gms | German Medical Science

Einleitung: Tumor cells at the invading front of several carcinomas differ in their protein pattern from cells in central tumor regions. As recently shown by us, this includes the EGF-seven transmembrane (7TM) receptor CD97 (Am J Pathol 2002,161:1657-67). It is our objective to link related differences in cell biological and biomechanical properties to the characteristics of tumor invasion and to prognosis. Here, we combine in vitro and in vivo experiments with computer simulations of tumor progression in de-differentiated carcinomas. As an example we analyze the particular role of CD97 in this process.

Material und Methoden: We compared the matrix-metalloproteinase (MMP) and chemokine cDNA pattern of clones with adjustable expression of normal CD97 or C- terminal truncated CD97 (CD97/1TM) using microarrays and confirmed the results by ELISA and zymography. Clonal cell motility was analyzed by time-lapse video microscopy. The scid mouse model was used to monitor tumor growth in vivo. We introduce a novel class of individual cell-based computer models of the invasion of de-differentiated carcinoma into stroma after breakdown the basal membrane. On one hand the approach enables us to analyze the impact of different cellular alterations on the organization and dynamics of the tumor invasion front. On the other hand we can study several assumptions about the origin of these alterations.

Ergebnisse: We found that 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 MMP activity and impaired in vitro motility and in vivo tumor growth. By computer simulation studies we demonstrate that the observed effects induced by CD97 overexpression 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.

Schlussfolgerung: 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.