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Individual Cell-based Models of Tumor-Environment Interactions: Multiple Effects of CD97 on Tumor Invasion
Jörg Galle, Jens-Peer Kuska
Interdisciplinary Centre for Bioinformatics
University of Leipzig
Institute for Medical Informatics, Statistics and Epidemiology
University of Leipzig
Center of Surgery, Research Laboratories
This ongoing experimental-theoretical project represents a first application of the developed model types to in vivo systems. It demonstrates that a major insight into the link between individual cell behavior and tissue dynamics can be gained by such modeling approaches.
Background: The presence of scattered tumor cells at the invading front of several carcinomas has clinical significance. These cells differ in their protein expression from cells in central tumor regions as recently shown for the EGF-TM7 receptor CD97. To understand the impact of such heterogeneity on tumor invasion we investigate tumor cells with modified CD97 expression in vitro and in vivo. We link specific cell properties of these cells to tumor invasion characteristics applying an individual cell-based model approach.
Models: We introduce an individual cell based, computer model of the growth and collective invasion of carcinoma into stroma after breakdown the basal membrane. Such a model requires a representation of the tumor stroma. For that purpose we introduce so-called “stroma cells” which represent both cell and matrix components of the stroma. We expand a population of these cells until it fills a closed box inducing a persistent ‘within-tissue’ pressure. This pressure keeps the stroma cells quiescent due to contact inhibition of growth. The resulting stroma is self-organized and is capable of self-regeneration by stroma cell division. An initial tumor is generated selecting a few cells at the center of the box and decreasing their threshold volume of contact inhibition of growth Vp. This reflects a partially loss of contact inhibition of growth in tumor cells. Furthermore, we introduced a number of specific tumor-stroma interactions (Fig. 1).
On one hand the approach enables us to analyze the impact of different cellular alterations on the growth and invasion dynamics (Fig. 1). On the other hand we can study several assumptions about the origin of these alterations (Fig. 2). We study two cases: i) stable alterations of the parameter set of selected cells and ii) the parameter set of all tumor cells depends reversibly on the number of its tumor cell neighbors. In the latter case we introduce a threshold number Nc below which the parameter set changes.
Fig 1: Modeling tumor invasion. A) Part of a model system: Tumor cells (blue), stroma cells (yellow). Saturated colour indicates immanent cell division. Tumor cells may perform an activated (D) and directed migration (arrow) and may change their stroma degradation rate w and their cell cycle time Ψ. The tumor cell apoptosis rate ω may also change. B) - E) Top-views on model systems. B) Initial tumor. C) Without stroma degradation tumor cell proliferation and thus expansion is stopped due to contact inhibition of growth after approximately 100Ψ. D) Considering stroma degradation a comparable tumor radius is reached after 25Ψ. E) Additionally considering elevated and directed migration promotes invasion. Box length: 800 µm.
Fig.2 On the origin of CD97 expression. A)-D): Top view on model systems after an invasion time of 25Ψ. Altered cells (red) are characterized by an increased migration coefficient and perform a directed migration at the tumor front. Saturated color indicates immanent cell division. Box length: 800 µm. A) Invasion following a stable alteration of a single cell. The clone of that cell has spread partially over the tumor front. B)-D) Regulated invasion for Nc = 2, 4 and 6, respectively. Alterations occur at the tumor front.
E) stronger expression of CD97 in scattered tumor cells or tumor cells groups (arrows) surrounded by stroma compared to tumor cells located in tumor glands or solid tumor trabecula (open arrow) of CC. Smooth muscle cells (*) also express CD97. Scale bar 50 mm.
Results: We find that CD97 overexpression stimulates single cell motility and increases proteolytic activity of matrix-metalloproteinases and chemokine secretion in an isoform specific manner in vitro. We demonstrate by simulation studies that these effects of CD97 can increase the invasion capacity of tumors. Furthermore, they can cause the appearance of scattered tumor cells at the invasion front. We identify local tumor-environment interactions as trigger of these multiple capabilities. Experimentally we support our simulation results by the findings that CD97 expression in tumor cells is regulated by their environment and promotes growth of tumors in scid mice.
Our combined experimental-theoretical analysis provides a novel insight in how variations of individual cell properties can be linked to individual patterns of tumor cell invasion. Ongoing studies comprise the characterization and quantification of the migration modes induced by CD97.