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 cellbased 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. The progression of carcinomas is associated with a loss of epithelial differentiation and gain of mesenchyme-like capabilities of scattered tumor cells at the invasive front. This transition is associated with alterations of the expression of molecules involved in cell-cell and/or cell-extracellular matrix interactions, such as motility-promoting molecules.1-3 Furthermore, the secretion of cytokines and extracellular matrix-degrading proteinases are altered.4,5 For colorectal carcinomas it has been shown that in metastases such alterations are reversed and the molecules show a similar expression pattern or level compared with the central region of the primary tumor. 6,7 Consequently, Brabletz and co-workers 6,7 suggested an active role of the tumor environment in malignant tumor progression. A tumor microenvironment invasion model was suggested by Condeelis and co-workers. 8 It is a challenge to understand how the complex tumor invasion behavior emerges from collective interactions on the molecular and cellular level. Although the effects of molecular changes on the individual cell behavior can be quantified directly in experiments, dynamic links between the changes at the cellular level and the characteristics of the tumor invasion process are hard to assess. Here, we exclusively focus on that problem. A major insight into the link between individual cell behavior and tissue dynamics can be gained by computer modeling approaches. They permit investigation of the potential role of generic organization principles in specific tissues. We chose Supported by the Deutsche Forschungsgemeinschaft (DFG; project AU 132/3-1 and grant BIZ-6 1/1 to J.G.) and by the

10103 Background: Tumor cells at the invasion front of several carcinomas differ in their molecule pattern from cells in central tumor regions. As recently shown by us, this includes the cell surface receptor CD97 (Am J Pathol 2002,161:1657–67). Here, we link related differences in cell biological and biomechanical properties to the characteristics of tumor invasion. We combine in vitro and in vivo experiments with computer simulations of tumor progression and analyze the particular role of CD97 in this process. Methods: We compared the cDNA pattern of clones with adjustable expression of normal or C- terminal truncated CD97 using microarrays and confirmed the results at the protein level. Clonal cell motility was analyzed by time-lapse video microscopy. The scid mouse model was used to monitor tumor growth in vivo. Additionally, we introduce a novel class of individual cell-based computer models of tumor invasion into stroma. The approach enables us to analyze the impact of different cellular alterations on the organization and dynamics of the tumor invasion front and we can study several assumptions about the origin of these alterations. Results: CD97 overexpression stimulates single cell motility and increases proteolytic activity and IL-8 secretion in vitro and promotes growth of tumors in scid mice. In contrast, tumor cells overexpressing truncated CD97 show lower proteolytic activity, impaired in vitro motility and in vivo tumor growth. By computer simulation studies we demonstrate that the observed effects induced by CD97 can strongly increase the invasion capacity of tumors. Furthermore, they can cause a specific morphology of the invasion front which is known to correlate with poor prognosis. Thus, as a consequence of our computer simulations and findings in vitro and in vivo, we suggest that CD97 plays an active role in the propagation of de-differentiated carcinomas. Conclusions: Our combined experimental and theoretical computer analysis provides a novel insight in how variations of individual cell properties can be linked to different patterns of tumor cell invasion. Our results suggest that proteolytic activity at the tumor front in conjunction with elevated and directed cell motility are key steps to aggressive tumor invasion. No significant financial relationships to disclose.

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