Extracellular matrix concentration exerts selection pressure on invasive cells.

The mortality associated with cancer depends upon the ability of malignant cells to invade and metastasise into adjacent and distant regions. Such malignant spread is caused by the acquisition of an invasive phenotype which involves variable changes in cell-cell adhesion, proteolysis of adjoining extracellular matrix molecules, and the ability to move in a directed fashion in response to fixed and soluble gradients. Whilst the degree of variability in the pattern of metastasis is large, several cancers show regional predilections for invasion. Tumour cell heterogeneity and extracellular matrix composition have been shown to account for some regional variations. In this study, an invasion assay was used to assess the invasiveness of HT1080 tumour cells migrating through a collagen gel. Our experiments showed that, in the absence of externally imposed chemical gradients, HT1080 invasiveness was related in a biphasic manner to collagen concentration. Using a mathematical model, developed to study this phenomenon, we predicted that tumour cell proliferation may also be related in a biphasic manner to collagen concentration. This model prediction was confirmed using a combination of collagen gel invasion and proliferation assays. Investigation of the mathematical model suggests that interactions between haptotaxis and proliferation of the HT1080 cells may be responsible for the biphasic dependence of the penetration depth and proliferation on collagen gel concentration. In conclusion, we showed how mathematical methods can be combined with experimental work to provide new and valuable insight into important biological issues.