progress in the prevention, early detection and treatment of cancer has contributed to a steep decline in age-standardized cancer mortality for years. Success of tumor therapeutics is strongly influenced by the three-dimensional (3D) tissue organization and the tumor environment, making it very difficult to predict therapeutic efficacy correctly with the currently used well established two-dimensional (2D) cell culture tests. While these models provide a well-controlled and homogeneous cell environment, they do not incorporate structural or mechanical tissue properties [2,3,4,5]. This leads to the failure of drug candidates that were considered hopeful in animal tests For this reason, human cell based 3D models have been established and optimized in recent years, to allow the analysis of interactions between different human cell types and the extracellular matrix (ECM)
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