Abstract
One of the most important steps in tumor progression involves the transformation from a differentiated epithelial phenotype to an aggressive, highly motile phenotype, where tumor cells invade neighboring tissues. Invasion can occur either by isolated mesenchymal cells or by aggregates that migrate collectively and do not lose completely the epithelial phenotype. Here, we show that, in a three-dimensional cancer cell culture, collective migration of cells eventually leads to aggregation in large clusters. We present quantitative measurements of cluster velocity, coalescence rates, and proliferation rates. These results cannot be explained in terms of random aggregation. Instead, a model of chemotaxis-driven aggregation – mediated by a diffusible attractant – is able to capture several quantitative aspects of our results. Experimental assays of chemotaxis towards culture conditioned media confirm this hypothesis. Theoretical and numerical results further suggest an important role for chemotactic-driven aggregation in spreading and survival of tumor cells.
Highlights
One of the most important steps in tumor progression involves the transformation from a differentiated epithelial phenotype to an aggressive, highly motile phenotype, where tumor cells invade neighboring tissues
About 90% of human cancers are carcinomas, i.e. malignancies originating from epithelial tissues, and a widely accepted view of tumor progression in carcinomas involves the growth of a tumor in situ followed by a transformation of cells which undergo an epithelial to mesenchymal transition (EMT)[3]
BME embedded cancer cell (CC) grow into larger aggregates in culture
Summary
One of the most important steps in tumor progression involves the transformation from a differentiated epithelial phenotype to an aggressive, highly motile phenotype, where tumor cells invade neighboring tissues. Growth regulation in healthy individuals is realized through the controlled cellular response to different stimuli such as growth factors, cell-matrix or cell-cell contact These components can be turned into mediators of unrestrained cell proliferation through either autocrine or paracrine mechanisms[1,2,3]. Once a tumor starts growing, other cellular functions become decisive for the tumor to outcompete the neighboring normal cells and evade the primary site One of such functions is the cell’s ability to move in response to stimuli: the migratory machinery is often found to be altered in tumors[4,5,6,7], and can be exploited by tumor cells to increase survival probability or gain selective advantage[8,9,10].
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