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Individual Cell-Based Models of Tumor-Environment Interactions: Multiple Effects of CD97 on Tumor Invasion

https://doi.org/10.2353/ajpath.2006.060006Get rights and content

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 investigated tumor cells with modified CD97 expression in vitro and in vivo. Applying an individual cell-based computer model approach, we linked specific cell properties of these cells to tumor invasion characteristics. CD97 overexpression promoted tumor growth in scid mice, stimulated single cell motility, increased proteolytic activity of matrix metalloproteinases, and secretion of chemokines in vitro in an isoform-specific manner. We demonstrated by computer 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 identified local tumor environment interactions as triggers of these multiple capabilities. Experimentally, our simulation results are supported by the finding that CD97 expression in tumor cells is regulated by their environment. Our combined experimental-theoretical analysis provides novel insight to how variations of individual cell properties can be linked to individual patterns of tumor cell invasion.

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Supported by the Deutsche Forschungsgemeinschaft (DFG; project AU 132/3-1 and grant BIZ-6 1/1 to J.G.) and by the Interdisciplinary Center of Clinical Research at the Faculty of Medicine of the University Leipzig (project D6).

E.W. is a fellow of the Interdisciplinary Center of Clinical Research Leipzig.

Supplementary material for this article can be found on http://ajp.amjpathol.org.

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