Individual Cell-Based Models of Tumor-Environment Interactions

Abstract

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

Site‐specific N‐glycosylation regulates the GPS auto‐proteolysis of CD97

“…The two molecules shared almost identical EGF-like domains and 50% homology in the stalk and the 7TM regions. As well as functional roles in leukocyte migration, recruitment and activation [18][19][20][21], CD97 is known to be involved in angiogenesis and the migration and invasion of tumor cells [22][23][24]. By analyzing the GPS cleavage of CD97-mFc-fusion protein, we show herein that CD97 and EMR2 have very different GPS cleavage efficiencies.…”

Transcriptional regulation of the human CD97 promoter by Sp1/Sp3 in smooth muscle cells

“…All leiomyomas and 9 out of 21 leiomyosarcomas were CD97 positive . The disability of muscular CD97 to bind the ligand CD55 implicates another function in this cell type (Wobus et al, 2004) as the suggested role as an adhesion molecule (Hamann et al, 1996) in tumor cells where CD97 promotes migration capacity (Galle et al, 2006;Steinert et al 2002). Based on these findings, we are eminently interested in CD97 regulatory mechanisms in SMCs.…”

Computational investigation of intrinsic and extrinsic mechanisms underlying the formation of carcinoma

“…Several mathematical models have addressed the dynamics of various receptors, such as integrins clustering (Paszek et al, 2009), integrinmediated cell migration (Cirit et al, 2010), E-cadherins signalling in cancer invasion (Ramis-Conde et al, 2008) and colorectal cancer development (van Leeuwen et al, 2009). Other models have handled cell adhesion in a more simplified way as an average adhesion strength between individual point cells (in both lattice-based (Anderson, 2005;Deutsch, 2007;Kim et al, 2009) and lattice-free (Drasdo & Hoehme, 2005;Galle et al, 2006;Norton et al, 2010) models) or as a mean value taken over a patch of tissue modelled as a continuum (Byrne & Chaplain, 1996;Armstrong et al, 2006).…”