(621g) Differential Effects of Chemokines and Growth Factors On Tumor Cell Migration Using a 3D Microfluidic in Vitro Model

Tumor cell chemotaxis within the interstitial space is an important transport mechanism in cancer metastasis. Despite its clinical importance, the molecular mechanism which tumor cells use to migrate in chemokine or growth factor gradients is largely unknown. Using a recently developed 3D microfluidic gradient generating device, we studied tumor cell migration in well-defined and steady linear chemical gradients. We used chemokines, SDF-1α and CCL19, and a growth factor, EGF, which are three well-known cytokines present in tumor microenvironments, to generate chemical gradients; we also used a malignant breast tumor cell line, MDA-MB-231, embedded in type I collagen for 3D cell cultures. Our experimental results demonstrate (1) The major motility type in our 3D microfluidic culture is amoeboid motility: tumor cells also exhibit plasticity and heterogeneity in motility; (2) Both EGF and CCL19 promote tumor cell motility only: the speed increases synergistically when 0.25 nM EGF and 111 nM/mm SDF-1α are applied; (3) Breast tumor cells are chemotactic towards high concentrations of SDF-1α with enhanced motility: this chemotactic behavior follows a ligand-receptor binding kinetics (11~222 nM/mm); (4) The chemotactic sensitivity to a SDF-1α gradient of 111 nM/mm diminishes when either 0.25 or 8.33 nM EGF is supplemented. These results will eventually help us better understand the physical and chemical factors in tumor cell migration, in the context of microenvironmental interactions.