During development, tissue injury and cancer, epithelial cells engage in communication with the vascular system by using several molecular mediators acting directly or through changes in the haemostatic system. The latter category is epitomized by the procoagulant cellular receptor known as tissue factor (TF). Here, we show that when cellular architecture is altered by a shift in culture conditions from monolayer to three-dimensional multicellular spheroids, expression of multiple angiogenesis effectors (VEGF, TSP-1, TSP-2, Ang-1, and TF) is profoundly altered. In particular, TF is dramatically upregulated in a transformed murine breast epithelial cell line (EMT6) under these conditions. This appears to be linked to a particular change in cell shape and cytoskeletal (actin) reorganization, as treatment of these cells with cytochalasin D (Cyt D), but not with latrunculin B recapitulates and potentiates TF upregulation. Collectively, these results suggest that the ability of epithelial cells to interact with the vascular system via expression of the TF gene (and other effectors) is under the control of complex alterations in cellular architecture. (c) 2005 Elsevier Inc. All rights reserved.